Inhibition of Aerobic Exercise on Enhanced Functional Coupling of RyR-BK_Ca Channel in Hypertension Cerebral Arterial Smooth Muscle Cells

Objective:The purpose of this study was to investigate the effects of aerobic exercise on the functional coupling of RyR-BK_Cachannel in cerebral arterial smooth muscle cells from spontaneously hypertensive rats.Methods:12-week-old male SHR and WKY rats were randomly assigned to sedentary groups (SHR-SED, WKY-SED) and exercise training groups (SHR-EX, WKY-EX) .Exercise groups were performed an 8-week moderate-intensity treadmill running.After 8weeks, cerebral arterial smooth muscle cells were enzymatically isolated.Spontaneous transient outward currents (STOC) and BK_Casingle channel currents were measured using whole-cell and inside-out patch, respectively.Cytosolic Ca2+response was acquired using Ca2+image;Immunofluorescence was performed to study the expression of BK_Cachannelαandβ₁ protein.Results:1) After 8 weeks of exercise, SBP in both WKY-EX and SHR-EX were significantly lower than that of their sedentary counterparts.2) The amplitude of STOC in SHR-SED was significantly higher than that in WKY-SED;After exercise, it was significantly lower in the SHR-EX than in SHR-SED;There was no significant difference of the frequency among four groups.3) The Po of BK_Cachannels from SHR-SED was larger than that of WKY-SED;The Po in SHR-EX became lower than in SHR-SED;in normotensive rats, the Po after exercise training (WKY-EX) was significantly higher than WKY-SED.4) Tamoxifen evoked a 3.4-fold and 8.9-fold increase in the Po of BK_Cachannels in WKY-SED and SHRSED patches, respectively;In WKY-EX, tamoxifen-evoked Po was significantly higher than in WKY-SED ones;However, in hypertensive rats, exercise training inhibited tamoxifen-evoked effects.5) The RyR agonist caffeine activated STOC effectively;Caffeine could lead to the release of SR Ca2+store, inducing cytosolic Ca2+transients, rapid application of caffeine evoked similar Ca2+transients in four groups.6) BK_Cachannelαandβ₁subunits were plasma membrane-localized in arterial myocytes, besides a large fraction ofβ₁subunits were intracellular;The expression ofαsubunits was similar in four groups;Compared with WKY-SED, β₁expression was significantly increased in WKY-EX and SHR-SED, exercise training markedly inhibited the upregulation ofβ₁subunits in SHR-EX.Conclusions:These data indicate that hypertension leads to enhanced functional coupling of RyR-BK_Cato buffer pressure-induced constriction of cerebral arteries, which attributes to an upregulation of BK_Caβ₁subunit function.Regular aerobic exercise efficiently prevents the augmented functional coupling of RyR-BK_Cain hypertension, so alleviates the pathological compensation and restores cerebral arterial function.