RESUMO
The relative importance of ATP as a functional sympathetic neurotransmitter in blood vessels has been shown to be increased when the level of preexisting vascular tone or pressure is increased, in studies carried out in rat mesenteric arteries. The aim of the present study was to determine whether tone influences the involvement of ATP as a sympathetic cotransmitter with noradrenaline in another species. We used the porcine perfused mesenteric arterial bed and porcine mesenteric large, medium and small arteries mounted for isometric tension recording, because purinergic cotransmission can vary depending on the size of the blood vessel. In the perfused mesenteric bed at basal tone, sympathetic neurogenic vasocontractile responses were abolished by prazosin, an α1-adrenoceptor antagonist, but there was no significant effect of α,ß-methylene ATP, a P2X receptor-desensitizing agent. Submaximal precontraction of the mesenteric arterial bed with U46619, a thromboxane A2 mimetic, augmented the sympathetic neurogenic vasocontractile responses; under these conditions, both α,ß-methylene ATP and prazosin attenuated the neurogenic responses. In the mesenteric large, medium and small arteries, prazosin attenuated the sympathetic neurogenic contractile responses under conditions of both basal and U46619-raised tone. α,ß-Methylene ATP was effective in all of these arteries only under conditions of U46619-induced tone, causing a similar inhibition in all arteries, but had no significant effect on sympathetic neurogenic contractions at basal tone. These data show that ATP is a cotransmitter with noradrenaline in porcine mesenteric arteries; the purinergic component was revealed under conditions of partial precontraction, which is more relevant to physiological conditions.
Assuntos
Trifosfato de Adenosina/metabolismo , Artérias Mesentéricas/metabolismo , Músculo Liso Vascular/metabolismo , Neurotransmissores/metabolismo , Animais , Feminino , Masculino , Tono Muscular/fisiologia , Técnicas de Cultura de Órgãos , Suínos , Sistema Nervoso Simpático/fisiologia , Vasoconstrição/fisiologiaRESUMO
Jupiter's bright persistent polar aurora and Earth's dark polar region indicate that the planets' magnetospheric topologies are very different. High-resolution global simulations show that the reconnection rate at the interface between the interplanetary and jovian magnetic fields is too slow to generate a magnetically open, Earth-like polar cap on the time scale of planetary rotation, resulting in only a small crescent-shaped region of magnetic flux interconnected with the interplanetary magnetic field. Most of the jovian polar cap is threaded by helical magnetic flux that closes within the planetary interior, extends into the outer magnetosphere, and piles up near its dawnside flank where fast differential plasma rotation pulls the field lines sunward. This unusual magnetic topology provides new insights into Jupiter's distinctive auroral morphology.
RESUMO
Jupiter's rapidly rotating, strong magnetic field provides a natural laboratory that is key to understanding the dynamics of high-energy plasmas. Spectacular auroral x-ray flares are diagnostic of the most energetic processes governing magnetospheres but seemingly unique to Jupiter. Since their discovery 40 years ago, the processes that produce Jupiter's x-ray flares have remained unknown. Here, we report simultaneous in situ satellite and space-based telescope observations that reveal the processes that produce Jupiter's x-ray flares, showing surprising similarities to terrestrial ion aurora. Planetary-scale electromagnetic waves are observed to modulate electromagnetic ion cyclotron waves, periodically causing heavy ions to precipitate and produce Jupiter's x-ray pulses. Our findings show that ion aurorae share common mechanisms across planetary systems, despite temporal, spatial, and energetic scales varying by orders of magnitude.
RESUMO
Energy circulation in geospace lies at the heart of space weather research. In the inner magnetosphere, the steep plasmapause boundary separates the cold dense plasmasphere, which corotates with the planet, from the hot ring current/plasma sheet outside. Theoretical studies suggested that plasmapause surface waves related to the sharp inhomogeneity exist and act as a source of geomagnetic pulsations, but direct evidence of the waves and their role in magnetospheric dynamics have not yet been detected. Here, we show direct observations of a plasmapause surface wave and its impacts during a geomagnetic storm using multi-satellite and ground-based measurements. The wave oscillates the plasmapause in the afternoon-dusk sector, triggers sawtooth auroral displays, and drives outward-propagating ultra-low frequency waves. We also show that the surface-wave-driven sawtooth auroras occurred in more than 90% of geomagnetic storms during 2014-2018, indicating that they are a systematic and crucial process in driving space energy dissipation.
RESUMO
AIMS: UDP-sugars can act as extracellular signalling molecules, but relatively little is known about their cardiovascular actions. The P2Y14 receptor is a Gi/o-coupled receptor which is activated by UDP-glucose and related sugar nucleotides. In this study we sought to investigate whether P2Y14 receptors are functionally expressed in the porcine coronary artery using a selective P2Y14 receptor agonist, MRS2690, and a novel selective P2Y14 receptor antagonist, PPTN (4,7-disubstituted naphthoic acid derivative). METHODS AND RESULTS: Isometric tension recordings were used to evaluate the effects of UDP-sugars in porcine isolated coronary artery segments. The effects of the P2 receptor antagonists suramin and PPADS, the P2Y14 receptor antagonist PPTN, and the P2Y6 receptor antagonist MRS2578, were investigated. Measurement of vasodilator-stimulated phosphoprotein (VASP) phosphorylation using flow cytometry was used to assess changes in cAMP levels. UDP-glucose, UDP-glucuronic acid UDP-N-acetylglucosamine (P2Y14 receptor agonists), elicited concentration-dependent contractions of the porcine coronary artery. MRS2690 was a more potent vasoconstrictor than the UDP-sugars. Concentration dependent contractile responses to MRS2690 and UDP-sugars were enhanced in the presence of forskolin (activator of cAMP), where the level of basal tone was maintained by addition of U46619, a thromboxane A2 mimetic. Contractile responses to MRS2690 were blocked by PPTN, but not by MRS2578. Contractile responses to UDP-glucose were also attenuated by PPTN and suramin, but not by MRS2578. Forskolin-induced VASP-phosphorylation was reduced in porcine coronary arteries exposed to UDP-glucose and MRS2690, consistent with P2Y14 receptor coupling to Gi/o proteins and inhibition of adenylyl cyclase activity. CONCLUSIONS: Our data support a role of UDP-sugars as extracellular signalling molecules and show for the first time that they mediate contraction of porcine coronary arteries via P2Y14 receptors.
Assuntos
Vasos Coronários/metabolismo , Receptores Purinérgicos P2/metabolismo , Açúcares de Uridina Difosfato/metabolismo , Vasoconstrição/fisiologia , Adulto , Animais , Colforsina/farmacologia , Feminino , Humanos , Isotiocianatos/farmacologia , Masculino , Receptores Purinérgicos P2/efeitos dos fármacos , Transdução de Sinais/fisiologia , Suínos , Tioureia/análogos & derivados , Tioureia/farmacologia , Uridina Difosfato Glucose/administração & dosagem , Uridina Difosfato Glucose/análogos & derivados , Uridina Difosfato Glucose/metabolismo , Uridina Difosfato Glucose/farmacologia , Vasoconstritores/farmacologiaRESUMO
Noradrenaline and ATP are sympathetic co-transmitters. In rat isolated mesenteric small arteries, activation of sympathetic nerves can produce a vasoconstrictor response mediated by ATP. In contrast, the rat perfused mesenteric bed displays vasoconstrictor responses that are blocked solely by alpha1-adrenoceptor antagonists. This study assessed the effect of raising tone with a vasoconstrictor on purinergic and noradrenergic responses to sympathetic nerve stimulation in the rat perfused mesentery. Rat mesenteric vascular beds were perfused with physiological salt solution and responses to nerve stimulation, or P2X-receptor agonists, were determined under basal conditions and after raising tone with endothelin-1. The contribution of noradrenaline and ATP to sympathetic nerve-mediated responses was assessed using the alpha1-adrenoceptor antagonist, prazosin and the P2X-receptor desensitizing agent, alpha,beta-methyleneATP. The effect of endothelin-1 on excitatory junction potentials generated in response to nerve stimulation in isolated mesenteric arteries was also assessed. Under baseline conditions, responses to nerve stimulation were mediated solely by activation of alpha1-adrenoceptors. After raising perfusion pressure with endothelin-1 or the thromboxane mimetic 9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F2alpha (U44619), sympathetic nerve-mediated responses were larger than under basal conditions and the response was partly sensitive to P2X-receptor desensitization. Responses to exogenous P2X-receptor agonists were enhanced after treatment with endothelin-1, while endothelin-1 decreased the amplitude of excitatory junction potentials. These results indicate that ATP acts as an important, functional, sympathetic neurotransmitter in the perfused mesentery under raised tone conditions, where the perfusion pressure is closer to that found in vivo. This effect is due to a postjunctional enhancement of purinergic function.
Assuntos
Trifosfato de Adenosina/metabolismo , Artérias Mesentéricas/inervação , Norepinefrina/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Purinérgicos P2/metabolismo , Sistema Nervoso Simpático/metabolismo , Vasoconstrição , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Relação Dose-Resposta a Droga , Estimulação Elétrica , Endotelina-1/farmacologia , Técnicas In Vitro , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Prazosina/farmacologia , Ratos , Ratos Wistar , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Receptores Purinérgicos P2/efeitos dos fármacos , Receptores Purinérgicos P2X , Circulação Esplâncnica , Sistema Nervoso Simpático/efeitos dos fármacos , Resistência Vascular , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologiaRESUMO
In recent years, it has become apparent that the gaseous pollutant, hydrogen sulphide (H2S) can be synthesised in the body and has a multitude of biological actions. This review summarizes some of the actions of this 'gasotransmitter' in influencing the smooth muscle that is responsible for controlling muscular activity of hollow organs. In the vasculature, while H2S can cause vasoconstriction by complex interactions with other biologically important gases, such as nitric oxide, the prevailing response is vasorelaxation. While most vasorelaxation responses occur by a direct action of H2S on smooth muscle cells, it has recently been proposed to be an endothelium-derived hyperpolarizing factor. H2S also promotes relaxation in other smooth muscle preparations including bronchioles, the bladder, gastrointestinal tract and myometrium, opening up the opportunity of exploiting the pharmacology of H2S in the treatment of conditions where smooth muscle tone is excessive. The original concept, that H2S caused smooth muscle relaxation by activating ATP-sensitive K(+) channels, has been supplemented with observations that H2S can also modify the activity of other potassium channels, intracellular pH, phosphodiesterase activity and transient receptor potential channels on sensory nerves. While the enzymes responsible for generating endogenous H2S are widely expressed in smooth muscle preparations, it is much less clear what the physiological role of H2S is in determining smooth muscle contractility. Clarification of this requires the development of potent and selective inhibitors of H2S-generating enzymes.
Assuntos
Sulfeto de Hidrogênio/farmacologia , Músculo Liso/efeitos dos fármacos , Animais , Humanos , Contração Muscular/efeitos dos fármacos , Relaxamento Muscular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
We report the first Jupiter X-ray observations planned to coincide with an interplanetary coronal mass ejection (ICME). At the predicted ICME arrival time, we observed a factor of â¼8 enhancement in Jupiter's X-ray aurora. Within 1.5 h of this enhancement, intense bursts of non-Io decametric radio emission occurred. Spatial, spectral, and temporal characteristics also varied between ICME arrival and another X-ray observation two days later. Gladstone et al. (2002) discovered the polar X-ray hot spot and found it pulsed with 45 min quasiperiodicity. During the ICME arrival, the hot spot expanded and exhibited two periods: 26 min periodicity from sulfur ions and 12 min periodicity from a mixture of carbon/sulfur and oxygen ions. After the ICME, the dominant period became 42 min. By comparing Vogt et al. (2011) Jovian mapping models with spectral analysis, we found that during ICME arrival at least two distinct ion populations, from Jupiter's dayside, produced the X-ray aurora. Auroras mapping to magnetospheric field lines between 50 and 70 RJ were dominated by emission from precipitating sulfur ions (S7+, ,14+). Emissions mapping to closed field lines between 70 and 120 RJ and to open field lines were generated by a mixture of precipitating oxygen (O7+,8+) and sulfur/carbon ions, possibly implying some solar wind precipitation. We suggest that the best explanation for the X-ray hot spot is pulsed dayside reconnection perturbing magnetospheric downward currents, as proposed by Bunce et al. (2004). The auroral enhancement has different spectral, spatial, and temporal characteristics to the hot spot. By analyzing these characteristics and coincident radio emissions, we propose that the enhancement is driven directly by the ICME through Jovian magnetosphere compression and/or a large-scale dayside reconnection event.
RESUMO
There are nineteen different receptor proteins for adenosine, adenine and uridine nucleotides, and nucleotide sugars, belonging to three families of G protein-coupled adenosine and P2Y receptors, and ionotropic P2X receptors. The majority are functionally expressed in blood vessels, as purinergic receptors in perivascular nerves, smooth muscle and endothelial cells, and roles in regulation of vascular contractility, immune function and growth have been identified. The endogenous ligands for purine receptors, ATP, ADP, UTP, UDP and adenosine, can be released from different cell types within the vasculature, as well as from circulating blood cells, including erythrocytes and platelets. Many purine receptors can be activated by two or more of the endogenous ligands. Further complexity arises because of interconversion between ligands, notably adenosine formation from the metabolism of ATP, leading to complex integrated responses through activation of different subtypes of purine receptors. The enzymes responsible for this conversion, ectonucleotidases, are present on the surface of smooth muscle and endothelial cells, and may be coreleased with neurotransmitters from nerves. What selectivity there is for the actions of purines/pyrimidines comes from differential expression of their receptors within the vasculature. P2X1 receptors mediate the vasocontractile actions of ATP released as a neurotransmitter with noradrenaline (NA) from sympathetic perivascular nerves, and are located on the vascular smooth muscle adjacent to the nerve varicosities, the sites of neurotransmitter release. The relative contribution of ATP and NA as functional cotransmitters varies with species, type and size of blood vessel, neuronal firing pattern, the tone/pressure of the blood vessel, and in ageing and disease. ATP is also a neurotransmitter in non-adrenergic non-cholinergic perivascular nerves and mediates vasorelaxation via smooth muscle P2Y-like receptors. ATP and adenosine can act as neuromodulators, with the most robust evidence being for prejunctional inhibition of neurotransmission via A1 adenosine receptors, but also prejunctional excitation and inhibition of neurotransmission via P2X and P2Y receptors, respectively. P2Y2, P2Y4 and P2Y6 receptors expressed on the vascular smooth muscle are coupled to vasocontraction, and may have a role in pathophysiological conditions, when purines are released from damaged cells, or when there is damage to the protective barrier that is the endothelium. Adenosine is released during hypoxia to increase blood flow via vasodilator A2A and A2B receptors expressed on the endothelium and smooth muscle. ATP is released from endothelial cells during hypoxia and shear stress and can act at P2Y and P2X4 receptors expressed on the endothelium to increase local blood flow. Activation of endothelial purine receptors leads to the release of nitric oxide, hyperpolarising factors and prostacyclin, which inhibits platelet aggregation and thus ensures patent blood flow. Vascular purine receptors also regulate endothelial and smooth muscle growth, and inflammation, and thus are involved in the underlying processes of a number of cardiovascular diseases.
Assuntos
Vasos Sanguíneos/metabolismo , Receptores Purinérgicos/metabolismo , Tecido Adiposo/metabolismo , Animais , Humanos , Músculo Liso Vascular/metabolismoRESUMO
Endothelium-dependent responses were assessed in myometrial small arteries isolated from pregnant women, using pressure myography. Responses to bradykinin were unaffected by the combined presence of the nitric oxide synthase (NOS) inhibitor, N-nitro-L-arginine methyl ester (L-NAME, 100 micro M) and the cyclo-oxygenase inhibitor, indomethacin (10 micro M). The additional presence of clotrimazole (50 micro M) attenuated, but did not abolish, vasodilator responses to bradykinin. Raising extracellular [K(+)] (by between 1 and 15 mM) did not evoke a vasodilator response, nor did the cannabinoids, anandamide and methanandamide. Responses to bradykinin were attenuated in the presence of the gap junction inhibitors 18-alpha-glycyrrhetinic acid (18-alpha GA, 100 micro M), carbenoxolone (100 micro M) and palmitoleic acid (50 micro M). SR141716A, the CB(1) receptor antagonist attenuated responses to bradykinin, but only at high concentrations (10 micro M). These results suggest that gap junctional communication is involved in the nitric oxide (NO)- and prostanoid-independent vasodilator responses to bradykinin in myometrial small arteries in normal pregnancy.
Assuntos
Fatores Biológicos/fisiologia , Bradicinina/farmacologia , Endotélio Vascular/fisiologia , Junções Comunicantes/fisiologia , Ácido Glicirretínico/análogos & derivados , Miométrio/fisiologia , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacologia , Artérias/fisiologia , Bradicinina/antagonistas & inibidores , Canabinoides/metabolismo , Canabinoides/farmacologia , Carbenoxolona/farmacologia , Clotrimazol/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Ácidos Graxos Monoinsaturados/farmacologia , Feminino , Ácido Glicirretínico/farmacologia , Humanos , Técnicas In Vitro , Indometacina/farmacologia , Miométrio/irrigação sanguínea , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Piperidinas/farmacologia , Gravidez , Pirazóis/farmacologia , Receptores de Canabinoides , Receptores de Droga/antagonistas & inibidores , Rimonabanto , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacosRESUMO
The present study examined the hypothesis that potassium ions act as an endothelium-derived hyperpolarizing factor (EDHF) released in response to ACh in small mesenteric arteries displaying myogenic tone. Small mesenteric arteries isolated from rats were set up in a pressure myograph at either 60 or 90 mmHg. After developing myogenic tone, responses to raising extracellular potassium were compared to those obtained with ACh (in the presence of nitric oxide synthase and cyclo-oxygenase inhibitors). The effects of barium and oubain, or capsaicin, on responses to raised extracellular potassium or ACh were also determined. The effects of raised extracellular potassium levels and ACh on membrane potential, were measured using sharp microelectrodes in pressurised arteries. Rat small mesenteric arteries developed myogenic tone when pressurised. On the background of vascular tone set by a physiological stimulus (i.e pressure), ACh fully dilated the small arteries in a concentration-dependent manner. This response was relatively insensitive to the combination of barium and ouabain, and insensitive to capsaicin. Raising extracellular potassium produced a more inconsistent and modest vasodilator response in pressurised small mesenteric arteries. Responses to raising extracellular potassium were sensitive to capsaicin, and the combination of barium and ouabain. ACh caused a substantial hyperpolarisation in pressurized arteries, while raising extracellular potassium did not. These data indicate that K+ is not the EDHF released in response to ACh in myogenically active rat mesenteric small arteries. Since the hyperpolarization produced by ACh was sensitive to carbenoxolone, gap junctions are the likely mediator of EDH responses under physiological conditions.
Assuntos
Pressão Arterial , Fatores Biológicos/metabolismo , Artérias Mesentéricas/metabolismo , Potássio/metabolismo , Acetilcolina/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Bário/metabolismo , Espaço Extracelular , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Ouabaína/metabolismo , Ratos , Vasodilatadores/farmacologiaRESUMO
OBJECTIVES: Enhanced sympathetic neurotransmission contributes to hypertension in the spontaneously hypertensive rat (SHR). We recently reported a method for studying sympathetic neurotransmission in pressurized small arteries, demonstrating a major role of adenosine triphosphate (ATP) as a sympathetic neurotransmitter under these physiological conditions. We have now used this methodology to assess the role of ATP as a sympathetic neurotransmitter in small mesenteric arteries isolated from SHRs. METHODS: Small arteries were mounted in a suction electrode, cannulated and pressurized to either 30 or 90 mmHg. Nerve-evoked alterations in membrane potential were assessed using sharp microelectrodes. Neurally evoked vasoconstrictor responses were measured in the absence and presence of the α1-adrenoceptor antagonist, tamsulosin (0.1 µmol/l), or the P2 purinoceptor antagonist suramin (0.1 mmol/l). RESULTS: At 30 mmHg the P2X-receptor-mediated excitatory junctional potential (EJP) was larger in arteries from SHRs (7.9 ± 0.9 mV) than Wistar-Kyoto (WKY) rats (3.2 ± 0.4 mV, P < 0.05). Increasing pressure increased the amplitude of the EJP, which again, was larger in SHRs. At 90 mmHg, activation of the perivascular nerves produced a larger vasoconstriction in arteries isolated from SHRs compared with WKY rats. The vasoconstrictor response in SHRs was abolished by either suramin or tamsulosin. CONCLUSION: These data provide electrophysiological evidence for enhanced purinergic function in the SHR and show that ATP is fundamentally important in contributing to the vasoconstriction produced after activation of the perivascular nerves in pressurized arteries from the SHR. This involves a synergistic interaction with noradrenaline to causes enhanced mesenteric arterial vasoconstriction, which may contribute to the hypertension in this model.
Assuntos
Trifosfato de Adenosina/metabolismo , Hipertensão/metabolismo , Artérias Mesentéricas/metabolismo , Animais , Masculino , Pressão , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
BACKGROUND AND PURPOSE: Hydrogen sulphide (H(2)S) is a gas that has recently been shown to have biological activity. In the majority of blood vessels studied so far, H(2)S has been shown to cause vasorelaxation, although contractile responses have been reported. In the present study, we have made a pharmacological assessment of the effects of H(2)S in mesenteric small arteries isolated from rats. EXPERIMENTAL APPROACH: Rat mesenteric small arteries were studied using pressure myography. In pressurised arteries, responses were obtained to the H(2)S donor, sodium hydrogen sulphide (NaHS), in the absence and presence of the NOS inhibitor L-NAME, raised extracellular potassium, the K(ATP) channel inhibitor glibenclamide, the Cl- channel blockers DIDS, NPPB and A9C, the TRPV1 receptor desensitizing agent, capsaicin, the CGRP antagonist, olcegepant, the TRPV1 channel blocker capsazepine and the TRPA1 channel blocker HC-030031. KEY RESULTS: NaHS produced a vasodilator response in rat mesenteric small arteries held at 90 mmHg. Responses to NaHS were not reproducible. Neither, glibenclamide nor, L-NAME inhibited responses to NaHS. DIDS abolished vasodilator responses to NaHS, but these were unaffected by the chloride channel blockers, NPPB and A9C. Responses to NaHS were attenuated after capsaicin pre-treatment, by a CGRP receptor antagonist and an inhibitor of TRPA1 channels. CONCLUSIONS AND IMPLICATIONS: In small arteries isolated from the rat mesentery, NaHS caused a vasodilatation. This response was not reproducible in vitro, since it was mediated by the release of sensory neurotransmitters in a capsaicin-like action. This release was mediated by a H(2)S-induced activation of TRPA1 channels.
Assuntos
Sulfeto de Hidrogênio/farmacologia , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/inervação , Neurotransmissores/metabolismo , Vasodilatação/efeitos dos fármacos , Animais , Pressão Arterial/efeitos dos fármacos , Capsaicina/farmacologia , Relação Dose-Resposta a Droga , Técnicas In Vitro , Masculino , Tono Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/inervação , Músculo Liso Vascular/fisiologia , Miografia , Nervos Periféricos/efeitos dos fármacos , Nervos Periféricos/metabolismo , Ratos , Ratos Wistar , Canal de Cátion TRPA1 , Canais de Cátion TRPC/metabolismo , Vasoconstritores/farmacologiaRESUMO
Oleamide is an endocannabinoid-like, fatty acid amide with structural similarities to anandamide. The cardiovascular effects of anandamide are enhanced in hypertension and we have now examined how hypertension affects responses to oleamide. Vasorelaxant responses to oleamide were significantly (P<0.001) enhanced in aortic rings from spontaneously hypertensive rats (SHRs), such that the maximal relaxation to oleamide was 40.3 ± 3.5%, compared to 15.7 ± 3.9% in normotensive Wistar Kyoto (WKY) controls. The augmented responses to oleamide in SHR arteries were unaffected by either inhibition of nitric oxide synthase (300 µM l-NAME) or fatty acid amide hydrolase (1 µM URB597) and independent of cannabinoid CB(1) receptors or the endothelium. The enhanced responses to oleamide were opposed by pre-treatment with capsaicin (such that R(max) was reduced to 9.8 ± 1.5%) and this occurred independently of TRPV1 receptor and sensory nerve activity, as the TRPV1 antagonist capsazepine (1-5 µM) and the cation channel inhibitor ruthenium red (10 µM) had no effect on the responses to oleamide. However, inhibition of cyclooxygenase (10 µM indomethacin) enhanced the responses in the WKY aortae, such that the responses were comparable to those in the SHR. The results suggest that the cyclooxygenase pathway has a role in modulating vasorelaxation caused by oleamide in normotensive aortae and that this is lost in hypertension, possibly as an adaptation to the increase in blood pressure.
Assuntos
Moduladores de Receptores de Canabinoides/metabolismo , Endocanabinoides , Hipertensão/fisiopatologia , Ácidos Oleicos/farmacologia , Vasodilatadores/farmacologia , Amidoidrolases/antagonistas & inibidores , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/fisiopatologia , Benzamidas/farmacologia , Materiais Biomiméticos/farmacologia , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Carbamatos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Técnicas In Vitro , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Ratos , Receptor CB1 de Canabinoide/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Vasodilatadores/uso terapêuticoRESUMO
Capsaicin, an activator of the transient potential vanilloid receptor type 1 (TRPV1), is a commonly used pharmacological tool for desensitising sensory nerves. Capsaicin can induce vasorelaxation of isolated blood vessels by activating perivascular TRPV1 receptors, causing the release of vasoactive neuropeptides. This study attempted to characterise the vascular effects of capsaicin in the rat isolated aorta and porcine coronary arteries. Capsaicin elicited concentration-dependent vasorelaxation of both rat aortae and porcine coronary arteries. Capsaicin-induced vasorelaxation of rat aorta was unaffected by a chronic pre-treatment of vessels with capsaicin. Moreover, relaxation was insensitive to the presence of capsazepine, a competitive TRPV1 antagonist, in both the rat aorta and porcine coronary artery. It was hypothesised that capsaicin may be inhibiting calcium influx into smooth muscle cells. Indeed, in vessels incubated in a Ca²âº-free high-k⺠buffer, the presence of 30 µM capsaicin significantly inhibited the contractile response to the re-introduction of Ca²âº. In porcine coronary arteries 100 µM capsaicin completely abolished the contractile response to the re-introduction of Ca²âº. In addition, capsaicin also abolished the concentration-dependent contraction of porcine coronary arteries induced by the L-type calcium activator Bay-K 8644. Therefore, we suggest that capsaicin causes vascular responses in arteries through the inhibition of L-type Ca²âº channels. In summary,we have identified a potential mechanism underlying TRPV1-independent capsaicin-induced vasorelaxation. Our results also question the use of chronic capsaicin pre-treatment in experimental pharmacology in order to elucidate the role of sensory nerves in vascular responses.
Assuntos
Canais de Cálcio Tipo L/efeitos dos fármacos , Cálcio/metabolismo , Capsaicina/farmacologia , Vasodilatação/efeitos dos fármacos , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacologia , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/metabolismo , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo L/metabolismo , Capsaicina/administração & dosagem , Capsaicina/análogos & derivados , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Wistar , Suínos , Canais de Cátion TRPV/antagonistas & inibidoresRESUMO
Altered endothelial function may underlie human cardiovascular diseases, including hypertension, diabetes and pre-eclampsia. While much is known about endothelial function in small arteries, very little is known about endothelial responses in small veins isolated from humans. Therefore, we assessed endothelium-dependent responses in omental arteries and veins isolated from healthy pregnant women, focussing on endothelium-dependent hyperpolarising (EDH) mechanisms. Human omental arteries and veins were obtained from women undergoing elective caesarean sections and examined using pressure myography. In pressurised vessels, the effects of proposed inhibitors of EDH production/function were examined on responses to bradykinin. The expression of connexins Cx37, 40 and 43 was assessed using immunohistochemistry. Bradykinin caused vasodilatation in human pressurised omental arteries and veins. In both vessels, responses to bradykinin were partially blocked in the presence of the gap junction uncoupler, carbenoxolone, and reduced further with the addition of catalase, which acts to degrade H(2)O(2). The effect of catalase alone was more pronounced in venous preparations. All three connexins were expressed in both arteries and veins, with a similar distribution pattern, where Cx37 and Cx40 were located mainly in the endothelium and Cx43 located mostly in the media. These data show that, in human omental vessels, an EDH mechanism is produced in response to bradykinin that involves gap junction communication and the production of H(2)O(2). These mechanisms may be involved in the haemodynamic alterations that take place during pregnancy, and any aberration in their function could contribute to raised blood pressure in hypertensive disorders of pregnancy, such as pre-eclampsia.
Assuntos
Bradicinina/farmacologia , Endotélio Vascular/citologia , Endotélio Vascular/metabolismo , Junções Comunicantes/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Omento/irrigação sanguínea , Artérias/citologia , Artérias/efeitos dos fármacos , Artérias/metabolismo , Artérias/fisiologia , Catalase/farmacologia , Endotélio Vascular/efeitos dos fármacos , Feminino , Humanos , Técnicas In Vitro , NG-Nitroarginina Metil Éster/farmacologia , Gravidez , Vasodilatação/efeitos dos fármacos , Veias/citologia , Veias/efeitos dos fármacos , Veias/metabolismo , Veias/fisiologiaRESUMO
The aim of this work was to use intravoxel incoherent motion (IVIM) to provide a non-invasive in vivo assessment of the function of the maternal spiral arteries that feed the placenta in normal pregnancy and in pre-eclampsia. Eleven normal pregnant women were scanned at 16, 22, 29 and 35 weeks gestation in a longitudinal study. Nine normal pregnant women and six women with pre-eclampsia were scanned in a cross-sectional study, within 10 days of delivery. The MRI IVIM technique was used to measure the moving blood fraction (f%) at the basal plate. There was no evidence that f% changed with gestational age (P = 0.84), but considering the cross-sectional groups, f% in women with pre-eclampsia was reduced compared with normal pregnancy (mean +/- SD: 36 +/- 5% and 27 +/- 5%; P < 0.005). In conclusion, pregnancies complicated by pre-eclampsia exhibit a reduced fraction of moving blood within the region of the spiral arteries. IVIM performed in the mid-trimester may provide an early means of predicting those pregnancies with an increased likelihood of being complicated by pre-eclampsia.
Assuntos
Volume Sanguíneo/fisiologia , Pré-Eclâmpsia/fisiopatologia , Adulto , Apresentação Pélvica/fisiopatologia , Feminino , Idade Gestacional , Humanos , GravidezRESUMO
Most studies of neurovascular transmission in isolated small mesenteric arteries have used either isometric recording techniques or measured vasoconstriction in vessels with no distending pressure. Here we have used pressure myography to assess the contribution of noradrenaline and ATP to sympathetic neurotransmission in rat second-order mesenteric arteries. In arteries pressurized to 30 or 90 mmHg, activation of sympathetic axons with trains of electrical stimuli (50 pulses, 0.5-10 Hz) evoked frequency-dependent vasoconstrictions that increased in amplitude at higher pressure. In the presence of the P2-receptor antagonist suramin (0.1 mM), the amplitude of vasoconstrictions to trains at 2 and 10 Hz did not differ at 30 and 90 mmHg. In contrast, in the presence of the alpha(1)-adrenoceptor antagonist prazosin (0.1 microm) vasoconstrictions at 90 mmHg were larger than those at 30 mmHg. At both pressures, the combination of prazosin and suramin virtually abolished constrictions. The purinergic component of vasoconstriction (prazosin-resistant) was almost abolished by the L-type Ca(2+) channel antagonist nifedipine (1 microm). Increasing pressure from 30 to 90 mmHg decreased the resting membrane potential and increased the amplitude of purinergic excitatory junction potentials. These findings indicate that the contribution of ATP to neurovascular transmission increases when the pressure is raised from 30 to 90 mmHg, which is similar to the pressure second-order mesenteric arteries experience in vivo, and that Ca(2+) influx through L-type Ca(2+) channels is largely responsible for purinergic activation of the vascular smooth muscle.
Assuntos
Trifosfato de Adenosina/fisiologia , Artérias Mesentéricas/fisiologia , Neurotransmissores/fisiologia , Trifosfato de Adenosina/análogos & derivados , Trifosfato de Adenosina/farmacologia , Animais , Axônios/fisiologia , Canais de Cálcio/fisiologia , Estimulação Elétrica , Eletrofisiologia , Técnicas In Vitro , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/inervação , Miografia , Nifedipino/farmacologia , Norepinefrina/fisiologia , Pressão , Ratos , Ratos Wistar , Vasoconstrição/fisiologia , Vasodilatadores/farmacologiaRESUMO
OBJECTIVE: This study was undertaken to test for structural differences between myometrial radial arteries isolated from women having normal pregnancies and pregnancies complicated by preeclampsia and intrauterine growth restriction. STUDY DESIGN: Pressure myography was used to study myometrial radial arteries obtained at cesarean section. With the use of a transilluminating system, lumen diameter, wall thickness, wall/lumen ratio, distensibility and stress-strain relationship were studied through a range of pressures. Arteries were then fixed in glutaraldehyde, embedded in resin, cross-sectioned, and studied in greater detail by light and electron microscopy. RESULTS: Pressure myography showed that arteries from women with preeclampsia had a reduced lumen diameter, thicker wall, and greater wall/lumen ratio compared with vessels isolated from women with normal pregnancy. Light microscopy indicated an identical media content remodeled around a smaller lumen. Electron microscopy indicated enlarged extracellular spaces in the media but no change in myocyte profile size or number. There was no clear evidence of structural changes in myometrial radial arteries isolated from women with intrauterine growth restriction compared with normal pregnancy. No differences in vessel distensibility or stress-strain relationships were detected in complicated pregnancies. CONCLUSION: The changes observed in myometrial radial arteries isolated from women with preeclampsia are due to inward eutrophic remodeling. Alterations in these vessels may contribute to increased uterine vascular resistance in preeclampsia.
Assuntos
Artérias/patologia , Miométrio/irrigação sanguínea , Pré-Eclâmpsia/patologia , Adulto , Artérias/fisiopatologia , Artérias/ultraestrutura , Feminino , Retardo do Crescimento Fetal/patologia , Retardo do Crescimento Fetal/fisiopatologia , Humanos , Microscopia Eletrônica , Miografia , Pré-Eclâmpsia/fisiopatologia , GravidezRESUMO
OBJECTIVE: Our purpose was to investigate whether there were structural differences between omental small arteries isolated from women with preeclampsia and intrauterine growth restriction and those isolated from women with normal pregnancy. STUDY DESIGN: A pressure myograph was used to study omental small arteries isolated from women with normal pregnancy and women with preeclampsia and intrauterine growth restriction (n = 16, 13, and 8, respectively). With the use of a transilluminating system, lumen diameter, wall thickness, wall/lumen ratio, distensibility, and the stress-strain relationship were studied through pressure ranges of 5 to 100 mm Hg. Arteries were then fixed with glutaraldehyde at the predelivery mean arterial pressure and embedded in epoxy resin. One-micrometer transverse sections were cut for more detailed morphologic examination. RESULTS: Wall thickness, lumen diameter, wall/lumen ratio, distensibility, and the stress-strain relationship of omental small arteries did not differ between patient groups (P >.05; repeated-measures analysis of variance). Detailed histologic examination confirmed these findings. CONCLUSIONS: Alterations in systemic vascular resistance associated with compromised pregnancies are unlikely to result from or produce an alteration in the structure of omental small arteries.