Arterial smooth muscle from hypertensive rats shows an increased membrane permeability to K+ that depends on Ca2+ influx. To define the mechanism of this membrane alteration, we tested the hypothesis that Ca(2+)-dependent K+ current (IK(Ca)) is increased in arterial muscle membranes from genetically hypertensive rats. Single-channel K+ currents measured in cell-attached and inside-out aortic membrane patches from spontaneously hypertensive rats (SHR) were compared with those from normotensive Wistar-Kyoto rats (WKY). Inside-out patches from both rat strains showed a predominant 225 pS, Ca(2+)- and voltage-dependent K+ channel in symmetrical 145 mM KCl solutions, which was blocked by tetraethylammonium [concentration for half-maximal block (IC50)< or = 0.3 mM]. In cell-attached patches of aortic muscle cells bathed in physiological salt solution, this channel [IK(Ca) channel] showed a fivefold higher open-state probability (NPo) in SHR as compared with WKY. This increased NPo of SHR IK(Ca) channels in membranes of intact aortic muscle cells was not correlated with an altered membrane potential in current-clamped SHR myocytes or with changes in cytosolic free Ca2+ concentration in fura-2-loaded aortic muscle cells. However, inside-out aortic membrane patches from SHR showed more detected IK(Ca) channels per patch, a higher IK(Ca) channel NPo, and a greater total patch current than their WKY counterparts. Further analysis revealed a greater Ca2+ sensitivity of SHR than WKY IK(Ca) channels. These results suggest that IK(Ca) channel function is altered in isolated membrane patches of arterial muscle from genetically hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

This study was designed to investigate the role and regulation of arterial membrane K + channels in hypertension. Aortic segments from normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were suspended for isometric tension recording. In other experiments, proximal aortic segments (PS) (exposed to high pressure) and distal aortic segments (DS) (exposed to lower pressure) were removed from surgically coarcted Sprague-Dawiey rats and similarly prepared. Aortas from SHR and PS dose-dependently contracted to the K + channel blocker tetraethylammonium (TEA) (0.1-10 mM), and this contraction was abolished by preincubation with 0.1 jtM nifedipine. In contrast, the same concentrations of TEA did not contract either WKY or DS aortas. Since block of K + channels by TEA had a different effect on aortic segments exposed to high versus low blood pressure, we compared whole-cell K + currents in isolated vascular cells from the same aortas. The reversal potentials of depolarizationinduced outward currents in WKY, SHR, DS, and PS aortic cells showed a Nernst relation to external K + concentration indicative of selective K + permeability. TEA (1 and 10 mM) was equipotent in blocking these K + currents in patch-clamped cells from all aortic preparations, suggesting that the lack of TEA-induced contractions in WKY and DS aortas was not due to an absence of TEA-sensitive K + channels in these arterial membranes. However, when the Ca 2+ ionophore A23187 (10 /iM) was used to increase the level of cytosolic Ca 2+ in patch-clamped cells, the K + current density in SHR and PS aortic cells was twofold or more higher than in WKY and DS cells. These data suggest that a Ca 2+ -activated, TEA-sensitive K + current is enhanced in aortic muscle cells exposed to high blood pressure. In the intact blood vessel, this may act as a compensatory mechanism to modulate the level of arterial contraction in hypertension. hypothesis that an increased K + permeability regulates arterial reactivity in genetic and experimental rat models of hypertension. In addition, patch-clamp experiments were performed to investigate the ionic channels and cellular mechanisms mediating the enhanced efflux. Our results suggest that a tetraethylammonium chloride (TEA)-sensitive, Ca 2+ -dependent K + current is increased in aortic muscle membranes from hypertensive rats. This K + current appears to be an important modulator of arterial contraction in arteries previously exposed to high blood pressure.Methods Adult (12-16 weeks) Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were obtained from Taconic Farms, Germantown, N.Y. On experimental days, blood pressure was measured by femoral catheterization during pentobarbital anesthesia (45 mg/kg i.p.). Mean arterial pressures (MAP) in WKY and SHR were 98±3 mm Hg and 140±5 mm Hg, respectively. In other experiments, Sprague-Dawiey rats (10 weeks) obtained from Sasco, Madison, Wis., were anesthetized with telazol (40 mg/kg i.m.), and the aorta was partially ligated between the renal art...

No abstract

No abstract

No abstract