RESUMEN
Clinical evidence indicates that female sex steroids may contribute to the high prevalence of migraine in women, as well as changes in the frequency or severity of migraine attacks that are in tandem with various reproductive milestones in women's life. While female sex steroids do not seem to be involved in the pathogenesis of migraine per se, they may modulate several mediators and/or receptor systems via both genomic and non-genomic mechanisms; these actions may be perpetuated at the central nervous system, as well as at the peripheral (neuro)vascular level. For example, female sex steroids have been shown to enhance: (i) neuronal excitability by elevating Ca(2+) and decreasing Mg(2+) concentrations, an action that may occur with other mechanisms triggering migraine; (ii) the synthesis and release of nitric oxide (NO) and neuropeptides, such as calcitonin gene-related peptide CGRP, a mechanism that reinforces vasodilatation and activates trigeminal sensory afferents with a subsequent stimulation of pain centres; and (iii) the function of receptors mediating vasodilatation, while the responses of receptors inducing vasoconstriction are attenuated. The serotonergic, adrenergic and gamma-aminobutyric acid (GABA)-ergic systems are also modulated by sex steroids, albeit to a varying degree and with potentially contrasting effects on migraine outcome. Taken together, female sex steroids seem to be involved in an array of components implicated in migraine pathogenesis. Future studies will further delineate the extent and the clinical relevance of each of these mechanisms, and will thus expand the knowledge on the femininity of migraine.
Asunto(s)
Hormonas Esteroides Gonadales/fisiología , Trastornos Migrañosos/fisiopatología , Animales , Femenino , Humanos , Trastornos Migrañosos/tratamiento farmacológico , Trastornos Migrañosos/epidemiologíaRESUMEN
Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, alpha-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT(1B/1D) receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT(2) receptor antagonists, Ca(2+) channel blockers, and beta-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT(1-7)), adrenergic (alpha(1), alpha(2,) and beta), calcitonin gene-related peptide (CGRP(1) and CGRP(2)), adenosine (A(1), A(2), and A(3)), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon.
Asunto(s)
Descubrimiento de Drogas/métodos , Quimioterapia/métodos , Trastornos Migrañosos/tratamiento farmacológico , Agonistas Adrenérgicos/uso terapéutico , Antagonistas Adrenérgicos/uso terapéutico , Animales , Descubrimiento de Drogas/tendencias , Quimioterapia/tendencias , Humanos , Modelos Biológicos , Antagonistas de la Serotonina/uso terapéutico , Agonistas de Receptores de Serotonina/uso terapéuticoRESUMEN
Airway remodeling and associated angiogenesis are documented features of asthma, of which the molecular mechanisms are not fully understood. Angiotensin (ANG)II and endothelin (ET)-1 are potent vasoconstricting circulatory hormones implicated in asthma. We investigated the effects of ANG II and ET-1 on human airway smooth muscle (ASM) cells proliferation and growth and examined the mRNA expression and release of the angiogenic peptide, vascular endothelial growth factor (VEGF). Serum deprived (48 h) human ASM cells were incubated with ANG II (100 nM) or ET-1 (10 nM) for 30 min, 1, 2, 4, 8, 16, and 24 h and the endogenous synthesis of VEGF was examined in relation to control cells receiving serum free culture medium. ET-1 induced time dependent DNA biosynthesis as determined by [3H]-thymidine incorporation assay. Using northern blot hybridization, we detected two mRNA species of 3.9 and 1.7 kb encoding VEGF in the cultured smooth muscle cells. Both ANG II and ET-1 induced the mRNA expression (two- to threefold) and secretion (1.8- to 2.8-fold) of VEGF reaching maximal levels between 4-8 h of incubation. Induced expression and release of VEGF declined after 8 h of ANG II incubation while levels remained elevated in the case of ET-1. The conditioned medium derived from ET-1-treated ASM cells induced [3H]-thymidine incorporation and cell number in porcine pulmonary artery endothelial as well as human umbilical vein endothelial cells. Moreover, the VEGF tyrosine kinase receptor inhibitor blocked the conditioned medium induced mitogenesis in endothelial cells. Our results suggest a potential role for ANG II and ET-1 in ASM cell growth and upregulation of VEGF that may participate in endothelial cell proliferation via paracrine mechanisms and thus causing pathological angiogenesis and vascular remodelling seen during asthma.
Asunto(s)
Angiotensina II/metabolismo , Regulación de la Expresión Génica , Miocitos del Músculo Liso/citología , Péptidos/farmacología , Tráquea/citología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Asma/patología , Proliferación Celular , Medios de Cultivo Condicionados/farmacología , Endotelina-1/metabolismo , Endotelio Vascular/citología , Humanos , Neovascularización Patológica , Porcinos , Factor A de Crecimiento Endotelial Vascular/fisiologíaRESUMEN
Capsaicin, a pungent constituent from red chilli peppers, activates sensory nerve fibres via transient receptor potential vanilloid receptors type 1 (TRPV1) to release neuropeptides like calcitonin gene-related peptide (CGRP) and substance P. Capsaicin-sensitive nerves are widely distributed in human and porcine vasculature. In this study, we examined the mechanism of capsaicin-induced relaxations, with special emphasis on the role of CGRP, using various pharmacological tools. Segments of human and porcine proximal and distal coronary arteries, as well as cranial arteries, were mounted in organ baths. Concentration response curves to capsaicin were constructed in the absence or presence of the CGRP receptor antagonist olcegepant (BIBN4096BS, 1 microM), the neurokinin NK1 receptor antagonist L-733060 (0.5 microM), the voltage-sensitive calcium channel blocker ruthenium red (100 microM), the TRPV1 receptor antagonist capsazepine (5 microM), the nitric oxide synthetase inhibitor Nomega-nitro-L-arginine methyl ester HCl (L-NAME; 100 microM), the gap junction blocker 18alpha-glycyrrhetinic acid (10 microM), as well as the RhoA kinase inhibitor Y-27632 (1 microM). Further, we also used the K+ channel inhibitors 4-aminopyridine (1 mM), charybdotoxin (0.5 microM) + apamin (0.1 microM) and iberiotoxin (0.5 microM) + apamin (0.1 microM). The role of the endothelium was assessed by endothelial denudation in distal coronary artery segments. In distal coronary artery segments, we also measured levels of cyclic adenosine monophosphate (cAMP) after exposure to capsaicin, and in human segments, we also assessed the amount of CGRP released in the organ bath fluid after exposure to capsaicin. Capsaicin evoked concentration-dependent relaxant responses in precontracted arteries, but none of the above-mentioned inhibitors did affect these relaxations. There was no increase in the cAMP levels after exposure to capsaicin, unlike after (exogenously administered) alpha-CGRP. Interestingly, there were significant increases in CGRP levels after exposure to vehicle (ethanol) as well as capsaicin, although this did not induce relaxant responses. In conclusion, the capsaicin-induced relaxations of the human and porcine distal coronary arteries are not mediated by CGRP, NK1, NO, vanilloid receptors, voltage-sensitive calcium channels, K+ channels or cAMP-mediated mechanisms. Therefore, these relaxant responses to capsaicin are likely to be attributed to a non-specific, CGRP-independent mechanism.
Asunto(s)
Arterias/efectos de los fármacos , Capsaicina/farmacología , Vasodilatación/efectos de los fármacos , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Adolescente , Adulto , Anciano , Analgésicos no Narcóticos/farmacología , Animales , Arterias/fisiología , Péptido Relacionado con Gen de Calcitonina/metabolismo , Capsaicina/análogos & derivados , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiología , AMP Cíclico/metabolismo , Dipéptidos/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , NG-Nitroarginina Metil Éster/farmacología , Piperazinas , Piperidinas/farmacología , Bloqueadores de los Canales de Potasio/farmacología , Cloruro de Potasio/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Quinazolinas/farmacología , PorcinosRESUMEN
It has recently been shown that A61603 (N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydro-naphthalen-1-yl]methane sulphonamide), a potent alpha(1A)-adrenoceptor agonist, decreased carotid artery conductance in anaesthetized pigs by a novel non-adrenergic mechanism. In this study, we set out to pharmacologically characterize A61603-induced contractions of the porcine isolated meningeal artery. While the maximum contractile responses of the artery were similar, A61603 (E(max): 183 +/- 23% of 100 mM KCl; pEC(50): 7.25 +/- 0.18) was more potent than noradrenaline (E(max): 156 +/- 16%; pEC(50): 5.75 +/- 0.17) or phenylephrine (E(max): 163 +/- 20%; pEC(50): 5.63 +/- 0.02). Prazosin (pA(2): 9.36 +/- 0.23) and, to a lesser extent, rauwolscine (pK(b): 6.36 +/- 0.38) and yohimbine (pK(b): 7.30 +/- 0.15) antagonised the contractions to A61603. The 5-HT(1B) (GR127935; N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1-biphenyl]-4-carboxamide) and 5-HT(2) (ritanserin) receptor antagonists failed to affect the responses to A61603, but methiothepin, which, in addition, has a high affinity for alpha-adrenoceptors, proved an effective antagonist. The A61603-induced responses were suppressed by the cAMP stimulator forskolin, but not by the protein kinase C inhibitor chelerythrine. Our results suggest that the contraction of porcine isolated meningeal artery by A61603 is mediated via mainly alpha(1)-(probably alpha(1A)) and, to a lesser extent, alpha(2)-adrenoceptors, involving the adenylyl cyclase, but not the diacylglycerol pathway.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 1 , Agonistas de Receptores Adrenérgicos alfa 2 , Imidazoles/farmacología , Arterias Meníngeas/efectos de los fármacos , Tetrahidronaftalenos/farmacología , Vasoconstricción/efectos de los fármacos , Antagonistas Adrenérgicos alfa/farmacología , Alcaloides/farmacología , Animales , Benzofenantridinas/farmacología , Colforsina/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Predicción , Técnicas In Vitro , Arterias Meníngeas/fisiología , Metiotepina/farmacología , Norepinefrina/farmacología , Oxadiazoles/farmacología , Fenilefrina/farmacología , Piperazinas/farmacología , Cloruro de Potasio/farmacología , Prazosina/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Receptores Adrenérgicos alfa 1/fisiología , Receptores Adrenérgicos alfa 2/fisiología , Ritanserina/farmacología , Antagonistas del Receptor de Serotonina 5-HT1 , Antagonistas de la Serotonina/farmacología , Porcinos , Yohimbina/farmacologíaRESUMEN
OBJECTIVE: To investigate the functional reactivity of 5-hydroxytryptamine (serotonin; 5-HT) receptors in foetal umbilical cord arteries (UCA) and maternal subcutaneous fat resistance arteries (SFA) in normotensive and pre-eclamptic pregnancy. DESIGN: Study groups were divided based on the presence or absence of pre-eclampsia and the duration of gestation. METHODS: Segments of UCA and SFA were mounted in tissue baths and concentration-response curves to 5-HT and sumatriptan (5-HT1B/1D receptor agonist) were constructed in the absence or presence of ketanserin (5-HT2A receptor antagonist) or GR125743 (5-HT1B/1D receptor antagonist). RESULTS: Both 5-HT and sumatriptan contracted all UCA segments studied. The responses to 5-HT and the potency of ketanserin in UCA were not different between the study groups, indicating a similar profile of the 5-HT2A receptor. In contrast, the potencies of sumatriptan and GR125743 were significantly higher in normotensive full-term pregnancies than in normotensive pre-term pregnancies in UCA. The response to sumatriptan in UCA arteries was not significantly different between pre-eclamptic and normotensive pregnancies. However, the potency of both sumatriptan and GR125743 was positively correlated to the gestational age in the normotensive group, whereas this relationship was absent in the pre-eclamptic group. In SFA, responses to 5-HT and sumatriptan were not different between the pre-eclamptic patients and normotensive controls. CONCLUSIONS: In both UCA and SFA, 5-HT1B/1D and 5-HT2A receptors mediate vasoconstriction. The sensitivity of 5-HT1B/1D receptors increases in the last trimester in the UCA in normal pregnancies, which seems to be expedited in pre-eclamptic patients. Further studies on 5-HT1B/ID receptors will thus give new insights into the foetal development and pathophysiology of pre-eclampsia.
Asunto(s)
Preeclampsia/fisiopatología , Receptor de Serotonina 5-HT2A/fisiología , Receptores de Serotonina 5-HT1/fisiología , Arterias Umbilicales/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Adulto , Arterias/efectos de los fármacos , Arterias/fisiopatología , Presión Sanguínea , Interpretación Estadística de Datos , Femenino , Feto/irrigación sanguínea , Humanos , Ketanserina/farmacología , Modelos Lineales , Cloruro de Potasio/farmacología , Embarazo , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Grasa Subcutánea/irrigación sanguínea , Sumatriptán/farmacología , Arterias Umbilicales/fisiopatología , Vasoconstricción/fisiologíaRESUMEN
This study sets out to characterise calcitonin gene-related peptide (CGRP) receptors in human and porcine isolated proximal and distal coronary arteries using BIBN4096BS. Human (h)-alphaCGRP induced relaxations that were blocked by BIBN4096BS in all arteries studied. In contrast to the other vessels, the Schild plot slope in the human distal coronary artery segments (0.68 +/- 0.07) was significantly less than unity and BIBN4096BS potently blocked these responses (pK(b) (10 nM): 9.29 +/- 0.34, n = 5). In the same preparation, h-alphaCGRP(8-37) behaved as a weak antagonist of h-alphaCGRP-induced relaxations (pK(b) (3 microM): 6.28 +/- 0.17, n = 4), with also a Schild plot slope smaller than unity. The linear agonists, [ethylamide-Cys(2,7)]-h-alphaCGRP ([Cys(Et)(2,7)]-h-alphaCGRP) and [acetimidomethyl-Cys(2,7)]-h-alphaCGRP ([Cys(Acm)(2,7)]-h-alphaCGRP), had a high potency (pEC(50): 8.21 +/- 0.25 and 7.25 +/- 0.14, respectively), suggesting the presence of CGRP(2) receptors, while the potent blockade by BIBN4096BS (pK(b) (10 nM): 10.13 +/- 0.29 and 9.95 +/- 0.11, respectively) points to the presence of CGRP(1) receptors. Using RT-PCR, mRNAs encoding for the essential components for functional CGRP(1) receptors were demonstrated in both human proximal and distal coronary artery. Further, h-alphaCGRP (100 nM) increased cAMP levels, and this was attenuated by BIBN4096BS (1 microM). The above results demonstrate the presence of CGRP(1) receptors in all coronary artery segments investigated, but the human distal coronary artery segments seem to have an additional population of CGRP receptors not complying with the currently classified CGRP(1) or CGRP(2) receptors.
Asunto(s)
Vasos Coronarios/efectos de los fármacos , Receptores de Péptido Relacionado con el Gen de Calcitonina/fisiología , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Proteínas Adaptadoras Transductoras de Señales , Adolescente , Adulto , Anciano , Animales , Péptido Relacionado con Gen de Calcitonina/análogos & derivados , Péptido Relacionado con Gen de Calcitonina/farmacología , Proteína Similar al Receptor de Calcitonina , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Niño , Preescolar , Colforsina/farmacología , Vasos Coronarios/metabolismo , Vasos Coronarios/fisiología , AMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Endotelio Vascular/fisiología , Femenino , Humanos , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Piperazinas/farmacología , Cloruro de Potasio/farmacología , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiología , Quinazolinas/farmacología , Proteínas Modificadoras de la Actividad de Receptores , Receptores de Calcitonina/genética , Receptores de Calcitonina/metabolismo , Receptores de Péptido Relacionado con el Gen de Calcitonina/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sustancia P/farmacología , Porcinos , Factores de Tiempo , Factor de Transcripción Brn-3A/genética , Factor de Transcripción Brn-3A/metabolismo , Vasoconstrictores/farmacología , Vasodilatación/efectos de los fármacosRESUMEN
Vasoconstriction to agonists at serotonin (5-hydroxytryptamine; 5-HT) receptors and alpha-adrenoceptors, as well as vasodilatation induced by alpha-CGRP, have been well described in the porcine carotid circulation in vivo. The present study sets out to investigate the effects of current and prospective antimigraine drugs on porcine meningeal artery segments in vitro. Sumatriptan, ergotamine, dihydroergotamine, isometheptene and clonidine failed to contract the meningeal artery, but 5-HT, noradrenaline and phenylephrine induced concentration-dependent contractions. The contractions to 5-HT were competitively antagonized by the 5-HT(2A) receptor antagonist ketanserin, whilst those to noradrenaline were antagonized by alpha(1)-(prazosin), alpha(2)-(rauwolscine and yohimbine) and alpha(2C/2B)-(OPC-28326) adrenoceptor antagonists. Whilst dobutamine and salbutamol were ineffective, alpha-CGRP produced concentration-dependent relaxations that were antagonized by the CGRP(1) receptor antagonist olcegepant. In agreement with their lack of contractile effect, sumatriptan and ergotamine failed to influence forskolin-stimulated cyclic AMP accumulation in the porcine meningeal artery; in contrast, both compounds decreased forskolin-stimulated cyclic AMP accumulation in the human isolated saphenous vein, where they induced contractions. Finally, using RT-PCR, we could demonstrate the presence of mRNAs encoding for several 5-HT receptors (5-HT(1B), 5-HT(1D), 5-HT(1F), 5-HT(2A) and 5-HT(7)) and adrenoceptors (alpha(1A), alpha(1B), alpha(1D), alpha(2A), alpha(2B), alpha(2C), beta(1) and beta(2)), as well as that for the calcitonin receptor like receptor, a component of the CGRP(1) receptor. These results suggest that: (i) the porcine meningeal artery may not be involved in the vasoconstriction of the carotid vascular bed elicited by antimigraine drugs in anaesthetized pigs, and (ii) the mismatch between the presence of receptor mRNA and the lack of response to sumatriptan, dobutamine and salbutamol implies that mRNAs for the 5-HT(1B) receptor and beta(1)- and beta(2)-adrenoceptors are probably unstable, or that their density is too low for being translated as receptor protein in sufficient quantities.
Asunto(s)
AMP Cíclico/metabolismo , Arterias Meníngeas/efectos de los fármacos , Vena Safena/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Agonistas alfa-Adrenérgicos/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Agonistas Adrenérgicos beta/farmacología , Animales , Péptido Relacionado con Gen de Calcitonina/agonistas , Péptido Relacionado con Gen de Calcitonina/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Humanos , Arterias Meníngeas/metabolismo , Trastornos Migrañosos/tratamiento farmacológico , ARN Mensajero/metabolismo , Vena Safena/metabolismo , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , PorcinosRESUMEN
Although the understanding of migraine pathophysiology is still incomplete, there seems to be little doubt that dilatation of cranial blood vessels, including meningeal arteries, is involved in the headache phase of migraine. Since calcitonin gene-related peptide (CGRP) has been implicated in this vasodilatation, the present study set out to compare the relaxant effects of the endogenous ligand h-alphaCGRP, and [ethylamide-Cys(2,7)]h-alphaCGRP ([Cys(Et)(2,7)]h-alphaCGRP), a CGRP(2) receptor agonist, on human isolated middle meningeal artery segments, precontracted with KCl. Classical Schild plot analysis was used to characterise the receptor population in this artery using BIBN4096BS and h-alphaCGRP(8-37) as antagonists. h-alphaCGRP relaxed arterial segments more potently than [Cys(Et)(2,7)]h-alphaCGRP (pEC(50): 8.51+/-0.16 and 7.48+/-0.24, respectively), while the maximal responses to these agonists were not significantly different. BIBN4096BS equipotently blocked the relaxations induced by both agonists with a pA(2) of approximately 10 and with a Schild plot slope not significantly different from unity. h-alphaCGRP(8-37) also antagonised the response to h-alphaCGRP with a pA(2) of 6.46+/-0.16 and a Schild plot slope not different from unity. Furthermore, the results obtained from RT-PCR studies confirmed the presence of all the essential components required for a functional CGRP(1) receptor in these arteries. Considering the high antagonist potency of BIBN4096BS, coupled to the lower agonist potency of [Cys (Et)(2,7)]h-alphaCGRP, it is reasonable to suggest a predominant role of CGRP(1) receptors in the human middle meningeal artery. This view is reinforced by Schild plot analysis, which revealed a slope of unity in all experiments, giving further evidence for a homogeneous CGRP receptor population in this vascular preparation.
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/análogos & derivados , Péptido Relacionado con Gen de Calcitonina/farmacología , Arterias Meníngeas/efectos de los fármacos , Trastornos Migrañosos , Receptores de Péptido Relacionado con el Gen de Calcitonina/efectos de los fármacos , Vasodilatadores/farmacología , Humanos , Técnicas In Vitro , Ligandos , Arterias Meníngeas/fisiología , Trastornos Migrañosos/genética , Trastornos Migrañosos/fisiopatología , Fragmentos de Péptidos/farmacología , Piperazinas/farmacología , Quinazolinas/farmacología , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Receptores de Péptido Relacionado con el Gen de Calcitonina/genética , Receptores de Péptido Relacionado con el Gen de Calcitonina/fisiología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Vasodilatación/genética , Vasodilatación/fisiologíaRESUMEN
BACKGROUND: Angiotensin (Ang) II type 2 (AT2) receptor stimulation results in coronary vasodilation in the rat heart. In contrast, AT2 receptor-mediated vasodilation could not be observed in large human coronary arteries. We studied Ang II-induced vasodilation of human coronary microarteries (HCMAs). METHODS AND RESULTS: HCMAs (diameter, 160 to 500 microm) were obtained from 49 heart valve donors (age, 3 to 65 years). Ang II constricted HCMAs, mounted in Mulvany myographs, in a concentration-dependent manner (pEC50, 8.6+/-0.2; maximal effect [E(max)], 79+/-13% of the contraction to 100 mmol/L K+). The Ang II type 1 receptor antagonist irbesartan prevented this vasoconstriction, whereas the AT2 receptor antagonist PD123319 increased E(max) to 97+/-14% (P<0.05). The increase in E(max) was larger in older donors (correlation DeltaE(max) versus age, r=0.47, P<0.05). The PD123319-induced potentiation was not observed in the presence of the NO synthase inhibitor L-NAME, the bradykinin type 2 (B2) receptor antagonist Hoe140, or after removal of the endothelium. Ang II relaxed U46619-preconstricted HCMAs in the presence of irbesartan by maximally 49+/-16%, and PD123319 prevented this relaxation. Finally, radioligand binding studies and reverse transcription-polymerase chain reaction confirmed the expression of AT2 receptors in HCMAs. CONCLUSIONS: AT2 receptor-mediated vasodilation in the human heart appears to be limited to coronary microarteries and is mediated by B2 receptors and NO. Most likely, AT2 receptors are located on endothelial cells, and their contribution increases with age.
Asunto(s)
Angiotensina II/farmacología , Circulación Coronaria , Vasos Coronarios/fisiología , Receptor de Angiotensina Tipo 2/fisiología , Adolescente , Adulto , Anciano , Bloqueadores del Receptor Tipo 2 de Angiotensina II , Compuestos de Bifenilo/farmacología , Niño , Preescolar , Circulación Coronaria/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , GMP Cíclico/metabolismo , Femenino , Humanos , Imidazoles/farmacología , Irbesartán , Masculino , Microcirculación/efectos de los fármacos , Persona de Mediana Edad , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/fisiología , Piridinas/farmacología , ARN Mensajero/biosíntesis , Ensayo de Unión Radioligante , Receptor de Angiotensina Tipo 1/biosíntesis , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 2/efectos de los fármacos , Receptor de Angiotensina Tipo 2/genética , Receptor de Bradiquinina B2/fisiología , Tetrazoles/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
OBJECTIVE: The objective of this study was to investigate ACE- and chymase-dependent angiotensin I-to-II conversion in human coronary arteries (HCAs). METHODS AND RESULTS: HCA rings were mounted in organ baths, and concentration-response curves to angiotensin II, angiotensin I, and the chymase-specific substrate Pro(11)-D-Ala(12)-angiotensin I (PA-angiotensin I) were constructed. All angiotensins displayed similar efficacy. For a given vasoconstriction, bath (but not interstitial) angiotensin II during angiotensin I and PA-angiotensin I was lower than during angiotensin II, indicating that interstitial (and not bath) angiotensin II determines vasoconstriction. PA-angiotensin I increased interstitial angiotensin II less efficiently than angiotensin I. Separate inhibition of ACE (with captopril) and chymase (with C41 or chymostatin) shifted the angiotensin I concentration-response curve approximately 5-fold to the right, whereas a 10-fold shift occurred during combined ACE and chymase inhibition. Chymostatin, but not captopril and/or C41, reduced bath angiotensin II and abolished PA-Ang I-induced vasoconstriction. Perfused HCA segments, exposed luminally or adventitially to angiotensin I, released angiotensin II into the luminal and adventitial fluid, respectively, and this release was blocked by chymostatin. CONCLUSIONS: Both ACE and chymase contribute to the generation of functionally active angiotensin II in HCAs. However, because angiotensin II loss in the organ bath is chymase-dependent, ACE-mediated conversion occurs more efficiently (ie, closer to AT(1) receptors) than chymase-mediated conversion.
Asunto(s)
Angiotensina II/metabolismo , Vasos Coronarios/enzimología , Vasos Coronarios/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Serina Endopeptidasas/metabolismo , Adolescente , Adulto , Angiotensina I/metabolismo , Angiotensina II/fisiología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Captopril/farmacología , Quimasas , Vasos Coronarios/efectos de los fármacos , Espacio Extracelular/química , Femenino , Humanos , Técnicas In Vitro , Soluciones Isotónicas , Masculino , Persona de Mediana Edad , Oligopéptidos/farmacología , Perfusión , Inhibidores de Serina Proteinasa/farmacología , Especificidad por Sustrato/efectos de los fármacos , Vasoconstricción/fisiologíaRESUMEN
OBJECTIVE: Postinfarction hypertrophied hearts have been shown to display a lower capillary density and reduced mechanical efficiency amplified by tachycardia. We investigated whether pharmacological reduction of postinfarction tachycardia would induce capillary growth by treating myocardial infarcted (MI) rats with aspirin, methylprednisolone, moxonidine or captopril, during the first 3 weeks after infarction. METHODS AND RESULTS: Effects on in vivo heart rate were measured in conscious unrestrained rats, while in vitro heart rate effects were evaluated in isolated perfused hearts. Compared to sham-rats, MI-rats manifested a significant in vivo as well as in vitro tachycardia (increase 9% and 20% vs. sham, respectively). Whereas aspirin, methylprednisolone and moxonidine significantly reduced postinfarction in vivo tachycardia, captopril rather increased in vivo heart rate. In vitro tachycardia of MI-hearts was reduced to sham-values with aspirin and methylprednisolone (P<0.05), but not with moxonidine and captopril. Capillary density defined as the number of Lectin stained capillaries per tissue area, which significantly decreased in MI-hearts (decrease 42% vs. sham), was restored by all treatments (P<0.05). Concentric left ventricular hypertrophy after MI, defined as increased cross-sectional area of transversally cut Gomori stained myocytes, was indicated by almost double myocyte size (P<0.05), while capillary to myocyte ratio remained unchanged. Methylprednisolone, moxonidine and captopril, but not aspirin, prevented hypertrophy (P<0.05). However, treatment with aspirin and methylprednisolone, but not moxonidine and captopril, increased capillary to myocyte ratio (P<0.05) up to twice the values of non-treated MI hearts, indicating newly formed capillaries. CONCLUSIONS: The above findings confirm that post-MI pharmacological treatment can increase capillary density in the remodeled left ventricle. Whereas prevention of left ventricular hypertrophy normalizes capillary density without actually affecting capillary number, increased capillary to myocyte ratio (at preserved hypertrophic response) indicates actual capillary growth.
Asunto(s)
Aspirina/uso terapéutico , Circulación Coronaria , Glucocorticoides/uso terapéutico , Frecuencia Cardíaca/efectos de los fármacos , Metilprednisolona/uso terapéutico , Infarto del Miocardio/tratamiento farmacológico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Capilares , Captopril/uso terapéutico , Hipertrofia Ventricular Izquierda/fisiopatología , Hipertrofia Ventricular Izquierda/prevención & control , Imidazoles/uso terapéutico , Masculino , Infarto del Miocardio/fisiopatología , Neovascularización Fisiológica , Distribución Aleatoria , Ratas , Ratas Wistar , Simpaticolíticos/uso terapéuticoRESUMEN
OBJECTIVE: Bradykinin-induced, endothelium-derived hyperpolarizing factor (EDHF)-mediated responses depend on Ca-dependent K-channels (KCa) of small (SKCa) and intermediate (IKCa) conductance, inwardly rectifying K (KIR) channels and/or Na-K-ATPase. Here we investigated in porcine coronary arteries (PCAs) whether S-nitrosothiols can act as EDHF. METHODS: Preconstricted PCAs were exposed to bradykinin, the NO donor S-nitroso-N-penicillamine (SNAP), or the S-nitrosothiols L-S-nitrosocysteine (L-SNC), D-SNC and L-S-nitrosoglutathione (L-SNG), with or without KCl, the NO scavenger hydroxocobalamin, the S-nitrosothiol-depleting agent p-hydroxymercurobenzoic acid (PHMBA) and/or inhibitors of NO synthase (L-NAME), guanylyl cyclase (ODQ), SKCa channels (apamin), KCa channels of large conductance (BKCa) (iberiotoxin), IKCa + BKCa channels (charybdotoxin), KIR channels (BaCl2) or Na-K-ATPase (ouabain). RESULTS: All agonists concentration-dependently relaxed PCAs. L-NAME, charybdotoxin + apamin, KCl, and ouabain shifted the bradykinin concentration-response curve (CRC) approximately 10-fold to the right. BaCl2 did not exert additional effects on top of ouabain. Full blockade of bradykinin was obtained when combining L-NAME with charybdotoxin + apamin, KCl or ouabain + BaCl2. PHMBA reduced the maximum effect of bradykinin. Iberiotoxin + apamin, alone or on top of L-NAME, did not affect bradykinin, SNAP or L-SNC. ODQ and hydroxocobalamin shifted the SNAP, L-SNC, D-SNC, and L-SNG CRCs approximately 10-fold to the right, and, in combination, fully blocked SNAP-induced effects. Charybdotoxin + apamin shifted the L-SNC and L-SNG CRCs, but not the D-SNC or SNAP CRCs, approximately 5-fold to the right. KCl and ouabain (but not BaCl2) shifted the SNAP, L-SNC and L-SNG CRCs 5-10 fold to the right. CONCLUSIONS: L-S-nitrosothiols activate SKCa + IKCa channels in a stereoselective manner, whereas NO activates Na-K-ATPase. Since S-nitrosothiols decompose to NO, stored L-S-nitrosothiols may mediate bradykinin-induced, EDHF-dependent relaxation.
Asunto(s)
Factores Biológicos/fisiología , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiología , Compuestos Nitrosos/farmacología , Compuestos de Sulfhidrilo/farmacología , Animales , Arterias/efectos de los fármacos , Arterias/fisiología , Bradiquinina/administración & dosificación , Bradiquinina/antagonistas & inhibidores , Bradiquinina/farmacología , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Electrofisiología , Técnicas In Vitro , Óxido Nítrico/fisiología , Cloruro de Potasio/farmacología , Porcinos , Vasodilatación/fisiologíaRESUMEN
OBJECTIVE: To investigate whether superoxide mediates angiotensin (Ang) II-induced vasoconstriction. METHODS: Human coronary arteries (HCAs), porcine femoral arteries (PFA) and porcine coronary arteries (PCAs) were mounted in organ baths and concentration-response curves to Ang II, the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) and the NAD(P)H oxidase substrate NADH were constructed in the absence and presence of superoxide inhibiting and activating drugs. Extracellular superoxide was measured using cytochrome c reduction. RESULTS: Ang II constricted both HCAs and PFAs. In HCAs, the NAD(P)H inhibitors diphenyleneiodonium (DPI) and apocynin, and the xanthine oxidase (XO) inhibitor allopurinol, but not the superoxide dismutase (SOD) mimetic tempol or the SOD inhibitor diethyldithiocarbamate (DETCA), reduced this constriction. Catalase potentiated Ang II in HCAs, indicating a vasodilator role for H2O2. DPI, tempol and SOD did not affect Ang II in PFAs. DPI, apocynin and allopurinol relaxed preconstricted HCAs. Although the relaxant effects of the NO donor SNAP in PCAs was reduced by DETCA, indicating that superoxide-induced constrictions depend on NO inactivation, the apocynin-induced relaxations were NO independent. Moreover, NADH relaxed all vessels, and this effect was blocked by KCl but not DPI or NO removal. Xanthine plus XO also relaxed HCAs and PCAs. Incubation of human or porcine arteries with Ang II or NADH did not result in detectable increases of extracellular superoxide within 1 h. CONCLUSIONS: Acute vasoconstriction by Ang II is not mediated via superoxide generated through NAD(P)H oxidase and/or XO activation. Such activation, if occurring, rather results in the generation of the vasodilator H2O2.
Asunto(s)
Angiotensina II/efectos de los fármacos , Angiotensina II/farmacología , Imidazolinas , Oxidantes/farmacología , Superóxidos/farmacología , Vasoconstrictores/farmacología , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Acetofenonas/farmacología , Adolescente , Adulto , Angiotensina II/metabolismo , Animales , Catecolaminas/farmacología , Niño , Preescolar , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/metabolismo , Vasos Coronarios/fisiopatología , Óxidos N-Cíclicos/farmacología , Agonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Endotelina-1/efectos de los fármacos , Endotelina-1/metabolismo , Endotelina-1/farmacología , Inhibidores Enzimáticos/farmacología , Femenino , Arteria Femoral/efectos de los fármacos , Arteria Femoral/metabolismo , Arteria Femoral/fisiopatología , Depuradores de Radicales Libres/farmacología , Humanos , Masculino , Contracción Miocárdica/efectos de los fármacos , NAD/farmacología , NADP/farmacología , Nitroprusiato/administración & dosificación , Oxidantes/metabolismo , S-Nitroso-N-Acetilpenicilamina/administración & dosificación , S-Nitroso-N-Acetilpenicilamina/antagonistas & inhibidores , Marcadores de Spin , Superóxido Dismutasa/farmacología , Superóxidos/metabolismo , Porcinos , Factores de Tiempo , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Vasodilatadores/administración & dosificación , Xantina Oxidasa/antagonistas & inhibidoresRESUMEN
1. In pithed rats, 5-HT mediates tachycardia both directly (by 5-HT(2) receptors) and indirectly (by a tyramine-like effect). The receptor mediating tachycardia directly has been classified as an 'atypical' 5-HT(2) receptor since it was 'weakly' blocked by ketanserin. Moreover, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT(2) agonist, failed to mimic 5-HT-induced tachycardia. Since 5-HT(2) receptors consist of 5-HT(2A), 5-HT(2B) and 5-HT(2C) subtypes, this study investigated if these subtypes mediate the above response. 2. In pithed rats, intraperitoneally (i.p.) pre-treated with reserpine (5 mg kg(-1)), intravenous (i.v.) administration of 5-HT, 5-methoxytryptamine (5-MeO-T), 1-(3-chlorophenyl) piperazine (mCPP) and 5-carboxamidotryptamine (5-CT) (10, 30, 100 and 300 microg kg(-1) each), produced dose-dependent tachycardic responses. Interestingly, DOI (10 - 1000 microg kg(-1), i.v.) induced only slight, dose-unrelated, tachycardic responses, whilst the 5-HT(2C) agonist, Ro 60-0175 (10 - 1000 microg kg(-1), i.v.), produced a slight tachycardia only at 300 and 1000 microg kg(-1). In contrast, sumatriptan and 1-(m-trifluoromethylphenyl)- piperazine (TFMPP) were inactive. The rank order of potency was: 5-HT > or =5-MeO-T> mCPP > or =5-CT > or =DOI > Ro 60-0175. 3. The tachycardic responses to 5-HT, which remained unaffected after i.v. saline (0.3 and 1 ml kg(-1)) or propranolol (3 mg kg(-1)), were selectively blocked by the 5-HT(2A) antagonists ketanserin (30 and 100 microg kg(-1)) or spiperone (10 and 30 microg kg(-1)) as well as by the non-selective 5-HT(2) antagonists, ritanserin (10 and 30 microg kg(-1)) or mesulergine (100 microg kg(-1)). Remarkably, these responses were unaffected by the antagonists rauwolscine (5-HT(2B)), SB204741 (5-HT(2B/2C)) or Ro 04-6790 (5-ht(6)) (300 and 1000 microg kg(-1) each). 4. These results suggest that the 'atypical' 5-HT(2) receptors mediating tachycardia in reserpinized pithed rats are pharmacologically similar to the 5-HT(2A) receptor subtype.
Asunto(s)
Receptores de Serotonina/fisiología , Taquicardia/metabolismo , Animales , Antihipertensivos/farmacología , Presión Sanguínea/fisiología , Relación Dosis-Respuesta a Droga , Depuradores de Radicales Libres/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Inyecciones Intravenosas , Masculino , Norepinefrina/farmacología , Norepinefrina/fisiología , Ratas , Ratas Wistar , Receptor de Serotonina 5-HT2A , Reserpina/farmacología , Serotonina/farmacología , Serotonina/fisiología , Agonistas de Receptores de Serotonina/farmacología , Vasoconstrictores/farmacologíaRESUMEN
1. Studies in isolated cells overexpressing ACE and bradykinin type 2 (B(2)) receptors suggest that ACE inhibitors potentiate bradykinin by inhibiting B(2) receptor desensitization, via a mechanism involving protein kinase C (PKC) and phosphatases. Here we investigated, in intact porcine coronary arteries, endothelial ACE/B(2) receptor 'crosstalk' as well as bradykinin potentiation through neutral endopeptidase (NEP) inhibition. 2. NEP inhibition with phosphoramidon did not affect the bradykinin concentration-response curve (CRC), nor did combined NEP/ACE inhibition with omapatrilat exert a further leftward shift on top of the approximately 10 fold leftward shift of the bradykinin CRC observed with ACE inhibition alone. 3. In arteries that, following repeated exposure to 0.1 microM bradykinin, no longer responded to bradykinin ('desensitized' arteries), the ACE inhibitors quinaprilat and angiotensin-(1-7) both induced complete relaxation, without affecting the organ bath fluid levels of bradykinin. This phenomenon was unaffected by inhibition of PKC or phosphatases (with calphostin C and okadaic acid, respectively). 4. When using bradykinin analogues that were either completely or largely ACE-resistant ([Phe(8)psi(CH(2)-NH)Arg(9)]-bradykinin and [deltaPhe(5)]-bradykinin, respectively), the ACE inhibitor-induced shift of the bradykinin CRC was absent, and its ability to reverse desensitization was absent or significantly reduced, respectively. Caveolar disruption with filipin did not affect the quinaprilat-induced effects. Filipin did however reduce the bradykinin-induced relaxation by approximately 25-30%, thereby confirming that B(2) receptor-endothelial NO synthase (eNOS) interaction occurs in caveolae. 5. In conclusion, in porcine arteries, in contrast to transfected cells, bradykinin potentiation by ACE inhibitors is a metabolic process, that can only be explained on the basis of ACE-B(2) receptor co-localization on the endothelial cell membrane. NEP does not appear to affect the bradykinin levels in close proximity to B(2) receptors, and the ACE inhibitor-induced bradykinin potentiation precedes B(2) receptor coupling to eNOS in caveolae.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Bradiquinina/farmacología , Animales , Bradiquinina/metabolismo , Caveolas/química , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiología , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Neprilisina/antagonistas & inhibidores , Peptidil-Dipeptidasa A/análisis , Receptor de Bradiquinina B2 , Receptores de Bradiquinina/análisis , Porcinos , Vasodilatación/efectos de los fármacosRESUMEN
Continuous infusions of 5-hydroxytryptamine (5-HT) inhibit the tachycardiac responses to preganglionic (C7-T1) sympathetic stimulation in pithed rats pretreated with desipramine. The present study identified the pharmacological profile of this inhibitory action of 5-HT. The inhibition induced by intravenous (i.v.) continuous infusions of 5-HT (5.6 microg x kg-1x min-1) on sympathetically induced tachycardiac responses remained unaltered after i.v. treatment with saline or the antagonists GR 127935 (5-HT1B/1D), the combination of WAY 100635 (5-HT1A) plus GR 127935, ritanserin (5-HT2), tropisetron (5-HT3/4), LY215840 (5-HT7) or a cocktail of antagonists/inhibitors consisting of yohimbine (alpha2), prazosin (alpha1), ritanserin, GR 127935, WAY 100635 and indomethacin (cyclooxygenase), but was abolished by methiothepin (5-HT1/2/6/7 and recombinant 5-ht5A/5B). These drugs, used in doses high enough to block their respective receptors/mechanisms, did not modify the sympathetically induced tachycardiac responses per se. I.v. continuous infusions of the agonists 5-carboxamidotryptamine (5-CT; 5-HT1/7 and recombinant 5-ht5A/5B), CP 93129 (r5-HT1B), sumatriptan (5-HT1B/1D), PNU-142633 (5-HT1D) and ergotamine (5-HT1B/1D and recombinant 5-ht5A/5B) mimicked the above sympatho-inhibition to 5-HT. In contrast, the agonists indorenate (5-HT1A) and LY344864 (5-ht1F) were inactive. Interestingly, 5-CT-induced cardiac sympatho-inhibition was abolished by methiothepin, the cocktail of antagonists/inhibitors, GR 127935 or the combination of SB224289 (5-HT1B) plus BRL15572 (5-HT1D), but remained unchanged when SB224289 or BRL15572 were given separately. Therefore, 5-HT-induced cardiac sympatho-inhibition, being unrelated to 5-HT2, 5-HT3, 5-HT4, 5-ht6, 5-HT7 receptors, alpha1/2-adrenoceptor or prostaglandin synthesis, seems to be primarily mediated by (i). 5-HT1 (probably 5-HT1B/1D) receptors and (ii). a novel mechanism antagonized by methiothepin that, most likely, involves putative 5-ht5A/5B receptors.
Asunto(s)
Estado de Descerebración/fisiopatología , Receptores de Serotonina 5-HT1/efectos de los fármacos , Receptores de Serotonina/efectos de los fármacos , Serotonina/análogos & derivados , Serotonina/farmacocinética , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología , Animales , Fibras Autónomas Preganglionares/efectos de los fármacos , Fibras Autónomas Preganglionares/fisiología , Presión Sanguínea/efectos de los fármacos , Desipramina/administración & dosificación , Desipramina/farmacocinética , Modelos Animales de Enfermedad , Quimioterapia Combinada , Estimulación Eléctrica/métodos , Ergotamina/administración & dosificación , Ergotamina/farmacocinética , Infusiones Intravenosas , Inyecciones Intravenosas , Masculino , Oxadiazoles/administración & dosificación , Oxadiazoles/farmacocinética , Piperazinas/administración & dosificación , Piperazinas/farmacocinética , Piridinas/administración & dosificación , Piridinas/farmacocinética , Ratas , Ratas Wistar , Receptores de Serotonina/clasificación , Receptores de Serotonina/fisiología , Receptores de Serotonina 5-HT1/clasificación , Receptores de Serotonina 5-HT1/fisiología , Serotonina/administración & dosificación , Antagonistas de la Serotonina/administración & dosificación , Antagonistas de la Serotonina/farmacocinética , Agonistas de Receptores de Serotonina/administración & dosificación , Agonistas de Receptores de Serotonina/farmacocinética , Taquicardia/tratamiento farmacológico , Taquicardia/fisiopatologíaRESUMEN
1. We investigated why angiotensin (Ang) I and II induce vasoconstriction with similar potencies, although Ang I-II conversion is limited. 2. Construction of concentration-response curves to Ang I and II in porcine femoral arteries, in the absence or presence of the AT(1) or AT(2) receptor antagonists irbesartan and PD123319, revealed that the approximately 2 fold difference in potency between Ang I and II was not due to stimulation of different AT receptor populations by exogenous and locally generated Ang II. 3. Measurement of Ang I and II and their metabolites at the time of vasoconstriction confirmed that, at equimolar application of Ang I and II, bath fluid Ang II during Ang I was approximately 18 times lower than during Ang II and that Ang II was by far the most important metabolite of Ang I. Tissue Ang II was 2.9+/-1.5% and 12.2+/-2.4% of the corresponding Ang I and II bath fluid levels, and was not affected by irbesartan or PD123319, suggesting that it was located extracellularly. 4. Since approximately 15% of tissue weight consists of interstitial fluid, it can be calculated that interstitial Ang II levels during Ang II resemble bath fluid Ang II levels, whereas during Ang I they are 8.8 - 27 fold higher. Consequently at equimolar application of Ang I and II, the interstitial Ang II levels differ only 2 - 4 fold. 5. Interstitial, rather than circulating Ang II determines vasoconstriction. Arterial Ang I, resulting in high interstitial Ang II levels via its local conversion by ACE, may be of greater physiological importance than arterial Ang II.
Asunto(s)
Angiotensina II/farmacología , Angiotensina I/farmacología , Tetrahidroisoquinolinas , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacología , Angiotensina I/sangre , Angiotensina II/sangre , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Compuestos de Bifenilo/farmacología , Arterias Carótidas/efectos de los fármacos , Arterias Carótidas/metabolismo , Relación Dosis-Respuesta a Droga , Arteria Femoral/efectos de los fármacos , Arteria Femoral/fisiología , Imidazoles/farmacología , Técnicas In Vitro , Irbesartán , Isoquinolinas/farmacología , Piridinas/farmacología , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2 , Receptores de Angiotensina/sangre , Porcinos , Tetrazoles/farmacologíaRESUMEN
1. Calcitonin gene-related peptide (CGRP), a potent vasodilator released from capsaicin-sensitive trigeminal sensory nerves, seems to be involved in the pathogenesis of migraine. Hence, CGRP receptor antagonists may serve as a novel treatment for migraine. This study was therefore designed to investigate the effects of BIBN4096BS (100, 300 and 1000 microg kg-1, i.v.), a potent and selective CGRP receptor antagonist, on capsaicin-induced carotid haemodynamic changes in anaesthetised pigs. Both vagosympathetic trunks were cut and phenylephrine was infused into the carotid artery (i.c.) to support carotid vascular tone. 2. Infusions of capsaicin (0.3, 1, 3 and 10 microg kg-1 min-1, i.c.) did not alter the heart rate, but dose-dependently increased the mean arterial blood pressure. This moderate hypertensive effect was not modified by BIBN4096BS. 3. Capsaicin infusion (10 microg kg-1 min-1, i.c.) increased total carotid, arteriovenous anastomotic and tissue blood flows and conductances as well as carotid pulsations, but decreased the difference between arterial and jugular venous oxygen saturations. These responses to capsaicin were dose-dependently blocked by BIBN4096BS. 4. Capsaicin infusion (10 microg kg-1 min-1, i.c.) more than doubled the jugular venous plasma concentration of CGRP. This effect was not blocked, but rather increased, by BIBN4096BS. 5. The above results show that BIBN4096BS behaves as a potent antagonist of capsaicin-induced carotid haemodynamic changes that are mediated via the release of CGRP. Therefore, this compound may prove effective in the treatment of migraine.