The secretion of renin is the first step in the renin-angiotensin cascade, which plays both physiological and pathophysiological roles in the regulation of arterial blood pressure and in the regulation of the volumes and compositions of the body fluids. The overall aim is to elucidate the actions and mechanisms of action of first messengers controlling renin secretion, the second messengers which mediate the effects, and how these second messengers interact. Evidence suggests that intracellular free ionic Ca (Cai) and cyclic AMP are inhibitory and stimulatory second messengers, respectively. It is proposed to test four hypotheses: (1) that there is a direct relationship between membrane potential and secretory activity of the renin-secreting juxtaglomerular cells, i.e., that inhibitory first messengers depolarize whereas stimulatory first messengers hyperpolarize; (2) that the """"""""Ca channels"""""""" opened by high perfusion pressure (inhibitory to renin secretion) are pharmacologically-identical to the """"""""Ca channels"""""""" opened by membrane depolarization; (3) that cyclic AMP and Cai are sequentially-acting second messengers, that cyclic AMP stimulates renin secretion by increasing Ca efflux and sequestration, thereby decreasing Cai; (4) that four first messengers (angiotensin II, vasopressin, alpha-adrenergic agonists, A1-adenosine receptor agonists) inhibit renin secretion by increasing Cai, either by (a) inhibiting adenylate cyclase, thereby decreasing Ca efflux and sequestration, or by (b) stimulating phospholipase C, presumably, thereby increasing Ca release from intracellular sequestration sites. A pharmacological approach is proposed. Renal cortical slices and isolated perfused kidneys will be used as the experimental preparations. SIGNIFICANCE: Considering the physiological and pathophysiological roles of the renin-angiotensin- aldosterone axis, understanding the mechanisms controlling renin secretion is of great importance. The results of these experiments will provide new information concerning first and second messengers, and also concerning the mechanisms of action of various substances which are frequently used not only in renin secretory studies, but also in treating cardiovascular diseases (e.g., cardiac glycosides and Ca channel blockers). Finally, elucidation of the role played by Cai in renin secretion has importance with respect to general cellular physiology, since Cai appears to be an inhibitory second messenger in the renin- secreting juxtaglomerular cells, but in nearly every other type of cell, Cai acts as a """"""""trigger,"""""""" or as a stimulatory second messenger.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL024880-11
Application #
3337864
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1988-12-01
Project End
1993-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
11
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Wayne State University
Department
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
Griffin, K A; Bidani, A K; Ouyang, J et al. (1993) Role of endothelium-derived nitric oxide in hemodynamic adaptations after graded renal mass reduction. Am J Physiol 264:R1254-9
Churchill, P; Churchill, M; Bidani, A et al. (1993) Streptozotocin-induced renal hemodynamic changes in isogenic Lewis rats: a kidney transplant study. Am J Physiol 264:F100-5
Jones-Dombi, T; Churchill, P (1993) BAY K 8644 inhibits renin secretion in isolated perfused rat kidneys. Life Sci 53:1531-7
Churchill, P C; Ellis, V R (1993) Pharmacological characterization of the renovascular P2 purinergic receptors. J Pharmacol Exp Ther 265:334-8
Churchill, P C; Ellis, V R (1993) Purinergic P2y receptors stimulate renin secretion by rat renal cortical slices. J Pharmacol Exp Ther 266:160-3
Jones-Dombi, T; Churchill, P (1993) The baroreceptor mechanism for controlling renin secretion: effect of calcium channel blockers. J Pharmacol Exp Ther 266:274-8
O'Leary, D S; Rossi, N F; Churchill, P C (1993) Muscle metaboreflex control of vasopressin and renin release. Am J Physiol 264:H1422-7
Churchill, M C; Churchill, P C; Bidani, A K (1993) The effects of cyclosporine in Lewis rats with native and transplanted kidneys. Transplantation 55:1256-60
Churchill, P C; Ellis, V R (1992) Dantrolene stimulates renin secretion by rat renal cortical slices but fails to block calcium-dependent inhibition. Life Sci 51:853-8
Churchill, P C; Churchill, M C; Bidani, A K (1992) Kidney cross transplants in Dahl salt-sensitive and salt-resistant rats. Am J Physiol 262:H1809-17

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