Abstract 043: Influence of Sex, Hormones and Age on Cerebrovascular Function: Role of Large Conductance Potassium Channel Subunits

Abstract

Although adult females are protected, the cerebrovascular disease is greater in aged post-menopause females than in age matched males, but the role of vascular function and large conductance potassium (BK) channel is not clear. We hypothesize that “compared to adult males, cerebral vasculature of intact adult female rats displays an attenuated myogenic response and greater intrinsic tone due to differential expression and function of BK channel subunits. Aging or menopause exaggerates myogenic response, diminishes intrinsic tone and thus, vasodilatory capacity in females more than males due to a reduction in the BK subunit function.” Our results suggest that middle cerebral arteries (MCA) of intact adult females had attenuated myogenic response compared to adult males and ovariectomy (OVX) females (% change in diameter: 16±8, -25±4 and -49±7). Development of intrinsic tone was greater in intact adult females than adult males and OVX females (% intrinsic tone: 47±5, 27±4 and 15±5). The ratio of BK β1 to α subunits was less in intact adult females than adult males and OVX females (0.4±0.07, 2±0.3 and 0.6±0.1). Spontaneous transient outward currents (STOC) were higher in smooth muscle cells of intact adult females compared to adult males (pA: 204±27 and 128±7). While aging exaggerated the myogenic response in females, it had no effect in males (fold change 4±1 Vs 0.8±0.5). However, intrinsic tone was decreased in aged females but increased in aged males (% change -43±9 Vs 37± 6). Aging decreased the amplitude of STOCs but with a greater magnitude of effect in females (fold change females: -4.9±1; males: -0.8±0.2). While aging increased BKα subunit, it decreased β1 subunit protein (β1 change: females -52±8; males -37±13). Acute activation of BKα subunit by NS1619, while had no effect in intact adult females (-5±3%), it dilated the MCA of adult males (32±9%). However, acute activation of BKβ1 by estradiol while relaxed MCA of adult females (35±7%) and males (22±2%), it had less effect in OVX females (-7±8%) and aged females (4±9%). In conclusion, a higher incidence of cerebrovascular disease in aged and menopause female may be due to sex-specific changes in vascular properties and BK channels that could result in diminished estradiol-mediated vasodilation.