The renin-angiotensin-aldosterone and prostaglandin (PG) systems normally participate in the homeostatic regulation of electrolyte and acid-base composition, extracellular fluid volume and blood pressure. We are studying abnormalities of these hormonal systems in disorders of electrolyte and acid-base metabolism, and hypertension in human beings. The possibility that conversion of prorenin to active renin may be impaired and may contribute to abnormalities in mineralocorticoid production in patients with diabetes mellitus is being investigated using direct radioimmunoassay techniques developed in collaboration with investigators in Paris. The response to stimuli such as isoproterenol and captopril and to suppression with saline and des-Asp1-angiotensin II (angiotensin III) will be compared in such patients and appropriate controls. Using measurements of the urinary excretion of prostaglandins (PGs) and the response of active and inactive renin to infusions of PGE1, we will test the hypothesis that reduction in renal PG synthesis causes impaired activation of renin in such individuals. We will also evaluate the response of active and inactive renin to insulin therapy of sufficient rigor to correct hyperglycemia and the defects of insulin action characteristic of diabetic patients. To test the hypothesis that hypoaldosteronism can result from prolonged diminution in the trophic influence normally provided by angiotensin, we will determine whether aldosterone secretion in patients with hyporeninemic hypoaldosteronism can be stimulated by prolonged infusions of angiotensin III. We are also studying the relationship between the major intracellular cations, K+ and Mg++, and the renin-angiotensin-aldosterone system in humans. In previous studies we discovered that dietary K+ restriction suppressed plasma renin activity and stimulated renal reabsorption of Cl- in humans. In this proposal we will determine whether dietary K+ loading has the opposite effect on renin secretion and will test the hypothesis that alterations in renal PG synthesis may mediate the K+-induced changes in renin secretion. The role of the renin-angiotensin-aldosterone and renal PG systems in the renal K+ wasting associated with Mg++ depletion is being investigated in patients with renal Mg++ wasting and in experimentally-induced Mg++ depletion in normal subjects.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL011046-24
Application #
3334410
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1977-01-01
Project End
1992-03-31
Budget Start
1990-01-01
Budget End
1992-03-31
Support Year
24
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Giacchetti, G; Sechi, L A; Griffin, C A et al. (2000) The tissue renin-angiotensin system in rats with fructose-induced hypertension: overexpression of type 1 angiotensin II receptor in adipose tissue. J Hypertens 18:695-702
Engler, M M; Schambelan, M; Engler, M B et al. (1998) Effects of dietary gamma-linolenic acid on blood pressure and adrenal angiotensin receptors in hypertensive rats. Proc Soc Exp Biol Med 218:234-7
Sechi, L A; Ceriello, A; Griffin, C A et al. (1997) Renal antioxidant enzyme mRNA levels are increased in rats with experimental diabetes mellitus. Diabetologia 40:23-9
Griffin, C A; Giacchetti, G; Schambelan, M et al. (1997) Ontogenic expression of renal and hepatic angiotensin II receptor genes in the rat. Nephron 76:103-10
Sechi, L A; Griffin, C A; Zingaro, L et al. (1997) Effects of angiotensin II on insulin receptor binding and mRNA levels in normal and diabetic rats. Diabetologia 40:770-7
Valentin, J P; Sechi, L A; Griffin, C A et al. (1997) The renin-angiotensin system and compensatory renal hypertrophy in the rat. Am J Hypertens 10:397-402
Sechi, L A; Griffin, C A; Giacchetti, G et al. (1996) Tissue-specific regulation of type 1 angiotensin II receptor mRNA levels in the rat. Hypertension 28:403-8
Sechi, L A; Griffin, C A; Giacchetti, G et al. (1996) Abnormalities of insulin receptors in spontaneously hypertensive rats. Hypertension 27:955-61
Sechi, L A; Valentin, J P; Griffin, C A et al. (1995) Receptors for atrial natriuretic peptide are decreased in the kidney of rats with streptozotocin-induced diabetes mellitus. J Clin Invest 95:2451-7
Schambelan, M (1994) Licorice ingestion and blood pressure regulating hormones. Steroids 59:127-30

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