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

Abstract

1 Mice lacking the apolipoprotein E and low density lipoprotein receptor genes (E86LDLR8) develop atherosclerosis. The aim of this study was to investigate changes in endothelium-dependent vasodilation and vasomotion in thoracic aortic rings of E86LDLR8 mice. 2 K + -induced contractions of the aorta from E86LDLR8 mice were stronger than those from control mice. The sensitivity of E86LDLR8 aorta to phenylephrine (PE) was decreased but the maximal contractions were increased. Acetylcholine-induced, but not sodium nitroprusside-induced, relaxations of E86LDLR8 aorta was decreased. 3 PE induced rhythmic activity in both E86LDLR8 and control aorta but the amplitude was larger in E86LDLR8 than in control mice. PE-induced rhythmic activity in both E86LDLR8 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 4-Aminopyridine, a voltage-dependent potassium (K V ) channel blocker, increased basal tension and induced rhythmic activity in E86LDLR8 aorta but not in control aorta. 5 The Ca 2+ -activated potassium (K Ca ) channel blockers tetraethylammonium and charybdotoxin abolished PE-induced rhythmic activity in E86LDLR8 aorta. 6 In conclusion, opening of K v channels in E86LDLR8 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.

Endothelial dysfunction in atherosclerotic mice: improved relaxation by combined supplementation with L‐arginine‐tetrahydrobiopterin and enhanced vasoconstriction by endothelin

“…The relaxations induced by Ach but not that to the NO donor SNP were signi®cantly reduced in E8xLDLR8 mouse aorta. This ®nding indicates impaired endothelial function in agreement with previous ®ndings in E8xLDLR8 mice (Jiang et al, 1999) as well as in mice de®cient in ApoE only (Barton et al, 1998;Deckert et al, 1999). The unchanged response to SNP demonstrates that the ability of the vascular smooth muscle cells to dilate when stimulated by NO is not a ected in E8xLDLR8 mice.…”

“…The precontractile tone induced by administration of phenylephrine was somewhat higher in the E8xLDLR8 mice than in control mice (415+10 vs 334+7 mg; P50.001) which is in agreement with a previous report (Jiang et al, 1999). Ach and SNP evoked concentration-dependent relaxation of aortic rings from both control mice and E8xLDLR8 mice.…”

“…Endothelium-dependent relaxations were determined by application of acetylcholine (Ach; 0.01 ± 10 mM) to precontracted vessels. The relaxations induced by Ach in the aorta from E8xLDLR8 and control mice are abolished or greatly reduced following endothelial removal or administration of NO synthase or cyclic GMP inhibitors (Jiang et al, 1999), demonstrating that Ach evokes relaxations via a NO and cyclic GMP-dependent pathway. After a washout period, similar concentration-response curves for sodium nitroprusside (SNP) were created to test endothelium-independent relaxation.…”

Doxorubicin-induced vasomotion and [Ca2+]i elevation in vascular smooth muscle cells from C57BL/6 mice

“…Studies on RC have been undertaken for more than 150 years [10][11][12][13] , after the first report by Jones regarding the veins of bats' wings in 1852 [11] . To date, the mechanism of RC is still not very clear, and plenty of cellular components of the vascular smooth muscle cell have been reported to participate in generating RC; these include RyR and the Ca 2+ -pump of SR, the L-type Ca 2+ channel, the K + channel, Na + , K + -ATPase and the nitric oxide (NO)-cGMP system.…”

Pharmacological Characterization of 1-Nitrosocyclohexyl Acetate, a Long-Acting Nitroxyl Donor That Shows Vasorelaxant and Antiaggregatory Effects

“…*** WT vs WT 1 GSH p,0.001, xxx WT vs ApoE 2/2 1 GSH p,0.001. selective voltage-dependent K 1 channel blocker 4-AP (10 mM, n 5 6) (Jiang et al, 1999) (Fig. 4B).…”