The goal of this research program is to increase understanding of cellular processes that control systemic arterial pressure as a basis to design improvements in therapy. The stragegy is a chemistry-to-medicine approach to study excitation-contraction coupling, excitation-secretion coupling, ion and water transport and the regulation of these and other cell and membrane mechanisms by norepinephrine, arachidonic acid metabolites, kallikrein-kinins, antihypertensive (propranolol) and other drugs (primaquine). These mechanisms and their manipulation by molecular probes are studied in isolated cells, cell fragments and/or isolated membrane vesicle preparations, isolated tissues, intact anesthetized and conscious animals, normal volunteers and patients with hypertension, shock, and other cardiovascular-renal abnormalities. Six projects (Halushka-arachidonic acid metabolites; Margolius-kallikrein-kinins; Lindenmayer-calcium; Webb:Gaffney-neurotransmitters: propranolol; Walle:Gaffney-drug disposition: propranolol; Jollow-drug toxicity) and five core units (Gaffney-administration; Daniel-physiology-pharmacology; Knapp-chemistry; Baron-structure-function and Brubaker-shops) with scientists representing he disciplines of chemistry, anatomy, biochemistry, physiology, pharmacology, pathology, internal medicine, pediatrics and surgery are involved. Facilities and techniques include: gas chromatography-mass spectrometry, nuclear magnetic resonance spectrometry, synthetic organic chemistry, light and electron microscopy with cytochemistry, immunocytochemistry, stereology, scanning and freeze-fracture electron microscopy, cell culture and fractionation facilities, laboratories for studies of isolated tissues and intact animals, a General Clinical Research Center and a Hypertension Clinic with 1,200 patients in follow-up. Quality control is provided by the P.I., Internal and External Research Advisory Committees, individual consultants, weekly research conferences and seminars.
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