Effects of two K+ channel openers, aprikalim and pinacidil, on hypoxic pulmonary vasoconstriction

Dumas, Jean-Paul; Dumas, Monique; Sgro, C; Advenier, C.; Giudicelli, Jean‐François

doi:10.1016/0014-2999(94)90518-5

Cited by 17 publications

(14 citation statements)

References 30 publications

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“…Hypoxic pulmonary vasoconstriction was not significantly augmented by glibenclamide or charybdotoxin. In a previous report, TEA but not glibenclamide enhanced hypoxic pulmonary vasoconstriction suggesting the involvement of K channels other than the ATPsensitive ones (Dumas et al, 1994). The additional results of the present study indicate that these channels do not belong to the KATP or the KCa types.…”

Section: Discussionsupporting

confidence: 66%

“…These discrepancies may be due to the presence of an additional apamin-like K channel blocker in the venom (Post et al, 1992). With regards to the effects of EDRF, and as previously described (Hasunuma et al, 1991b;Liu et al, 1991;Dumas et al, 1994), the inhibition of nitric oxide synthesis and/or of guanylate cyclase enhanced hypoxic pulmonary vasoconstriction suggesting that the release of EDRF attenuated hypoxic vasoconstriction (Zhao et al, 1991).…”

Section: Discussionmentioning

confidence: 90%

“…P02 was maintained below 35 mmHg and the pH was between 7.3 and 7.4. Each hypoxic challenge (4 min) was followed by the addition of 0.25 Mg angiotensin II in normoxic ventilation (4 min) and the pressure was allowed to return to baseline before the initiation of hypoxic ventilation (Dumas et al, 1994). After 3 or 4 hypoxic pulmonary vasoconstrictions the responses became reproducible and in a second series of experiments, the perfusate was then gassed during hypoxic period with a mixture of 40% CO2 + 60% N2 to produce hypercapnic acidosis.…”

Section: Experimental Protocolsmentioning

confidence: 99%

“…P02 was maintained below 35 mmHg and the pH was between 7.3 and 7.4. Each hypoxic challenge (4 min) was followed by the addition of 0.25 Mg angiotensin II in normoxic ventilation (4 min) and the pressure was allowed to return to baseline before the initiation of hypoxic ventilation (Dumas et al, 1994 (30,uM), was tested on the baseline perfusion pressure in normoxic ventilation and on hypoxic pressure response with or without hypercapnic acidosis. Drugs were tested after a stable response to hypoxia was reached.…”

Section: Experimental Protocolsmentioning

confidence: 99%

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Comparison of the effects of nicorandil, pinacidil and nitroglycerin on hypoxic and hypercapnic pulmonary vasoconstriction in the isolated perfused lung of rat

Dumas¹,

Dumas²,

Rochette³

et al. 1996

British J Pharmacology

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1 The aims of this study were to compare in the rat isolated perfused lung preparation, the dilator actions of nicorandil, pinacidil and nitroglycerin on the hypoxic pulmonary pressure response with or without hypercapnic acidosis and to investigate the possible involvement of K channels and EDRF in these effects. 2 Isolated lungs from male Wistar rats (260-320 g) were ventilated with 21%02 + 5%CO2 + 74%N2 (normoxia) or 5%CO2+95%N2 (hypoxia) and perfused with a salt solution supplemented with ficoll and gassed with 40%CO2+60%N2 to produce hypercapnic acidosis. Glibenclamide (1 gM), charybdotoxin (0.1 tIM), NG-nitro-L-arginine methyl ester (L-NAME, 100 pM) and methylene blue (30 gM) were used to block KATP channels, KCa channels, EDRF synthesis and guanylate cyclase, respectively.3 Hypoxic pressure response was significantly increased by hypercapnic acidosis (+ 115%, P<0.001), L-NAME (+ 111%, P<0.001), methylene blue (+ 100%, P<0.05) but not by glibenclamide or charybdotoxin. In contrast none of these inhibitors affected the hypoxic hypercapnic acidosis response. 4 Nicorandil, pinacidil and nitroglycerin caused relaxation during the hypoxic pressure response and hypoxic hypercapnic acidosis response. Nicorandil was more potent in the latter. Glibenclamide inhibited the relaxant effects of nicorandil and pinacidil but not those of nitroglycerin during hypoxia alone. In contrast, glibenclamide inhibited the relaxant effects of the three drugs during hypoxia + hypercapnia. Charybdotoxin inhibited the relaxant effect of pinacidil during normocapnia and hypoxia but not those of nicorandil or nitroglycerin. Methylene blue inhibited partially the dilator response to pinacidil but did not modify the effects of nitroglycerin or nicorandil. 5 It is concluded that in the rat isolated lung preparation, EDRF limits hypoxic pulmonary vasoconstriction but not hypoxic vasoconstriction potentiated by hypercapnic acidosis, whereas KATP or KCa channels are not involved in either case. Nicorandil and pinacidil dilate pulmonary vessels mainly through KATP channels but the effects of pinacidil may also involve an additional mechanism of action through KCa channels. Finally it is suggested that nitroglycerin may partly exert its relaxant effects through KATP channels.

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Section: Discussionsupporting

confidence: 66%

Section: Discussionmentioning

confidence: 90%

Section: Experimental Protocolsmentioning

confidence: 99%

“…P02 was maintained below 35 mmHg and the pH was between 7.3 and 7.4. Each hypoxic challenge (4 min) was followed by the addition of 0.25 Mg angiotensin II in normoxic ventilation (4 min) and the pressure was allowed to return to baseline before the initiation of hypoxic ventilation (Dumas et al, 1994 (30,uM), was tested on the baseline perfusion pressure in normoxic ventilation and on hypoxic pressure response with or without hypercapnic acidosis. Drugs were tested after a stable response to hypoxia was reached.…”

Section: Experimental Protocolsmentioning

confidence: 99%

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Comparison of the effects of nicorandil, pinacidil and nitroglycerin on hypoxic and hypercapnic pulmonary vasoconstriction in the isolated perfused lung of rat

Dumas¹,

Dumas²,

Rochette³

et al. 1996

British J Pharmacology

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“…The results of most studies in isolated perfused rat lungs show little or no effect of L-NAME and other NO synthesis inhibitors on pulmonary perfusion pressure (5,9,13,15,19). Although most studies in intact rats show no significant pulmonary vasoconstrictor response to NO synthesis inhibitors, increases have been reported in some studies, and these have been attributed to "nonspecific effects" (18,49).…”

Section: Discussionmentioning

confidence: 92%

Rho kinase and Ca²⁺ entry mediate increased pulmonary and systemic vascular resistance in l-NAME-treated rats

Dhaliwal

Casey²,

Greco³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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The small GTP-binding protein and its downstream effector Rho kinase play an important role in the regulation of vasoconstrictor tone. Rho kinase activation maintains increased pulmonary vascular tone and mediates the vasoconstrictor response to nitric oxide (NO) synthesis inhibition in chronically hypoxic rats and in the ovine fetal lung. However, the role of Rho kinase in mediating pulmonary vasoconstriction after NO synthesis inhibition has not been examined in the intact rat. To address this question, cardiovascular responses to the Rho kinase inhibitor fasudil were studied at baseline and after administration of an NO synthesis inhibitor. In the intact rat, intravenous injections of fasudil cause dose-dependent decreases in systemic arterial pressure, small decreases in pulmonary arterial pressure, and increases in cardiac output. L-NAME caused a significant increase in pulmonary and systemic arterial pressures and a decrease in cardiac output. The intravenous injections of fasudil after L-NAME caused dose-dependent decreases in pulmonary and systemic arterial pressure and increases in cardiac output, and the percent decreases in pulmonary arterial pressure in response to the lower doses of fasudil were greater than decreases in systemic arterial pressure. The Ca(++) entry blocker isradipine also decreased pulmonary and systemic arterial pressure in L-NAME-treated rats. Infusion of sodium nitroprusside restored pulmonary arterial pressure to baseline values after administration of L-NAME. These data provide evidence in support of the hypothesis that increases in pulmonary and systemic vascular resistance following L-NAME treatment are mediated by Rho kinase and Ca(++) entry through L-type channels, and that responses to L-NAME can be reversed by an NO donor.

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Nitric Oxide and the Pulmonary Circulation in the Adult

Nossaman¹,

Kaye²,

Kadowitz³

2000

Nitric Oxide and the Regulation of the Peripheral Circulation

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Effects of two K+ channel openers, aprikalim and pinacidil, on hypoxic pulmonary vasoconstriction

Cited by 17 publications

References 30 publications

Comparison of the effects of nicorandil, pinacidil and nitroglycerin on hypoxic and hypercapnic pulmonary vasoconstriction in the isolated perfused lung of rat

Comparison of the effects of nicorandil, pinacidil and nitroglycerin on hypoxic and hypercapnic pulmonary vasoconstriction in the isolated perfused lung of rat

Rho kinase and Ca²⁺ entry mediate increased pulmonary and systemic vascular resistance in l-NAME-treated rats

Nitric Oxide and the Pulmonary Circulation in the Adult

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Effects of two K+ channel openers, aprikalim and pinacidil, on hypoxic pulmonary vasoconstriction

Cited by 17 publications

References 30 publications

Comparison of the effects of nicorandil, pinacidil and nitroglycerin on hypoxic and hypercapnic pulmonary vasoconstriction in the isolated perfused lung of rat

Comparison of the effects of nicorandil, pinacidil and nitroglycerin on hypoxic and hypercapnic pulmonary vasoconstriction in the isolated perfused lung of rat

Rho kinase and Ca2+ entry mediate increased pulmonary and systemic vascular resistance in l-NAME-treated rats

Nitric Oxide and the Pulmonary Circulation in the Adult

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Rho kinase and Ca²⁺ entry mediate increased pulmonary and systemic vascular resistance in l-NAME-treated rats