Loss of cerebrovascular Shaker-type K+ channels: a shared vasodilator defect of genetic and renal hypertensive rats

1 Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; 2 Department of Physiology, College of Medicine, Sultan Qaboos University, Al-khod, Sultanate of Oman; 3 Department of Neurology, Medical College of Wisconsin and Clement J. Zablocki Department of Veterans Affairs Medical Center, Milwaukee, Wisconsin; and 4 Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas Submitted 11 September 2008 ; accepted in final form 24 April 2009 The cerebral arteries of hypertensive rats are depolarized and highly myogenic, suggesting a loss of K + channels in the vascular smooth muscle cells (VSMCs). The present study evaluated whether the dilator function of the prominent Shaker -type voltage-gated K + (K V 1) channels is attenuated in middle cerebral arteries from two rat models of hypertension. Block of K V 1 channels by correolide (1 µmol/l) or psora-4 (100 nmol/l) reduced the resting diameter of pressurized (80 mmHg) cerebral arteries from normotensive rats by an average of 28 ± 3% or 26 ± 3%, respectively. In contrast, arteries from spontaneously hypertensive rats (SHR) and aortic-banded (Ao-B) rats with chronic hypertension showed enhanced Ca 2+ -dependent tone and failed to significantly constrict to correolide or psora-4, implying a loss of K V 1 channel-mediated vasodilation. Patch-clamp studies in the VSMCs of SHR confirmed that the peak K + current density attributed to K V 1 channels averaged only 5.47 ± 1.03 pA/pF, compared with 9.58 ± 0.82 pA/pF in VSMCs of control Wistar-Kyoto rats. Subsequently, Western blots revealed a 49 ± 7% to 66 ± 7% loss of the pore-forming 1.2 - and 1.5 -subunits that compose K V 1 channels in cerebral arteries of SHR and Ao-B rats compared with control animals. In each case, the deficiency of K V 1 channels was associated with reduced mRNA levels encoding either or both -subunits. Collectively, these findings demonstrate that a deficit of 1.2 - and 1.5 -subunits results in a reduced contribution of K V 1 channels to the resting diameters of cerebral arteries from two rat models of hypertension that originate from different etiologies. potassium channels; vascular smooth muscle; cerebral arteries; hypertension Address for reprint requests and other correspondence: S. W. Rhee, Dept. of Pharmacology and Toxicology, College of Medicine, Univ. of Arkansas for Medical Sciences, 4301 West Markham St., #611, Little Rock,