Enhanced phenylephrine‐induced rhythmic activity in the atherosclerotic mouse aorta via an increase in opening of KCa channels: relation to Kv channels and nitric oxide

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Abstract
Mice lacking the apolipoprotein E and low density lipoprotein receptor genes (E°×LDLR°) develop atherosclerosis. The aim of this study was to investigate changes in endothelium‐dependent vasodilation and vasomotion in thoracic aortic rings of E°×LDLR° mice. K+‐induced contractions of the aorta from E°×LDLR° mice were stronger than those from control mice. The sensitivity of E°×LDLR° aorta to phenylephrine (PE) was decreased but the maximal contractions were increased. Acetylcholine‐induced, but not sodium nitroprusside‐induced, relaxations of E°×LDLR° aorta was decreased. PE induced rhythmic activity in both E°×LDLR° and control aorta but the amplitude was larger in E°×LDLR° than in control mice. PE‐induced rhythmic activity in both E°×LDLR° and control aorta was augmented by increase in extracellular Ca2+‐concentration, but was abolished by removal of the endothelium, the nitric oxide (NO) synthase inhibitor N‐nitro‐L‐arginine methyl ester, the guanylate cyclase inhibitor LY‐83583, high K+ solution and ryanodine. 4‐Aminopyridine, a voltage‐dependent potassium (KV) channel blocker, increased basal tension and induced rhythmic activity in E°×LDLR° aorta but not in control aorta. The Ca2+‐activated potassium (KCa) channel blockers tetraethylammonium and charybdotoxin abolished PE‐induced rhythmic activity in E°×LDLR° aorta. In conclusion, opening of Kv channels in E°×LDLR° mice aorta is reduced and it is susceptible to be depolarized resulting in Ca2+ entry. The vascular smooth muscle is then dependent on compensatory mechanisms to limit Ca2+‐entry. Such mechanisms may be decreased sensitivity to vasoconstrictors, or increased opening of KCa channels by NO via a cyclic GMP‐dependent mechanism. British Journal of Pharmacology (1999) 128, 637–646; doi:10.1038/sj.bjp.0702855