CARDIAC AND VASCULAR FUNCTIONAL RESPONSES TO β2-ADRENERGIC RECEPTOR STIMULATION: EFFECTS OF SEX, AGE AND HEART FAILURE

Abstract

Proper cardiovascular function is necessary to regulate the flow of blood to different partsof the body in response to demand. The ability of the heart to increase the amount of blood pumped and the precise control of blood flow to the skeletal muscle are of critical importance during movement – whether during exercise or while performing activities of daily living. This dissertation aims to assess the functional responses of the cardiac and vascular systems to β2- adrenergic receptor stimulation and identify factors influencing their responsiveness. Utilizing rat models of aging and heart failure, we investigated how sex, age, and heart failure impact the cardiac and vasculature responses to β-adrenergic receptor stimulation. In the first Aim, we explored the influence of the presence of estrogen on heart rate, coronary flow rate, and oxygen consumption rate when stimulated with a β2-adrenergic receptor agonist in perfused hearts from young and old, male and female rats. The presence of estrogen rescued the blunted heart rate response to β2-adrenergic receptor stimulation seen in young female compared to young male hearts. Old male and female hearts showed blunted heart rate responses compared to their young sex-matched controls; however, old males and females were similar in their responsiveness to β- adrenergic stimulation. In the second Aim, we evaluated the effects of a rat model of pressureoverload induced heart failure on cardiac responsiveness to β2-adrenergic stimulation in male and female hearts, again in the absence and presence of estrogen. Failing male and female hearts had similar heart rate responses to their sham counterparts. Comparing to the sham control female heart, heart failure female hearts show an impaired coronary flow rate increase in response to β- adrenergic stimulation with presence of estrogen, despite similar increases in heart rate. Aim 3 focused on measuring vascular responsiveness of an isolated muscular artery to β-adrenergic and estrogen receptor stimulation in young and middle-aged, male and female rats. Female rats demonstrated augmented vasodilation responses to β-adrenergic receptor stimulation compared to males, and estrogen enhances artery vasodilation response to β-adrenergic receptor stimulation in young female rats. The primary goal was to investigate how the acute presence of estrogen affected cardiovascular regulation in young and old, male and female rats. Conducting experiments in young and old, male and female, heart failure and healthy rats uncovers how the acute presence of estrogen affects β-adrenergic receptor stimulation responsiveness in the ventricular myocardium and muscular artery vasculature. Our findings reveal sex differences in cardiac and vascular responses to β-adrenergic receptor stimulation, highlighting the influence of sex hormones, particularly estrogen in the regulation of the cardiovascular system. We propose these are due, at least in part, to the membrane estrogen receptor, GPR30, and its downstream signaling pathway. These insights contribute to a better understanding of estrogen's role in the acute regulation of cardiac and vascular function, informing future age and sex-specific treatments for cardiovascular diseases.