The development of hypertension is sexually dimorphic. Blood pressure rises more quickly and to a greater extent in males. While considerable research attention has been directed toward the arterial circulation, there has been relatively little investigation of venous changes in hypertension. Our previous work indicated that venous tone was elevated by neural mechanisms in the developmental stages of hypertension in the spontaneously hypertensive rat, an animal model of that resembles essential hypertension in humans. Recent data suggest that veins and arteries are affected differently by hypertension. Thus, this project will test the general hypothesis that androgens amplify adrenergic tone of the arterial and venous vascular compartments via different mechanisms.
Specific aim I will address the possibility that this effect occurs at the level of vascular smooth muscle.
Specific aim II will assess the role of changes in norepinephrine release mechanisms.
Specific aim III will investigate the effects of androgens on CNS mechanisms controlling sympathetic nervous system outflow from the hypothalamus. Functional studies will be conducted in vivo and in isolated perfused vascular beds. Androgen induced changes in protein and gene expression will be assessed with Western blot and real time RT-PCR approaches. Collectively we expect these studies to show that androgens amplify adrenergic tone in veins and arteries but that the underlying mechanisms are different in these two vascular compartments. These data will expand our understanding of sex steroid modulation of vascular function and of hypertension development. Hypertension is a significant public health problem that is a risk factor for many other cardiovascular diseases. In addition, in patients hypertension is poorly controlled. Moreover, postural hypotension is common adverse effect of antihypertensive therapy, implying dysregulation of venous function. A better understanding the factors that control arterial and venous tone in hypertension may lead to design antihypertensive drugs with fewer adverse effects
Cardiovascular disease is the leading cause of death for both men and women in the U.S. Essential hypertension afflicts 20-30% of the U.S. population and is a major risk factor for other diseases such as myocardial infarction, heart failure, kidney disease and stroke. Thus hypertension contributes significantly to morbidity and mortality in the U.S.. Moreover, since the cause(s) of essential hypertension are poorly understood, treatment and control of hypertension remain suboptimal. Some estimates suggest that only 30% of hypertensive patients'blood pressures are adequately controlled. This project aims to understand mechanisms that contribute to hypertension development and amplification. Improved understanding of these mechanisms will identify new targets for antihypertensive drug development. New therapies that improve blood pressure control will lead to reduction in the sequelae of hypertension including myocardial infarction, heart failure, kidney disease and stroke, which in turn should ameliorate morbidity and mortality in the U.S. population.
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