Adenosine contributes to hypoxia-induced vasodilation through ATP-sensitive K+ channel activation

Abstract

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.

ATP-sensitive potassium channels mediate contraction-induced attenuation of sympathetic vasoconstriction in rat skeletal muscle.

“…In contrast, contracting skeletal muscle produces a number of metabolites that have been postulated to act at least in part by opening K ATP channels. These include hydrogen ion (48), lactate (49), adenosine (14)(15)(16)(17)(18), prostacyclin (21,22), and nitric oxide (19,20). In addition, skeletal muscle hypoxia also could play an important role in K ATP channel activation during contraction.…”

“…Pharmacologic activation of K ATP channels has been shown to increase potassium efflux, causing membrane hyperpolarization and relaxation of vascular smooth muscle (13). There also is increasing evidence that endogenous vasodilators, such as adenosine (14)(15)(16)(17)(18), nitric oxide (19,20), and prostacyclin (21,22), act at least in part by opening K ATP channels. In addition to producing vasodilation, K ATP channel activation has been shown to attenuate ␣ -adrenergic vasoconstriction in intact coronary arteries (23) and in isolated vascular smooth muscle (24,25).…”

Activation of inward rectifier K+channels by hypoxia in rabbit coronary arterial smooth muscle cells

“…For many years, hypoxic vasodilation in the peripheral vasculature has been recognized as an important regulatory response, but the mechanisms for this response remain controversial. The mechanisms proposed to explain coronary hypoxic vasodilation include the release of vasodilator substances, such as nitric oxide or prostaglandins, from endothelial cells and erythrocytes or the production of vasodilator metabolites, such as adenosine, by the cardiac myocytes (2,5,11,26,35,36). Another postulation is that hypoxia directly activates ATPsensitive K ϩ (K ATP ) channels in arterial smooth muscle cell membranes, resulting in vascular hyperpolarization and relaxation (4, 7).…”

Role of myocardium and endothelium in coronary vascular smooth muscle responses to hypoxia

“…A single mediator does not induce those effects. endothelial cells; smooth muscle cells; cardiomyocytes; ATPsensitive potassium channels; adenosine SEVERAL INVESTIGATORS (1,2,4,6,10,20,21,27) have shown in isolated whole heart preparations that hypoxia (lowering the PO 2 in the perfusion solution) induces vasodilation in the whole heart. However, it is not clear whether or not mediators of hypoxia-induced vasodilation originate from vascular or myocardial tissue.…”