RESUMO

Although rat aorta smooth muscle cells in culture constitutively express bradykinin B1 receptors, the normotensive rat aorta does not respond to the bradykinin B1 receptor agonist des-Arg9-bradykinin, whereas vessels from the spontaneously hypertensive rat (SHR) respond to bradykinin B1 receptor agonists with cell membrane hyperpolarization and relaxation. Bacterial lipopolysaccharide also is inactive on the normotensive rat but hyperpolarizes the SHR aorta. To determine whether this could be due to the increased intracellular Ca2+ concentration ([Ca2+]i) in the SHR, we raised [Ca2+]i in normotensive rats by treatment with thapsigargin. In the thapsigargin-treated aorta, both lipopolysaccharide and des-Arg9-bradykinin induced hyperpolarization, which was reversed by the Ca2+-dependent K+ channel inhibitor iberiotoxin and by the bradykinin B1 receptor antagonists Lys-[Leu8]-des-Arg9-bradykinin and [Leu8]-des-Arg9-bradykinin. Thus the bradykinin B1 receptor, as well as lipopolysaccharide, needs activated Ca2+-dependent K+ channels for functional expression. The two bradykinin B1 receptor inhibitors, however, have effects on Ca2+-dependent K+ channels which are not mediated by bradykinin B1 receptors.

Assuntos

Aorta/efeitos dos fármacos , Antagonistas de Receptor B1 da Bradicinina , Bradicinina/análogos & derivados , Calidina/análogos & derivados , Lipopolissacarídeos/farmacologia , Canais de Potássio Cálcio-Ativados/antagonistas & inibidores , Animais , Aorta/metabolismo , Aorta/fisiologia , Bradicinina/farmacologia , Cálcio/metabolismo , ATPases Transportadoras de Cálcio/antagonistas & inibidores , Técnicas In Vitro , Calidina/farmacologia , Ligantes , Masculino , Potenciais da Membrana/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/fisiologia , Peptídeos/farmacologia , Canais de Potássio Cálcio-Ativados/fisiologia , Ratos , Ratos Wistar , Receptor B1 da Bradicinina/metabolismo , Tapsigargina/farmacologia

RESUMO

The mediators involved in the hyperpolarizing effects of lipopolysaccharide and of the bradykinin B1 receptor agonist des-Arg9-bradykinin on the rat aorta were investigated by comparing the responses of aortic rings of spontaneously hypertensive and normotensive Wistar rats. Endothelized rings from hypertensive rats were hyperpolarized by des-Arg9-bradykinin and lipopolysaccharide, whereas de-endothelized rings responded to lipopolysaccharide but not to des-Arg9-bradykinin. In endothelized preparations, the responses to des-Arg9-bradykinin were inhibited by Nomega-nitro-L-arginine and iberiotoxin. De-endothelized ring responses to lipopolysaccharide were inhibited by iberiotoxin, glibenclamide and B1 antagonist Lys-[Leu8,des-Arg9]-bradykinin. This antagonist also inhibited hyperpolarization by des-Arg9-bradykinin and by the á2-adrenoceptor agonist, brimonidine. Our results indicate that Ca(2+)-sensitive K+ channels are the final mediators of the responses to des-Arg9-bradykinin, whereas both Ca(2+)- and ATP-sensitive K+ channels mediate the responses to lipopolysaccharide. The inhibitory effects of Lys-[Leu8,des-Arg9]-bradykinin is due to a direct action on Ca(2+)- and ATP-sensitive potassium channels.

Assuntos

Aorta Torácica/efeitos dos fármacos , Bradicinina/análogos & derivados , Calidina/análogos & derivados , Calidina/farmacologia , Lipopolissacarídeos/farmacologia , Canais de Potássio Cálcio-Ativados/antagonistas & inibidores , Acetilcolina/farmacologia , Trifosfato de Adenosina/fisiologia , Animais , Aorta Torácica/fisiologia , Bradicinina/farmacologia , Tartarato de Brimonidina , Cromakalim/farmacologia , Relação Dose-Resposta a Droga , Endotélio Vascular/fisiologia , Técnicas In Vitro , Masculino , Potenciais da Membrana/efeitos dos fármacos , Peptídeos/farmacologia , Canais de Potássio Cálcio-Ativados/fisiologia , Quinoxalinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Vasodilatadores/farmacologia

RESUMO

We examined the roles played by impaired K+ channels, diminished nitric oxide (NO) production, endothelin release, and smooth muscle membrane potential in the increased restenosis observed in spontaneously hypertensive rat (SHR) carotid arteries after angioplasty. The SHR carotid was found to be less polarized than that of normotensive Wistar rats (NWR), and it was further depolarized by the alpha2 agonist UK 14,304. This response was blocked by iberiotoxin, indicating that calcium-dependent K+ channels operate normally in the SHR carotid. Acetylcholine caused a hyperpolarization that was significantly smaller in SHR than in NWR carotids, indicating a deficient release of NO in the SHR. After angioplasty, SHR and NWR vessels were depolarized, returning to baseline after 10 days. In the SHR but not in the NWR the contralateral carotid was also depolarized, and this was prevented by the endothelin A/B receptor antagonist bosentan. After angioplasty, endothelin-1 plasma levels increased in both SHR and NWR, but the increase was significantly more prolonged in SHR. We found that the more pronounced restenosis observed in the SHR carotid after angioplasty is not due to impairment of calcium-dependent K+ channels but is related to the relatively depolarized vascular smooth muscles, involving endothelin release caused by reduced NO levels in that strain.

Assuntos

Arteriopatias Oclusivas/metabolismo , Arteriopatias Oclusivas/fisiopatologia , Hipertensão/complicações , Agonistas alfa-Adrenérgicos/farmacologia , Angioplastia com Balão , Animais , Arteriopatias Oclusivas/etiologia , Tartarato de Brimonidina , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/fisiopatologia , Endotelina-1/sangue , Endotélio Vascular/metabolismo , Técnicas In Vitro , Masculino , Potenciais da Membrana/efeitos dos fármacos , Óxido Nítrico/biossíntese , Peptídeos/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Wistar

RESUMO

Previous works have shown that the alpha(2)-adrenoceptor agonist UK 14,304 induced the relaxation and hyperpolarization of the rat aorta, mediated by alpha(2)-adrenoceptors present in the smooth muscles, through small-conductance, ATP-sensitive K(+) channels. We now report that in spontaneously hypertensive rat (SHR) aortic rings, UK 14,304 induced concentration-dependent hyperpolarizing responses, which were inhibited by yohimbine, an alpha(2)-adrenoceptor inhibitor, and by glibenclamide, a specific inhibitor of small-conductance, ATP-sensitive K(+) channels. The responses were also partially inhibited by iberiotoxin and by apamin. Treatment with N(omega)-nitro-L-arginine (L-NNA) did not affect the response to UK 14,304. These results indicate that alpha(2)-adrenoceptors are present in SHR aortic smooth muscle cell membranes, but differ from those of normotensive animals regarding the K(+) channels involved in their responses. Moreover, the resting membrane potential (RMP) was significantly more negative in SHR than in normotensive rats. This relative hyperpolarized state is probably due to Ca(2+)-dependent K(+) channels being constitutively open in SHR, since the addition of iberiotoxin caused a significant depolarization of the aortic smooth muscle membranes in this strain.

Assuntos

Músculo Liso Vascular/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Tartarato de Brimonidina , Cálcio/fisiologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/efeitos dos fármacos , Canais de Cálcio/fisiologia , Feminino , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Quinoxalinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Wistar , Receptores Adrenérgicos alfa 2/fisiologia

RESUMO

1. The direct and endothelium-dependent effects of lipopolysaccharide (LPS) were investigated on resistance and conductance arteries from normotensive Wistar (NWR) and spontaneously hypertensive (SHR) rats. 2. In both NWR and SHR, LPS induced dose-dependent relaxations of the mesenteric vascular bed, which were inhibited by L-NNA in SHR but not in NWR. Iberiotoxin (IBTX) inhibited the responses to LPS in both groups, indicating the participation of high conductance Ca(2+)-dependent K(+) channels. 3. In mesenteric artery rings, the resting membrane potentials and the hyperpolarizing responses of NWR to LPS did not differ in endothelized and denuded preparations but L-NNA inhibited the responses only in endothelized rings. These responses were reduced by bosentan, suggesting that endothelin release may mask a possible hyperpolarizing response to LPS. The hyperpolarizing responses to LPS were blocked by IBTX in both endothelized and de-endothelized NWR rings. In the SHR only intact rings showed hyperpolarization to LPS, which was inhibited by IBTX and byL-NNA. 4. In SHR aortic endothelized or denuded rings, LPS induced hyperpolarizing responses which, in endothelized rings, were partially blocked by L-NNA, by IBTX or by glibenclamide, but totally abolished by IBTX plus glibenclamide. No response to LPS was observed in NWR aortic rings. 5. Our results indicate that LPS activates large conductance Ca(2+)-sensitive K(+) channels located in the smooth muscle cell membrane both directly and indirectly, through NO release from the endothelium in NWR, whereas NO is the major mediator of the LPS responses in SHR resistance vessels.

Assuntos

Hipertensão/fisiopatologia , Lipopolissacarídeos/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Artérias/efeitos dos fármacos , Artérias/fisiologia , Relação Dose-Resposta a Droga , Técnicas In Vitro , Masculino , Potenciais da Membrana/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/fisiologia , Óxido Nítrico/fisiologia , Nitroarginina/farmacologia , Peptídeos/farmacologia , Canais de Potássio/fisiologia , Ratos , Ratos Endogâmicos SHR , Ratos Wistar

RESUMO

The vasodilation and hyperpolarization induced by bradykinin (BK) in the mesenteric vascular bed and mesenteric arteries from spontaneously hypertensive rats (SHR) and from normotensive Wistar rats (NWR), as well as Wistar Kyoto rats (WKY), was investigated before and after prolonged oral treatment with cholecalciferol (125 mg kg(-1) body weight per day) for 3 weeks. The cholecalciferol treatment caused a decrease in the SHR blood pressure, as well as a normalization in the resting potential of the smooth muscle cell membrane of mesenteric arteries and restored their hyperpolarizing response to BK. The concentration-response curves for the vasodilator effect of BK on the mesenteric vascular bed were significantly decreased in SHR and in WKY when compared with NWR. Cholecalciferol treatment improved the maximum responses of the SHR preparation, bringing them to levels similar to those of the NWR preparations, which themselves were unaffected by the treatment. In the presence of apamin, a Ca(2+)-dependent K(+) channel inhibitor, the maximum responses to BK in preparations from NWR or cholecalciferol-treated SHR decreased to values similar to those observed in untreated SHR. Our results indicate that the low responsivity of the SHR resistance vessels to the relaxant effect of BK is due to impaired Ca(2+)-dependent K(+) channels and that reversion of this impairment contributes to the blood pressure reduction caused by the cholecalciferol treatment. However, the mechanism of the low responsivity in WKY remains to be investigated.