RESUMO
BACKGROUND AND PURPOSE: The incretin hormone, glucagon-like peptide (GLP)-1(7-36), is rapidly cleaved by dipeptidyl peptidase 4 (DPP-4) into GLP-1(9-36), and although it is agreed that most, if not all, of the metabolic effects are attributable to the intact peptide, the degree to which the cardiovascular effects are due to the cleavage product is unclear. The purpose of this study was to measure the regional haemodynamic effects of GLP-1(7-36), and determine the extent to which the cardiovascular effects of GLP-1(7-36) were influenced by DPP-4 inhibition and reproduced by GLP-1(9-36). Additional experiments investigated the involvement of autonomic mechanisms in the cardiovascular effects of GLP-1(7-36). EXPERIMENTAL APPROACH: Regional haemodynamic effects of bolus doses and 4 h infusions of GLP-1(7-36) amide and GLP-1(9-36) amide were measured in conscious, chronically instrumented rats; the influence of DPP-4 inhibition and autonomic blockade on responses to GLP-1(7-36) were also assessed. KEY RESULTS: Glucagon-like peptide-1(7-36) had clear regional haemodynamic effects comprising tachycardia, a rise in blood pressure, renal and mesenteric vasoconstriction and hindquarters vasodilatation, whereas GLP-1(9-36) was devoid of any cardiovascular actions. The effects of GLP-1(7-36) were enhanced by DPP-4 inhibition, and the tachycardia and hindquarters vasodilatation were beta-adrenoceptor-mediated. CONCLUSIONS AND IMPLICATIONS: In conscious rats, the cardiovascular effects of GLP-1(7-36) resemble those of the GLP analogue, exendin-4, and are attributable to the intact peptide rather than the cleavage product, GLP-1(9-36).
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Fragmentos de Peptídeos/farmacologia , Peptídeos/farmacologia , Taquicardia/induzido quimicamente , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/farmacologia , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Masculino , Fragmentos de Peptídeos/administração & dosagem , Peptídeos/administração & dosagem , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
BACKGROUND AND PURPOSE: In vitro evidence suggests that metabolism of anandamide by cyclooxygenase-2 (COX-2) may be more important when the primary metabolic pathway [i.e. fatty acid amide hydrolase (FAAH)] is inhibited. Thus, the first aim of the present study was to assess the effects of COX-2 and/or FAAH inhibition, on the cardiovascular actions of anandamide. The second aim was to compare the effects of anandamide with those of the metabolically stable analogue (i.e. methanandamide) and investigate mechanisms involved in responses to the latter in conscious rats. EXPERIMENTAL APPROACH: Rats were chronically instrumented for recording blood pressure, heart rate and renal, mesenteric and hindquarters vascular conductances in the freely moving state. KEY RESULTS: Inhibition of FAAH with URB597 (cyclohexycarbamic acid 3'-carbamoyl-biphenyl-3-yl-ester) augmented the haemodynamic actions of anandamide, but there was no effect of COX-2 inhibition with parecoxib, either in the absence or the presence of URB597. Methanandamide caused CB(1) receptor-mediated renal and mesenteric vasoconstriction and evoked beta(2)-adrenoceptor-mediated hindquarters vasodilatation. CONCLUSIONS AND IMPLICATIONS: No evidence for an involvement of COX-2 in the systemic cardiovascular actions of anandamide could be demonstrated. Vasoconstrictor actions of methanandamide were shown to involve CB(1) receptors, whereas no involvement of CB(1) receptors in such actions of anandamide has been shown. However, beta(2)-adrenoceptor-mediated hindquarters vasodilatation, independent of CB(1) receptors, observed here with methanandamide, has previously been seen with anandamide and differs from previous results with other synthetic cannabinoids for which the response was CB(1) receptor-dependent. Thus, mechanisms underlying the cardiovascular actions of endocannabinoids and synthetic analogues appear to be agonist-specific.
Assuntos
Ácidos Araquidônicos/farmacologia , Estado de Consciência , Hemodinâmica/efeitos dos fármacos , Alcamidas Poli-Insaturadas/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Endocanabinoides , Frequência Cardíaca/efeitos dos fármacos , Hemodinâmica/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fatores de Tempo , Vasoconstrição/efeitos dos fármacosRESUMO
BACKGROUND AND PURPOSE: Intermedin (IMD) is a newly identified member of the calcitonin family of peptides that shares structural and functional homology with adrenomedullin (AM). In vivo cardiovascular effects of AM have been described, but relatively little is known of the in vivo actions of IMD. The purpose of this study was to compare the regional haemodynamic effects of IMD with those of AM in conscious rats, and investigate possible underlying mechanisms. EXPERIMENTAL APPROACH: Measurements of blood pressure, heart rate and renal, mesenteric and hindquarters haemodynamics were made in conscious, chronically-instrumented rats. KEY RESULTS: IMD caused tachycardia and vasodilatation in all three vascular beds, associated with modest hypotension. At an equimolar dose (1 nmol.kg(-1)), most of the cardiovascular effects of IMD were greater than those of AM. The AM receptor antagonist, AM(22-52), was equally effective in attenuating the renal and mesenteric vasodilator effects of IMD (1 nmol.kg(-1)) and AM (3 nmol.kg(-1)), but inhibition of NO synthase was more effective at reducing the vasodilator effects of IMD than AM. Vascular K(ATP) channel blockade with U-37883A did not inhibit the vasodilator effects of either peptide. CONCLUSIONS AND IMPLICATIONS: In vivo, the regional haemodynamic profile of IMD resembles that of AM, and some of the vasodilator effects of IMD are mediated by AM receptors and NO, but not by K(ATP) channels. The cardiovascular effects of AM have been implicated in various pathological conditions, but whether or not endogenous IMD fulfils a similar role remains to be determined.
Assuntos
Adrenomedulina/fisiologia , Hemodinâmica/efeitos dos fármacos , Neuropeptídeos/fisiologia , Vasodilatadores/farmacologia , Adrenomedulina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Hipotensão/induzido quimicamente , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Masculino , Neuropeptídeos/farmacologia , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Circulação Esplâncnica/efeitos dos fármacos , Taquicardia/induzido quimicamente , Vasodilatação/efeitos dos fármacosRESUMO
BACKGROUND AND PURPOSE: Studies using adenosine receptor antagonists have shown that adenosine-mediated vasodilatations play an important role in the maintenance of regional perfusion during sepsis, but it is unclear whether vascular sensitivity to adenosine is affected. Here, we assessed regional haemodynamic responses to adenosine agonists and antagonists in normal and lipopolysaccharide (LPS)-treated rats to investigate a possible role for adenosine in the haemodynamic sequelae. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats were chronically instrumented with pulsed Doppler flow probes to measure regional haemodynamic responses to adenosine-receptor agonists (adenosine, 2-choloro-N6-cyclopentyladenosine (CCPA)) and antagonists (8-phenyltheophylline (8-PT), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX)), at selected time points in control and LPS-treated rats. KEY RESULTS: The responses to 8-PT were consistent with endogenous adenosine causing bradycardia, and renal and hindquarters vasodilatation in control rats, whereas in LPS-treated rats, there was evidence for endogenous adenosine causing renal (at 1.5 h) and hindquarters (at 6 h) vasoconstriction. In control animals, exogenous adenosine caused hypotension, tachycardia and widespread vasodilatation, whereas in LPS-treated rats, the adenosine-induced renal (at 1.5 h) and hindquarters (at 6 h) vasodilatations were abolished. As enhanced A1 receptor-mediated vasoconstriction could explain the results in LPS-treated rats, vascular responsiveness to a selective A1-receptor agonist (CCPA) or antagonist (DPCPX) was assessed. There was no evidence for enhanced vasoconstrictor responsiveness to CCPA in LPS-treated rats, but DPCPX caused renal vasodilatation, consistent with endogenous adenosine mediating renal vasoconstriction under these conditions. CONCLUSIONS AND IMPLICATIONS: The results show changes in adenosine receptor-mediated cardiovascular effects in endotoxaemia that may have implications for the use of adenosine-based therapies in sepsis.
Assuntos
Adenosina/metabolismo , Agonistas do Receptor Purinérgico P1 , Antagonistas de Receptores Purinérgicos P1 , Adenosina/farmacologia , Agonistas do Receptor A1 de Adenosina , Antagonistas do Receptor A1 de Adenosina , Animais , Sistemas de Liberação de Medicamentos , Ecocardiografia Doppler de Pulso , Endotoxemia/tratamento farmacológico , Endotoxemia/fisiopatologia , Lipopolissacarídeos , Masculino , Ratos , Ratos Sprague-Dawley , Receptor A1 de Adenosina/metabolismo , Receptores Purinérgicos P1/metabolismo , Sepse/tratamento farmacológico , Sepse/fisiopatologia , Fatores de Tempo , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
BACKGROUND AND PURPOSE: Glucagon-like peptide-1 (GLP) receptor agonists are promising therapeutic agents for the treatment of type II diabetes, but effects other than those on glucoregulation need assessing. Cardiovascular actions of bolus doses of the GLP receptor agonist exendin-4 have been reported, but to date the effects of continuous infusions have not been described. EXPERIMENTAL APPROACH: The regional haemodynamic effects and possible underlying mechanisms of 6 h infusions of exendin-4 were measured in conscious, chronically instrumented rats. KEY RESULTS: A 6 h infusion of exendin-4 (up to 6 pmol kg(-1) min(-1)) only modestly influenced blood pressure, but caused substantial, opposing, regionally selective vascular effects and tachycardia. A major involvement of beta-adrenoceptors in the vasodilator and cardiac effects was identified, with little or no direct contribution from alpha-adrenoceptors to the vasoconstriction seen. Under conditions where alpha- and beta-adrenoceptors were antagonized, or when ganglionic transmission was blocked, a marked vasoconstrictor effect of exendin-4 was revealed in the mesenteric and hindquarters vascular beds (about 50% fall in vascular conductances). No role for endogenous angiotensin II, vasopressin, endothelin, neuropeptide Y or prostanoids could be shown in these vasoconstrictor actions of exendin-4. CONCLUSIONS AND IMPLICATIONS: The results show not only an important involvement of the autonomic nervous system in the cardiovascular actions of exendin-4 infusion but also an underlying non-autonomically mediated vasoconstrictor action, the mechanism of which remains to be identified.
Assuntos
Sistema Nervoso Autônomo/fisiologia , Sistema Cardiovascular/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Peptídeos/farmacologia , Peçonhas/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Glicemia/metabolismo , Inibidores de Ciclo-Oxigenase/farmacologia , Antagonistas do Receptor de Endotelina A , Antagonistas do Receptor de Endotelina B , Exenatida , Bloqueadores Ganglionares/farmacologia , Membro Posterior/irrigação sanguínea , Hipoglicemiantes/administração & dosagem , Infusões Intravenosas , Masculino , Peptídeos/administração & dosagem , Fentolamina/farmacologia , Propranolol/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Receptores de Vasopressinas/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos dos fármacos , Peçonhas/administração & dosagemRESUMO
A characteristic manifestation of sepsis is muscle lactate accumulation. This study examined any putative (causative) association between pyruvate dehydrogenase complex (PDC) inhibition and lactate accumulation in the extensor digitorum longus (EDL) muscle of rats infused with lipopolysaccharide (LPS), and explored the involvement of increased transcription of muscle-specific pyruvate dehydrogenase kinase (PDK) isoenzymes. Conscious, male Sprague-Dawley rats were infused i.v. with saline (0.4 ml h(-1), control) or LPS (150 mug kg(-1) h(-1)) for 2 h, 6 h or 24 h (n = 6-8). Muscle lactate concentration was elevated after 2, 6 and 24 h LPS infusion. Muscle PDC activity was the same at 2 h and 6 h, but was 65% lower after 24 h of LPS infusion (P < 0.01), when there was a 47% decrease in acetylcarnitine concentration (P < 0.05), and a 24-fold increase in PDK4 mRNA expression (P < 0.001). These changes were preceded by marked increases in tumour necrosis factor-alpha and interleukin-6 mRNA expression at 2 h. The findings indicate that the early (2 and 6 h) elevation in muscle lactate concentration during LPS infusion was not attributable to limited muscle oxygen availability or ATP production (evidenced by unchanged ATP and phosphocreatine (PCr) concentrations) or to PDC inhibition, whereas after 24 h, muscle lactate accumulation appears to have resulted from PDC activation status limiting pyruvate flux, most probably due to cytokine-mediated up-regulation of PDK4 transcription.
Assuntos
Interleucina-6/metabolismo , Ácido Láctico/metabolismo , Lipopolissacarídeos , Músculo Esquelético/metabolismo , Complexo Piruvato Desidrogenase/metabolismo , Sepse/induzido quimicamente , Sepse/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Infusões Parenterais , Masculino , Músculo Esquelético/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND AND PURPOSE: A putative novel cannabinoid receptor mediates vasorelaxation to anandamide and abnormal-cannabidiol and is blocked by O-1918 and by high concentrations of rimonabant. This study investigates VSN16, a novel water-soluble agonist, as a vasorelaxant potentially acting at non-CB1, non-CB2 cannabinoid receptors in the vasculature. EXPERIMENTAL APPROACH: VSN16 and some analogues were synthesized and assayed for vasodilator activity in the rat third generation mesenteric artery using wire myography. Also carried out with VSN16 were haemodynamic studies in conscious rats and binding studies to CB1 receptors of rat cerebellum. KEY RESULTS: VSN16 relaxed mesenteric arteries in an endothelium-dependent manner. The vasorelaxation was antagonized by high concentrations of the classical cannabinoid antagonists, rimonabant and AM 251, as well as by O-1918, an antagonist at the abnormal-cannabidiol receptor but not at CB1 or CB2 receptors. It did not affect [3H]CP55,940 binding to CB1 receptors in rat cerebellum. The vasorelaxation was not pertussis toxin-sensitive but was reduced by inhibition of nitric oxide synthesis, Ca(2+)-sensitive K+ channels (KCa) and TRPV1 receptors. In conscious rats VSN16 transiently increased blood pressure and caused a longer-lasting increase in mesenteric vascular conductance. Structure-activity studies on vasorelaxation showed a stringent interaction with the target receptor. CONCLUSIONS AND IMPLICATIONS: VSN16 is an agonist at a novel cannabinoid receptor of the vasculature. It acts on the endothelium to release nitric oxide and activate KCa and TRPV1. As it is water-soluble it might be useful in bringing about peripheral cannabinoid-like effects without accompanying central or severe cardiovascular responses.
Assuntos
Benzamidas/farmacologia , Endotélio Vascular/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Animais , Apamina/farmacologia , Benzamidas/síntese química , Benzamidas/química , Agonistas de Receptores de Canabinoides , Antagonistas de Receptores de Canabinoides , Canabinoides/farmacologia , Cerebelo/metabolismo , Charibdotoxina/farmacologia , Cicloexanóis/metabolismo , Relação Dose-Resposta a Droga , Endotélio Vascular/fisiologia , Técnicas In Vitro , Indometacina/farmacologia , Masculino , Artérias Mesentéricas/fisiologia , Estrutura Molecular , NG-Nitroarginina Metil Éster/farmacologia , Toxina Pertussis/farmacologia , Piperidinas/farmacologia , Pirazóis/farmacologia , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores de Canabinoides/metabolismo , Resorcinóis/farmacologia , Rimonabanto , Canais de Cátion TRPV/metabolismo , Trítio , Resistência Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
BACKGROUND AND PURPOSE: In anaesthetized spontaneously hypertensive rats (SHR), there is evidence for up-regulation of cannabinoid (CB1) receptors: antagonism of CB1 receptors causes a rise in blood pressure, and administration of the endocannabinoid, anandamide, or inhibition of anandamide degradation causes hypotension. These findings have led to the suggestion that the endocannabinoid system may be a therapeutic target in hypertension. However, since the cardiovascular responses to cannabinoids are substantially influenced by anaesthesia, the purpose of this study was to assess regional haemodynamic responses to cannabinoid receptor stimulation and inhibition in conscious SHR. EXPERIMENTAL APPROACH: Cardiovascular responses to i.v. administration of anandamide, the cannabinoid receptor agonist, WIN 55212-2, and the CB(1) receptor antagonist, AM 251, were measured in male SHR, Wistar Kyoto rats and outbred Wistar rats, chronically instrumented for recording renal, mesenteric and hindquarters haemodynamics in the conscious, freely-moving state. KEY RESULTS: Hypotensive responses to anandamide and WIN 55212-2 only occurred in SHR, but these were relatively modest and not associated with CB1 receptor-mediated vasodilatation. In SHR only, anandamide caused bradycardia, which was inhibited by AM 251. Furthermore, a pressor response to CB1 receptor antagonism occurred only in SHR, but was not associated with vasoconstriction. Moreover, there was some evidence for CB1 receptor-mediated vasoconstrictor actions of anandamide in SHR, which was not seen in the normotensive strains. CONCLUSIONS AND IMPLICATIONS: The results are consistent with activation of CB1 receptors in SHR by endogenous ligands exerting an antihypertensive effect, but the findings do not indicate enhanced CB1 receptor-mediated vasodilator mechanisms in SHR.
Assuntos
Canabinoides/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Hipertensão/fisiopatologia , Animais , Ácidos Araquidônicos/farmacologia , Benzoxazinas/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Canabinoides/administração & dosagem , Estado de Consciência , Endocanabinoides , Frequência Cardíaca/efeitos dos fármacos , Membro Posterior/irrigação sanguínea , Membro Posterior/efeitos dos fármacos , Infusões Intravenosas , Injeções Intravenosas , Masculino , Morfolinas/farmacologia , Naftalenos/farmacologia , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidores , Circulação Renal/efeitos dos fármacos , Especificidade da Espécie , Circulação Esplâncnica/efeitos dos fármacos , Resistência Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
The aims of the study were, in conscious Sprague-Dawley rats, to compare the effects of stresscopin-related peptide (SRP) and urocortin (UCN) 1 on blood pressure, heart rate, and regional hemodynamics; to determine whether or not there were residual tachycardic effects of SRP or UCN1 after cardiac autonomic blockade; and to investigate a possible involvement of corticotropin releasing factor type 1 (CRF1) receptor-mediated histamine release in the vasodilator actions of UCN1. SRP and UCN1 (both at 3 nmol/kg i.v.) caused hypotension, tachycardia, and mesenteric and hindquarters vasodilatation, but the magnitude and/or duration of the effects of UCN1 were generally greater than those of SRP. Pretreatment with atropine plus propranolol abolished the tachycardic effects of SRP and UCN1, and, under those conditions, the hypotensive effect of SRP, but not that of UCN1, was enhanced, probably because the hindquarters vasodilator effect of the latter was also reduced. Pretreatment with mepyramine plus cimetidine had no effect on the hemodynamic actions of either SRP or UCN1. It is concluded that, in conscious rats, the tachycardic effects of SRP and UCN1 are due to autonomic nervous activation mainly through baroreflex mechanisms. There is no evidence for an involvement of CRF1 receptor-mediated histamine release in the vasodilator actions of UCN1, but a propranolol-sensitive hindquarters vasodilator action of UCN, but not of SRP, was identified.
Assuntos
Fármacos Cardiovasculares , Hormônio Liberador da Corticotropina/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Atropina/farmacologia , Cimetidina/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores H2 da Histamina/farmacologia , Masculino , Antagonistas Muscarínicos/farmacologia , Fragmentos de Peptídeos/farmacologia , Propranolol/farmacologia , Pirilamina/farmacologia , Ratos , Ratos Sprague-Dawley , UrocortinasRESUMO
BACKGROUND AND PURPOSE: Since the vasorelaxant potency of the endocannabinoid anandamide is enhanced in perfused mesenteric vascular beds from rats made hypertensive by chronic inhibition of NO synthase (L-NAME in drinking water), we hypothesized that in vivo, anandamide-induced vasodilatation would be similarly enhanced in L-NAME-treated animals. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats were given L-NAME in drinking water (7.5 mg kg(-1) day(-1)) for 4 weeks. Relaxant effects of anandamide were measured in perfused mesenteric vascular beds and in isolated small mesenteric arteries. Renal, mesenteric and hindquarters haemodynamic responses to anandamide, methanandamide, the synthetic cannabinoid agonist WIN-55212-2 and the cannabinoid receptor antagonist AM251 were assessed in conscious, chronically-instrumented rats. KEY RESULTS: Vasorelaxant responses to anandamide were enhanced in the perfused mesentery but not in isolated mesenteric resistance vessels. In vivo, anandamide caused vasodilatation only in the hindquarters vascular bed and only in control rats. Methanandamide caused a late-onset (40 min after administration) tachycardia, mesenteric and hindquarters vasoconstriction, and renal vasodilatation, which did not differ between control and L-NAME-treated rats. AM251 had no effect on resting blood pressure in control or L-NAME-treated rats and WIN55212-2 caused pressor and renal and mesenteric vasoconstrictor responses, with hindquarters vasodilatation in both groups of animals. CONCLUSIONS AND IMPLICATIONS: The results provide no in vivo evidence for enhanced vasodilator responses to cannabinoids, or up-regulation of endocannabinoids or their receptor activity, following chronic NO synthase inhibition.
Assuntos
Canabinoides/farmacologia , Hipertensão/fisiopatologia , Artérias Mesentéricas/efeitos dos fármacos , Óxido Nítrico Sintase/antagonistas & inibidores , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Animais , Ácidos Araquidônicos/farmacologia , Benzoxazinas/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Endocanabinoides , Inibidores Enzimáticos , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , Morfolinas/farmacologia , Músculo Esquelético/irrigação sanguínea , NG-Nitroarginina Metil Éster , Naftalenos/farmacologia , Óxido Nítrico Sintase/metabolismo , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Canabinoides/efeitos dos fármacos , Circulação Renal , Circulação Esplâncnica , Fatores de Tempo , Resistência Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacosRESUMO
BACKGROUND AND PURPOSE: Interactions between the NO system and the cyclooxygenase systems may be important in cardiovascular regulation. Here we measured the effects of acute cyclooxygenase-2 inhibition (with parecoxib), alone and in combination with NOS inhibition (with NG-nitro-L-arginine methyl ester (L-NAME)), on resting cardiovascular variables and on responses to the glucagon-like peptide 1 agonist, exendin-4, which causes regionally-selective vasoconstriction and vasodilatation. EXPERIMENTAL APPROACH: Rats were instrumented with flow probes and intravascular catheters to measure regional haemodynamics in the conscious, freely moving state. L-NAME was administered as a primed infusion 180 min after administration of parecoxib or vehicle, and exendin-4 was given 60 min after the onset of L-NAME infusion. KEY RESULTS: Parecoxib had no effect on resting cardiovascular variables or on responses to L-NAME. Exendin-4 caused a pressor response accompanied by tachycardia, mesenteric vasoconstriction and hindquarters vasodilatation. Parecoxib did not affect haemodynamic responses to exendin-4, but L-NAME inhibited its hindquarters vasodilator and tachycardic effects. When combined, L-NAME and parecoxib almost abolished the hindquarters vasodilatation while enhancing the pressor response. CONCLUSIONS AND IMPLICATIONS: Cyclooxygenase-2-derived products do not affect basal haemodynamic status in conscious normotensive rats, or influence the NO system acutely. The inhibitory effects of L-NAME on the hindquarters vasodilator and tachycardic effects of exendin-4 are consistent with a previous study that showed those events to be beta-adrenoceptor mediated. The additional effect of parecoxib on responses to exendin-4 in the presence of L-NAME, is consistent with other evidence for enhanced involvement of vasodilator prostanoids when NO production is reduced.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Ciclo-Oxigenase 2/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Peptídeos/farmacologia , Peçonhas/farmacologia , Animais , Exenatida , Isoxazóis/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos WistarRESUMO
We tested the hypothesis that angiotensin (AT(1)) receptor antagonism (with losartan) would enhance the cardiovascular actions of neutral endopeptidase (NEP) inhibition [with candoxatrilat or (2S)-2-{[1-({[(1S)-1-carboxy-2-(5-phenyl-1,3-oxazol-2-yl)ethyl]amino}carbonyl)cyclopentyl]methyl}-4-methoxybutanoic acid (UK-489,329)] in conscious spontaneously hypertensive rats (SHR). Four-day continuous intravenous infusion of candoxatrilat (1.9 microg kg(-1) min(-1)) or UK-489,329 (0.15 microg kg(-1) min(-1)) had no significant cardiovascular effects, whereas candoxatrilat (6.4 microg kg(-1) min(-1)) had a modest antihypertensive effect (-10.9 mm Hg on day 4) but no significant sustained effects on regional hemodynamics. Losartan caused a fall in blood pressure (maximum -29.2 mm Hg on day 4) that was associated with renal, mesenteric, and, to a lesser extent, hindquarters vasodilatation. The combination of losartan with either dose of candoxatrilat had no greater antihypertensive or vasodilator effects than losartan alone, with the exception of the increase in renal vascular conductance, which was greater with the combination of the drugs than with either drug alone (significant only in the lower dose study). Losartan combined with UK-489,329 showed a greater antihypertensive effect than losartan alone (-14.6 mm Hg greater on day 4), although the effects of the combination were not significantly greater than the sum of the effects of both agents administered separately. However, losartan combined with UK-489,329 caused increases in renal and hindquarters vascular conductance that were significantly greater with the combination than with either agent given alone. Thus, in conscious SHR, the renin-angiotensin system may act to oppose a vasodilator action of NEP inhibition, particularly in the renal vascular bed.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Ácidos Cicloexanocarboxílicos/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/fisiopatologia , Losartan/farmacologia , Neprilisina/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Animais , Masculino , Ratos , Ratos Endogâmicos SHR , Circulação Renal/efeitos dos fármacosRESUMO
A possible involvement of endocannabinoids in a chronic model of endotoxemia was assessed by measuring the regional (renal, mesenteric, hindquarters) hemodynamic responses to continuous 24-h LPS infusion (150 microg.kg(-1).h(-1)) in conscious, male Sprague-Dawley rats, in the absence or presence of the cannabinoid (CB1) receptor antagonist AM-251 (3 mg/kg). AM-251 inhibited the tachycardic and hindquarters vasodilator effects of LPS, but did not influence the other hemodynamic changes. In subsequent experiments, it was shown that the tachycardic and hindquarters vasodilator effects of LPS were also inhibited by the nonselective beta-adrenoceptor antagonist propranolol. In addition, the late (at 24 h) hindquarters vasodilator effects of LPS were inhibited by the beta2-adrenoceptor antagonist ICI-118551. Against the background of our previous work showing beta-adrenoceptor involvement in the cardiovascular effects of exogenous cannabinoids, we conclude that AM-251 may have been inhibiting endocannabinoid-modulated, sympathoadrenal-mediated activation of vasodilator beta-adrenoceptors in LPS-infused rats rather than suppressing a direct vasodilator action of endocannabinoids.
Assuntos
Endotoxemia/fisiopatologia , Lipopolissacarídeos/farmacologia , Receptor CB1 de Canabinoide/fisiologia , Receptores Adrenérgicos beta/fisiologia , Vasodilatação/fisiologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Pressão Sanguínea/fisiologia , Estado de Consciência , Modelos Animais de Doenças , Interações Medicamentosas , Endotoxemia/induzido quimicamente , Masculino , Piperidinas/farmacologia , Propanolaminas/farmacologia , Propranolol/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor CB1 de Canabinoide/antagonistas & inibidores , Sistema Nervoso Simpático/fisiologia , Taquicardia/fisiopatologiaRESUMO
The regional hemodynamic responses to continuous 4-day infusion of UK-357,903 [1-ethyl-4-{3-[3-ethyl-6,7-dihydro-7-oxo-2-(2-pyridylmethyl)-2H-pyrazolo[4,3-d]pyrimidin-5-yl]-2-(2-methoxyethoxy)-5-pyridylsulphonyl}piperazine] (266 microg kg(-1) h(-1)) alone and in combination with a low dose of enalapril (10 microg kg(-1) h(-1)) were measured in conscious spontaneously hypertensive rats to test the hypothesis that the renin-angiotensin system may influence the cardiovascular consequences of inhibition of phosphodiesterase 5 (PDE5) by UK-357,903 or vice versa. UK-357,903 alone caused a fall in mean blood pressure (-12.1 mm Hg) associated with vasodilatation in the mesenteric and hindquarters vascular beds. The only way in which the effects of enalapril given alone differed significantly from those of the vehicle was in causing mesenteric vasodilatation, which developed over the 4 days of infusion. UK-357,903 given in combination with enalapril caused hypotension (-17.8 mm Hg) and vasodilatation in the renal, mesenteric, and hindquarter vascular beds. There was evidence of a significant interaction between the effects of the two compounds on renal Doppler shift and vascular conductance with the combined action of the two compounds being greater than the sum of their individual effects. However, although there was a trend for the combination to have greater effects than either of the individual agents on blood pressure and mesenteric vascular conductance, there was no statistical evidence of an interaction. The results indicate that inhibition of the renin-angiotensin system uncovers additional renal vasodilator effects of UK-357,903, and/or inhibition of PDE5 enhances the renal vasodilator effects of angiotensin-converting enzyme inhibition.
Assuntos
3',5'-GMP Cíclico Fosfodiesterases/antagonistas & inibidores , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , GMP Cíclico/sangue , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Feminino , Frequência Cardíaca/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/fisiologia , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Ratos , Ratos Endogâmicos SHR , Renina/sangueRESUMO
The intracellular mechanisms that regulate changes in postnatal myosin heavy chain (MHC) expression are not well established. The major objective of this study was to examine the acute and chronic effects of administration of BRL-47672, the prodrug of the beta2-adrenoceptor agonist clenbuterol on MHC and MyoD transcription factor expression to determine whether or not changes in MHC composition are preceded by changes in MyoD protein expression. To assess to what extent the use of BRL-47672 minimized cardiovascular effects, its hemodynamic actions were compared with those of clenbuterol. The effect of BRL-47672 on heart rate, mean arterial blood pressure, and hindquarters vascular conductance was significantly less than that of clenbuterol after a single i.p. injection (250 microg kg(-1) body mass). In the main study, 4-week old rats were given BRL-47672 (900 microg kg(-1) body mass) or an equivalent volume of saline (control) daily for 1, 28, or 56 days. Soleus muscle (SOL) was excised and MHC and MyoD expression analyzed. After 4 weeks, SOL from the BRL-47672-treated animals had significantly faster MHC composition (49 +/- 2% MHCIIA) compared with those from the control animal (39 +/- 3% MHCIIA, P <0.05). MyoD expression increased by 40% after 1 day of BRL-47672 administration (P <0.05) before a change in MHC composition. In conclusion, these data suggest that increased expression of fast-type MHCIIA expression in rat SOL induced by BRL-47672 administration is preceded by changes in the level of MyoD transcription factor expression.
Assuntos
Agonistas de Receptores Adrenérgicos alfa 2 , Agonistas Adrenérgicos beta/farmacologia , Hemodinâmica/efeitos dos fármacos , Músculo Esquelético/metabolismo , Proteína MyoD/biossíntese , Cadeias Pesadas de Miosina/metabolismo , Adenosina Trifosfatases/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Clembuterol/farmacologia , Relação Dose-Resposta a Droga , Eletroforese em Gel de Poliacrilamida , Frequência Cardíaca/efeitos dos fármacos , Masculino , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/efeitos dos fármacos , Proteína MyoD/genética , Miofibrilas/metabolismo , Compostos Orgânicos , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Fatores de TempoRESUMO
BACKGROUND: Reduced pressor responsiveness to norepinephrine (NE) in sepsis is well documented but the associated regional haemodynamic changes are less well characterized, and there are varying reports of changes in haemodynamic responses to arginine vasopressin (AVP). We compared changes in regional haemodynamic responsiveness to AVP and NE during a 24 h continuous infusion of lipopolysaccharide (LPS) in conscious rats. METHODS: Conscious, male Sprague-Dawley rats were infused with saline (0.4 ml h(-1)) or LPS (150 micro g kg(-1) h(-1)). Renal, mesenteric, and hindquarter haemodynamic responses to 3 min infusions of AVP (0.25, 0.625, and 1.25 ng kg(-1) min(-1)) or NE (75, 250, and 750 ng kg(-1) min(-1)) were assessed 2, 6, and 24 h after the onset of LPS or saline. RESULTS: Two and six hours after the onset of LPS, all haemodynamic effects of NE were markedly reduced, but by 24 h, there was some recovery in the vasoconstrictor actions of NE although the pressor and bradycardic effects were still depressed. Two hours after the onset of LPS, the cardiovascular effects of AVP were depressed but there was some recovery in vascular responsiveness at 6 h. By 24 h, only the mesenteric vasoconstrictor effect of AVP was consistently reduced. CONCLUSIONS: During low dose LPS infusion, there are differential changes in haemodynamic responsiveness to AVP and NE, which show different temporal and regional profiles of recovery with time. Furthermore, reduced pressor responsiveness to NE is not necessarily accompanied by a reduced capacity of vessels for vasoconstriction.
Assuntos
Endotoxemia/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Norepinefrina/farmacologia , Vasoconstritores/farmacologia , Vasopressinas/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Endotoxemia/induzido quimicamente , Frequência Cardíaca/efeitos dos fármacos , Lipopolissacarídeos , Masculino , Ratos , Ratos Sprague-Dawley , Resistência Vascular/efeitos dos fármacosRESUMO
1. The observation that the immunosuppressants, cyclosporine A (CsA) and tacrolimus, have pressor effects, but sirolimus does not, has led to an hypothesis that generalised sympathoexcitation, resulting from inhibition of calcineurin by CsA and tacrolimus underlies their pressor effects, because sirolimus does not inhibit calcineurin. It is unknown if sirolimus has haemodynamic actions not accompanied by a pressor effect, and whether or not the pressor effects of CsA and tacrolimus are accompanied by similar haemodynamic changes. Therefore, the first aim of our studies was to investigate these possibilities in conscious, chronically-instrumented, male, Sprague-Dawley rats. 2. CsA (5.9 mg kg(-1) bolus i.v.) caused rapid-onset, prolonged hypertension, tachycardia and mesenteric vasoconstriction. There was a slower onset renal vasoconstriction, but no significant change in hindquarters vascular conductance; all the effects of CsA were significantly greater than those of vehicle. CsA given by infusion (over 30 min or 2 h) caused changes qualitatively similar to those above. Repeated administration of CsA over 4 days did not enhance its cardiovascular effects. 3. Pretreatment with the angiotensin (AT(1)) receptor antagonist, losartan, and the endothelin (ET(A) and ET(B)) receptor antagonist, SB 209670, reduced the pressor and mesenteric vasoconstrictor effects of CsA. Additional administration of the alpha-adrenoceptor antagonist, phentolamine, completely inhibited the cardiovascular effects of CsA. 4. Tacrolimus (450 microg kg(-1) bolus i.v.) caused similar peak pressor and tachycardic effects to CsA, but these were much slower in onset, and were maximal when there were no significant regional vasoconstrictions, indicating that the pressor effect was probably due to a rise in cardiac output. However, although propranolol reversed the tachycardic effect of tacrolimus, it did not influence the pressor response. 5. Sirolimus (450 microg kg(-1) bolus i.v.) had no tachycardic action, and only a modest, transient pressor effect, accompanied by equally brief reductions in renal, mesenteric, and hindquarters vascular conductances. 6. The differences between the regional haemodynamic profiles of equipressor doses of CsA and tacrolimus, and the finding that sirolimus has significant cardiovascular actions, indicate that generalised sympathoexcitation, resulting from calcineurin inhibition (with CsA and tacrolimus), is unlikely to be the sole explanation of their pressor effects.
Assuntos
Ciclosporina/farmacologia , Hemodinâmica/efeitos dos fármacos , Imunossupressores/farmacologia , Sirolimo/farmacologia , Tacrolimo/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Ciclosporina/administração & dosagem , Interações Medicamentosas , Frequência Cardíaca/efeitos dos fármacos , Imunossupressores/administração & dosagem , Indanos/farmacologia , Infusões Intravenosas , Losartan/farmacologia , Masculino , Fentolamina/farmacologia , Propranolol/farmacologia , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Circulação Renal/efeitos dos fármacos , Sirolimo/administração & dosagem , Tacrolimo/administração & dosagemRESUMO
AIMS: We aim to modulate the renin-angiotensin system (RAS) by active immunization against angiotensin I hormone (AI), potentially providing a novel conjugate vaccine treatment for hypertension in man. METHODS: Immunization studies in rat and human subjects compare the effectiveness of tetanus toxoid (TT) and keyhole limpet haemocyanin (KLH) vaccines for immunotherapy following conjugation with an AI peptide analogue (AI). Cardiovascular responses were assessed in immunized rats and human subjects (two-dose trial only), following increasing i.v. infusions of either AI or angiotensin II hormone (AII). RESULTS: The AI-TT and AI-KLH conjugate vaccines induced an equivalent immune response, and inhibition of the pressor effects to exogenous AI in rats. Single-dose clinical trials with both conjugate vaccines only resulted in an immune response to the KLH carrier protein. A two-dose clinical trial of AI-KLH conjugate vaccine resulted in a significant immune response to AI. A shift in diastolic blood pressure (DBP) dose-response was demonstrated following challenge with AI and AII for the study volunteer showing the largest anti-AI IgG induction. CONCLUSION: KLH was shown to be a suitable alternative to TT as a carrier protein for AI, thus supporting continued evaluation of our AI-KLH conjugate vaccine for treatment of hypertension in man.
Assuntos
Angiotensina I/imunologia , Proteínas de Transporte/uso terapêutico , Hemocianinas/uso terapêutico , Hipertensão/terapia , Toxoide Tetânico/uso terapêutico , Adolescente , Adulto , Animais , Relação Dose-Resposta Imunológica , Avaliação de Medicamentos , Ensaio de Imunoadsorção Enzimática , Humanos , Hipertensão/imunologia , Imunização , Imunoglobulinas/imunologia , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-Dawley , Vacinas Conjugadas/uso terapêuticoRESUMO
In conscious, freely-moving, male, Sprague-Dawley rats, the regional haemodynamic responses to the synthetic cannabinoids, WIN-55212-2 and HU 210, were compared. The possible involvement of cannabinoid, CB(1)-receptors, or beta(2)-adrenoceptors in the responses to WIN-55212-2 and HU 210 were investigated using the CB(1)-receptor antagonist, AM 251, or the beta(2)-adrenoceptor antagonist, ICI 118551, respectively. Both WIN-55212-2 (150 microg kg(-1)) and HU 210 (100 microg kg(-1)) had pressor, renal, and mesenteric vasoconstrictor and hindquarters vasodilator actions, although the effects of HU 210 were much more sustained than those of WIN-55212-2. Lower doses of the cannabinoids (WIN-55212-2, 50 microg kg(-1), HU 210, 10 microg kg(-1)) had less consistent actions. All the significant cardiovascular effects of WIN-55212-2 and HU 210 were antagonized by pretreatment with AM 251 (3 mg kg(-1)). Furthermore, pretreatment with the beta(2)-adrenoceptor antagonist, ICI 118551, inhibited the hindquarters vasodilator effects of WIN-55212-2 and of HU 210. On the basis of the present findings, and our earlier work, it is suggested that, in conscious rats, the pressor and vasoconstrictor effects of HU 210 and WIN-55212-2 involve cannabinoid-receptor-mediated increases in sympathetic activity. The accompanying hindquarters vasodilator actions of these agonists are cannabinoid receptor-mediated and appear to involve beta(2)-adrenoceptors.