Effect of hypercholesterolemia on Ca2+-dependent K+ channel-mediated vasodilatation in vivo

Abstract

Nitric oxide (NO)-mediated and NO-independent mechanisms of endothelium-dependent vasodilatation involve Ca2+-dependent K+ (KCa) channels. We examined the role in vivo of KCa channels in NO-independent vasodilatation in hypercholesterolemia. Hindlimb vascular conductance was measured at rest and after aortic injection of ACh, bradykinin (BK), and sodium nitroprusside in anesthetized control and cholesterol-fed rabbits. Conductances were measured before and after treatment with the NO synthase antagonist N ω-nitro-l-arginine methyl ester (l-NAME, 10 mg/kg) or KCa blockers tetraethylammonium (30 mg/kg), charybdotoxin (10 μg/kg), and apamin (50 μg/kg). The contribution of NO to basal conductance was greater in control than in cholesterol-fed rabbits [2.2 ± 0.4 vs. 1.1 ± 0.3 (SE) ml · min−1 · kg−1 · 100 mmHg−1, P < 0.05], but the NO-independent KCa channel-mediated component was greater in the cholesterol-fed than in the control group (1.1 + 0.4 vs. 0.3 ± 0.1 ml · min−1 · kg−1 · 100 mmHg−1, P < 0.05). Maximum conductance response to ACh and BK was less in cholesterol-fed than in control rabbits, and the difference persisted after l-NAME (ACh: 7.7 ± 0.7 vs. 10.1 ± 0.5 ml · min−1 · kg−1 · 100 mmHg−1, P < 0.005). Blockade of KCa channels with tetraethylammonium or charybdotoxin + apamin almost completely abolished l-NAME-resistant vasodilatation after ACh or BK. The magnitude of KCa-mediated vasodilatation after ACh or BK was impaired in hypercholesterolemic rabbits. Vasodilator responses to nitroprusside did not differ between groups. In vivo , hypercholesterolemia is associated with an altered balance between NO-mediated and NO-independent KCa channel contributions to resting vasomotor tone and impairment of both mechanisms of endothelium-dependent vasodilatation.