This application focuses upon the role played by small arteries in the pathogensis of hypertension, and more specifically, how the renin-angiotensin and adrenergic nervous systems affect these small arteries. Two projects are planned. The first will explore mechanisms that may be responsible for the occurrence of focal constrictions in small arteries during severe hypertension. The phenomenon of focal vasoconstriction is of importance not only because the constrictions contribute to the production of hypertension (by increasing vascular resistance) but also because the nonconstricted segments of the arteries become susceptible to hypertension-induced damage. Since the mechanisms responsible for focal constriction are largely unknown, the aim of the proposed experiments is to examine two possible explanations: first, that angiotensin in II and/or adrenergic receptors are unevenly distributed along the length of small arteries, with a greater density of receptors in constricted segements; second, that adrenergic nerve terminals are more densely aggregated in constricted regions. To label and quantitate both vascular receptors and adrenergic nerves, and in vitro autoradiography method will be employed. In the second project, the aim is to investigate the role of the vascular (intramural) renin-angiotensin system (RAS) in small arteries in different forms of hypertension. Recent research suggests that some forms of hypertension may be maintained by a RAS in blood vessel walls. This is a concept which may lead to a clearer understanding of the pathogenesis of some forms of hypertention, and may also suggest new approaches to treatment (i.e., attempting to block the RAS specifically within vessel walls.) However, most of the evidence for a vascular RAS has been obtained from studies of large arteries, and little is known about this system in the walls of smaller vessels. Therefore the experiments outlined in this proposal use small arteries to study the vascular RAS in models of hypertension with high, normal, and low levels of plasma renin activity. One set of experiments will quantitate intramural renin in the different models of hypertension using a protein A-gold immunolabeling technique. In a second set intramural binding of (H3)-captopril will be compared in the various hypertensive models by using in vitro autoradiography; the intent is to investigate the idea that the antihypertensive effects of captopril be attributed (at least in part) to inhibition of the intramural RAS in small arteries.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Unknown (R23)
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Experimental Cardiovascular Sciences Study Section (ECS)
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Johns Hopkins University
Schools of Medicine
United States
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