Vasodilator therapy has been used successfully in patients with congestive heart failure to counteract inappropriate and excessive vasoconstriction. An augmented sympathoadrenal discharge (especially during exercise), increased circulating vasoactive hormones, and local factors producing a vascular stiffness, all may result in diminished regional blood flow, however the pattern of vasoconstriction depends on the mechanisms producing the heart failure, the species studied, and the point during the course of the disease at which the subject is studied. The first of these mechansims is the subject of this project which proposes to study sympathetic nerve function in two rat models of chronic congestive heart failure, aortocaval fistula and myocardial infarction (produced by coronary ligation). The principal investigator has preliminary evidence to suggest that vascular sympathetic nerves more readily release morepinephrine at lower electrical stimulation frequencies, however, at higher frequencies nerve function fails. Diminished presynaptic alpha2 receptor function may explain the former and failure of nerve conduction, the latter observation. In this project, three groups of studies are proposed, 1). The evaluation of evoked overflow of 3H norepinephrine in four vascular preparations preincubated with the labeled neurotransmitter (superfused pulmonary artery, helical strip of tail artery, and a longitudinal strip of bilateral renal arteries with connecting aorta, and the perfused mesenteric artery), during field electrical stimulation, localized perivascular electrical stimulation, and pharmacological stimulation. Inhibitory and facilatory presynaptic receptor function will be studied in this preparation using yohimbine, clonidine, adenosine, and angiotensin. 2). It will be determined if there is a generalized abnormality of presynaptic receptor function by the evaluation of norepinephrine release rate during steady state infusion of 3H norepinephrine during concomitatnt presynaptic receptor agonist and antagonist administration. 3). Norepinephrine inactivation mechanisms will be evaluated in isolated vessels with intact neuroeffector mechanisms. It is hoped that the work proposed in this project may define better the best point at which to interact with the sympathetic neuroeffector apparatus to remedy the excessive sympathetically mediated vasoconstriction which is such a prominent characteristic of advanced heart failure.
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