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

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 Ca 2+ ‐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 (K V ) channel blocker, increased basal tension and induced rhythmic activity in E°×LDLR° aorta but not in control aorta. The Ca 2+ ‐activated potassium (K Ca ) channel blockers tetraethylammonium and charybdotoxin abolished PE‐induced rhythmic activity in E°×LDLR° aorta. In conclusion, opening of K v channels in E°×LDLR° mice aorta is reduced and it is susceptible to be depolarized resulting in Ca 2+ entry. The vascular smooth muscle is then dependent on compensatory mechanisms to limit Ca 2+ ‐entry. Such mechanisms may be decreased sensitivity to vasoconstrictors, or increased opening of K Ca channels by NO via a cyclic GMP‐dependent mechanism.British Journal of Pharmacology (1999) 128 , 637–646; doi: 10.1038/sj.bjp.0702855