Exercise Prevents Upregulation of RyRs–BK Ca Coupling in Cerebral Arterial Smooth Muscle Cells From Spontaneously Hypertensive Rats

Abstract

Objective— Regular exercise is an effective nonpharmacological means of preventing and controlling hypertension. However, the molecular mechanisms underlying its effects remain undetermined. The hypothesis that hypertension increases the functional coupling of large-conductance Ca 2+ -activated K + (BK Ca ) channels with ryanodine receptors in spontaneously hypertensive rats (SHR) as a compensatory response to an increase in intracellular Ca 2+ concentration in cerebral artery smooth muscle cells was assessed here. It was further hypothesized that exercise training would prevent this increase in functional coupling. Approach and Results— SHR and Wistar–Kyoto (WKY) rats were randomly assigned to sedentary groups (SHR-SED and WKY-SED) and exercise training groups (SHR-EX and WKY-EX). Cerebral artery smooth muscle cells displayed spontaneous transient outward currents at membrane potentials more positive than −40 mV. The amplitude of spontaneous transient outward currents together with the spontaneous Ca 2+ sparks in isolated cerebral artery smooth muscle cells was significantly higher in SHR-SED than in WKY-SED. Moreover, hypertension displayed increased whole-cell BK Ca , voltage-gated Ca 2+ channel, but decreased K V currents in cerebral artery smooth muscle cells. In SHRs, the activity of the single BK Ca channel increased markedly, and the protein expression of BK Ca (β1, but not α-subunit) also increased, but K V 1.2 decreased significantly. Exercise training ameliorated all of these functional and molecular alterations in hypertensive rats. Conclusions— These data indicate that hypertension leads to enhanced functional coupling of ryanodine receptors–BK Ca to buffer pressure–induced constriction of cerebral arteries, which attributes not only to an upregulation of BK Ca β1-subunit function but also to an increase of Ca 2+ release from ryanodine receptors. However, regular aerobic exercise efficiently prevents augmented coupling and so alleviates the pathological compensation and restores cerebral arterial function.