Hypertension: Contribution of Arterial Wall Changes

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DESCRIPTION (provided by applicant): Voltage-gated K+ (Kv) currents in native vascular smooth muscle cells (VSMC) are inhibited by an increase in cytosolic free Ca2+, secondary to intracellular Ca 2+ release or extracellular Ca2+ influx. This inhibitory effect is enhanced in VSMCs from resistance versus conduit arteries and from hypertensive compared to normotensive rats. Thus, Ca2+-mediated inhibition of Kv currents may contribute to the regulation of tone in small arteries and to the pathogenesis of hypertensive disease. In our previous studies to identify the molecular mechanisms responsible for this effect, we found that 1) Kv1.2 and Kv1.5 are the dominant Shaker channels in rat small mesenteric arteries (SMA) and expression of these proteins is higher in hypertensive arteries; 2) intracellular Ca2+ inhibits Kv1.2, Kv1.5 and Kv1.2-1.5 heteromeric channels expressed in Xenopus laevis oocytes and in CHO cells; 3) this Ca2+ inhibition is enhanced by added calmodulin (CaM) but is not affected by staruosporine, an inhibitor of protein kinases A, G and C; and 4) more than one mechanism may be involved in Ca2+-mediated Kv inhibition. Our data also suggest that Kv1.2 and Kv1.5 are coassembled in a heterotetramic structure to form functional Kv1.2-1.5 channels, and that the properties of Kv1.2 and Kv1.5 alone are not sufficient to represent those of Kv currents in rat SMA VSMCs. Based on these findings, this renewal application will test the hypotheses that 1) multiple Kv channel assemblies (alpha and beta subunits) contribute to Kv current and to contractile function in SMA; 2) only Shaker Kv1 channels are inhibited by Ca2+; 3) Ca2+ inhibition of Kv channels is mediated by multiple mechanisms involving CaM; and 4) these processes are enhanced in VSMC from hypertensive animals. These hypotheses will be tested using SMA from normal (WKY) and hypertensive (SHR) animals. We suggest that this process couples changes in intracellular Ca2+ to changes in membrane potential and voltage-gated Ca2+ channel activity thereby contributing to the regulation of arterial force maintenance and vascular resistance. The differential "expression" of this effect in VSMCs from SHR versus WKY will aid in confirming candidate mechanisms. These studies will define a novel therapeutic target for antihypertensive drug development based upon the mechanism(s) of Ca2+-Kv channel modulation.