ANGIOTENSINS PROSTAGLANDINS-ADRENERGIC INTERACTIONS

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We propose to investigate the mechanism by which adrenergic neurotransmitter, norepinephrine and angiotensin II (AII) stimulate prostaglandin (PG) synthesis and PGs influence adrenergic neuroeffector events and the metabolic actions (lipolysis) of catecholamines in the cardiovascular system. We will address the following topics: 1. characterization of the type of adrenergic receptor(s) involved in the action of catecholamines on PG synthesis in selected cardiac (ventricular myocytes and coronary microvascular endothelial) and renal (glomerular messangial and renomedullary interstitial) cells. 2. Contribution of cAMP and protein kinase C activation to the action of catecholamines on PG synthesis in intact heart and kidney and in cell cultures, utilizing selective activators and inhibitors of these second messenger systems. 3. Determination of the source of arachidonic acid (AA) for PG synthesis released from tissue lipids in response to neurohormonal stimuli. Tissue lipids will be individually labeled with various classes of radioactive phospholipids and triglycerides and generation of radiolabeled products, including PGs, in response to neurohormonal stimuli will be followed. 4. Modulation by PGs of the lipolytic action of catecholamines in the heart will be assessed by determining the effect of exogenous PGs, AA, and inhibitors of PG synthesis. Finally, we will investigate the mechanism by which products of AA influence release of the adrenergic neurotransmitter as well as the postjunctional actions of norepinephrine. We will utilize RIAs for individual PGs and TLC and HPLC and liquid scintillation counting for determination of products of labeled glycerolipid and catecholamine metabolism. These studies will further our understanding of the mechanisms of neurohormonal interactions in the regulation of cardiovascular function in health and disease.