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Abstract

Troglitazone (tro) and other thiazolidinediones are thought to relax arterial smooth muscle (SM) by directly inhibiting calcium (Ca) channels in SM cell membranes. However, until recently such inhibition was only examined acutely, i.e. within only seconds or minutes after administration of these agents to arterial SM preparations. Recently, a novel experiment was reported in which tro caused a two-phase relaxation of perfused resistance arteries, viz. an acute relaxation phase (within the first 20 minutes of treatment) which was dependent on intact receptor-operated Ca channels and a delayed relaxation phase (after 2 hours) which was not (J Hyper 18: suppl 4, S31, 2000). Both phases were endothelium-independent. We sought to determine if any of the 4 major potassium (K) channels in vascular SM play a role in the delayed relaxation phase. We incubated vascular contractile rings, prepared from ventral tail arteries of rats, with physiological buffer containing 0, 2, 4 and 8 μM tro (typical of plasma levels from diabetic patients) for 3-4 hours. Different K channel inhibitors (1 mM 4AP, 1 mM TEA, 5 μM glyburide, 20 μM barium) were co-administered with each level of tro in additional preparations. Then these arterial rings were contracted with graded levels of either norepinephrine (NE) or arginine vasopressin (AVP). Both maximal and submaximal NE and AVP contractions were notably relaxed by tro. At maximal NE, the relaxation was 22±5% at 2μM tro, 40±4% at 4 μM tro and 66±2% at 8 μM tro (p<0.05; 16 rings each). Results were nearly identical for AVP. 4AP and TEA attenuated these relaxant effects (p<0.05), each by approximately one-third. Glyburide and barium had no influence. Removal of the endothelium had no influence. Thus, therapeutically-relevant (long-term) arterial vasorelaxation by tro may be mediated in part by activation of 4AP-sensitive (voltage-operated) and TEA-sensitive (Ca-activated) K channels in arterial SM cell membranes. Whether 4AP-sensitive K channels in the sarcoplasmic reticulum are involved is currently under study.

Troglitazone, Potassium Channels, Vascular Smooth Muscle
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© American Journal of Hypertension, Ltd. 2001
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