the relative contribution of adenosine and ATP-sensitive potassium (KATP) channels in hypoxia-induced vasodilation was studied in isolated, saline-perfused rabbit hearts under constant flow conditions. Adenosine infusion induced a dose-dependent reduction in coronary perfusion pressure. Inhibition of KATP-channels with glibenclamide (0.3 microM) significantly reduced the dilator response to adenosine (-26 +/- 6 ys. -6 +/- 2% at 1 microM), whereas those of 1 microM acetylcholine or 10 microM papaverine were unaffected. The dilator responses to the A1-receptor selective agonist, N6-cyclopentyladenosine (CPA), and the mixed A1- and A2-receptor agonist, 5'-(N-ethylcarboxamido) adenosine (NECA), were comparable to that of adenosine. Treatment with glibenclamide reduced partially but significantly the NECA-induced vasodilation (-28 +/- 4 vs. -17 +/- 4%) and changed the CPA dilator response to a significant vasoconstriction. Both the nonselective adenosine-receptor antagonist, 8-phenyltheophylline (10 microM), and glibenclamide blocked the dilator response to adenosine and significantly reduced the hypoxia-induced vasodilation to the same extent. In conclusion, we suggest that the activation of KATP channels plays a major role in hypoxia-induced vasodilation. A major part of this activation results from the action of adenosine on receptors closely related to the A1 type.

The mechanism of hypoxia-induced coronary vasodilation was studied in isolated, saline-perfused rabbit hearts under constant flow conditions. Reduction in the perfusion solution PO2 (from 520 +/- 6 to 103 +/- 9 mm Hg) under control conditions halved the coronary resistance and was accompanied by a significant release of the prostaglandin (PG) 6-keto-PGF1 alpha (from 1.8 +/- 0.3 to a maximum of 4.4 +/- 0.9 pmol min-1 g-1). The cyclooxygenase inhibitor, diclofenac (1 microM), blocked the release of PGI2 and reduced hypoxia-induced vasodilation (from 47 +/- 8% to 25 +/- 5%, P < 0.05). The relative contribution of adenosine, prostaglandins, and adenosine triphosphate (ATP)-sensitive K+ channel (KATP channel) activation in hypoxia-induced vasodilation was assessed by comparing the differential change (control response minus response after treatment) in coronary perfusion pressure (CPP) during infusion of 8-phenyltheophylline (8-PT), diclofenac, and glibenclamide, respectively. The differential change in CPP with 8-PT and diclofenac given together (-48 +/- 7%) was found to be equivalent to the sum of their respective effects (-24 +/- 7 and -19 +/- 4%, respectively). Glibenclamide (0.3 microM) reduced significantly hypoxia-induced vasodilation (differential change in CPP of -27 +/- 6%) as well as the dilator response to 10 microM adenosine and to the stable PGI2-analogue, iloprost. Forskolin-induced coronary vasodilation in arrested hearts was slightly, but significantly, reduced by glibenclamide. Our results suggest that both cyclooxygenase products and adenosine, acting independently, and concomitantly, contribute to the dilator response of coronary resistance vessels to hypoxia, in part through the activation of KATP channels.(ABSTRACT TRUNCATED AT 250 WORDS)

1 Vasodepressor responses to intravenous (i.v.) injection of bradykinin (BK) and des-Arg9-BK, a selective B, kinin receptor agonist, were characterized following i.v. pretreatment with selective B, ([Leu8]-des-Arg9-BK) and B2 (Hoe 140) kinin receptor antagonists in anaesthetized dogs. 2 Des-Arg9-BK (0.05-3.3 nmol kg-') produced dose-dependent decreases in mean arterial blood pressure with a ED_0 0.4 nmol kg-'. The vasodepressor effects evoked by des-Arg9-BK (0.6 nmol kg-') and BK (0.2 nmol kg-') were greater after i.v. and i.a. injections, respectively. 3 The vasodepressor response to BK (0.6 nmol kg-') but not to des-Arg9-BK (0.6 nmol kg-') was significantly (P<0.001) blocked by pretreatment with the B2 receptor antagonist, Hoe 140. 4 The vasodepressor response to des-Arg9-BK (0.6 nmol kg-') but not to BK (0.6 nmol kg-') was significantly (P<0.001) reduced by pretreatment with the selective B, receptor antagonist, [Leu8]-desArg9-BK. Although both B, and B2 receptor antagonists caused a transient fall in blood pressure, their inhibitory action was unlikely to be related to a desensitization mechanism. 5 Inhibition of prostaglandin synthesis with indomethacin prevented the vasodepressor response induced by arachidonic acid (1 mg kg-', i.v.) but not that to BK or des-Arg9-BK (0.6 nmol kg-').6 These results suggest, firstly, that the vasodepressor responses to i.v. BK and des-Arg9-BK are mediated by the activation of B2 and B, receptors, respectively; secondly, that prostaglandins are not involved in the vasodepressor responses to kinins. These findings provide pharmacological evidence for the existence of functionally active B, receptors in canine cardiovascular homeostasis.

Our study was performed to investigate the mechanism underlying the phypotensive effect of kinin B1-receptor activation with des-Arg9-bradykinin (des-Arg9-BK), in comparison with B2-receptor activation with bradykinin (BK), in anesthetized dogs. Bolus intravenous and intraarterial injections of both kinins were compared. BK (0.6 microgram/kg) produced a transient hypotension of the same magnitude, regardless of the route of administration (from 110 +/- 6 mm Hg to 66 +/- 6 mm Hg, or -41 +/- 5%). In contrast, intraarterial injection of des-Arg9-BK (0.6 microgram/kg) induced a weaker hypotension compared with its intravenous injection (-27 +/- 2% vs. -39 +/- 3%, p < 0.05). The hypotension induced by both kinins was accompanied by increases in heart rate, maximum left ventricular dP/dt, and aortic blood flow, suggesting a reduction in peripheral resistance. The positive inotropic and chronotropic effects of BK and des-Arg9-BK were found to be mediated by the sympathetic nervous system, because they were abolished by propranolol. The hypotension induced by intravenous and intraarterial injections of BK and intravenous injections of des-Arg9-BK was only slightly reduced after nitric oxide (NO) synthase inhibition with NG-nitro-L-arginine (L-NNA). In contrast, the hypotensive effect of intraarterial injection of des-Arg9-BK was reduced by half after treatment with L-NNA (p < 0.05). Neither bilateral vagotomy nor ganglionic blockade with pentolinium reduced the hypotension induced by both kinins. In conclusion, the hypotensive effect of des-Arg9-BK and BK results from a peripheral vasodilation. The contribution of NO in this vasodilation is substantial for des-Arg9-BK when administered intraarterial but limited for BK and intravenous des-Arg9-BK.