To identify the K+ channels responsible for endothelium-derived hyperpolarizing factor (EDHF)-dependent relaxation, we studied the effects of various K+ channel blockers on acetylcholine-induced relaxation, which persists even in the presence of both an inhibitor of nitric oxide synthase and that of cyclooxygenase, in canine coronary artery rings. A nonselective K+ channel blocker, tetrabutylammonium (TBA), a large and intermediate conductance Ca2+-activated K+ channel blocker, charybdotoxin (CTX), and a voltage-dependent K+ channel blocker, 4-aminopyridine (4-AP), significantly inhibited this residual relaxation. A combined treatment with CTX and 4-AP almost completely blocked the relaxation. Neither a large (iberiotoxin) nor a small (apamin) conductance Ca2+-activated K+ channel blocker blocked the relaxation. We also investigated effects of K+ channel blockers on basal tone to determine whether or not EDHF is involved in regulating basal tone. TBA and CTX substantially raised basal tone to a greater degree in endothelium-intact preparations than in endothelium-denuded preparations. These results indicate that EDHF may exert its relaxing action through intermediate conductance Ca2+-activated and voltage-dependent K+ channels in canine coronary arteries. In addition, EDHF may play a role in maintaining basal vascular tone.

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Nipradilol (CAS 81486-22-8), a vasodilatory beta-blocker, has been shown to dilate smaller vessels than nitroglycerin does, and the vasodilative effects of nipradilol have been reported to be less mediated by cyclic GMP (guanosine monophosphate) than those of nitroglycerin. To test the hypothesis that cyclic GMP-independent potassium channels have a larger role in nipradilol-induced aortic relaxation than cyclic GMP-dependent mechanisms, the effects of a potassium channel blocker, tetraethylammonium (TEA, CAS 56-34-8), and of a guanylate cyclase inhibitor, methylene blue (MB, CAS 61-73-4), on nipradilol-induced aortic relaxation were investigated and compared with those on nitroglycerin-induced aortic relaxation in isolated rat aortic rings. Relaxation response was expressed as percent relaxation, which is a percentage of the tension developed by 10(-7) mol/l norepinephrine. Nitroglycerin and nipradilol similarly relaxed the aortic ring in a concentration-dependent manner (10(-9)-10(-4) mol/l). In contrast, desnitronipradilol, a nipradilol analogue which has no nitroxy group, induced almost no aortic relaxation. TEA at 10(-3) mol/l, which is selective for calcium-activated potassium channels, inhibited the aortic relaxation induced by nipradilol (10(-5) mol/l) to a significantly greater extent than that induced by nitroglycerin (10(-5) mol/l) (% relaxation: 30.0 +/- 6.8 vs. 51.1 +/- 6.1%, p < 0.05). MB (10(-5) mol/l) suppressed the relaxation by nitroglycerin slightly but not significantly more than that by nipradilol. (% relaxation: 54.7 +/- 9.9 vs. 64.6 +/- 5.7%). The combination of TEA and MB almost completely eliminated the relaxation induced by nipradilol as well as by nitroglycerin. Thus, cyclic GMP-independent calcium activated potassium channels may be more involved in the aortic relaxation by nipradilol than that by nitroglycerin in rats.

Nitroglycerin-mediated vasorelaxation is chiefly attributed to the cyclic guanosine monophosphate (cGMP)-dependent pathway, and partly to the cGMP-independent pathway via calcium-activated K(+) channels (K(Ca)). To investigate whether chronic hypertension alters responses of vascular smooth muscle to vasoactive agonists, we determined nitroglycerin-mediated relaxation of aortic rings from coarctation hypertensive rats. Banding the abdominal aorta above the renal arteries for 4 weeks elevated blood pressure and caused cardiac hypertrophy by 49%. In response to nitroglycerin, the relaxation of aortic rings precontracted with 10(-7) M norepinephrine was lower in the banded group than in the sham-operated group. Methylene blue, a guanylate cyclase inhibitor, suppressed a greater part of nitroglycerin-mediated relaxation and reached similar levels of relaxation in the two groups. Charybdotoxin, a specific K(Ca) channel blocker, also suppressed the relaxation by about 40% in the aortic rings from sham-operated animals, but not in those from the banded group. The response to charybdotoxin was markedly diminished or virtually eliminated in the banded group in the presence or absence of methylene blue. The combination of charybdotoxin and methylene blue nearly abolished nitroglycerin-mediated relaxation in the sham-operated group, whereas nitroglycerin-mediated relaxation was seen to remain in the banded group. These results indicate that the involvement of cGMP-independent K(Ca) channels in nitroglycerin-mediated relaxation disappeared after the development of hypertension produced by aortic coarctation.

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