Renin-angiotensin system: biochemistry and mechanisms of action.

Weekly clinicopathological exercises

A B S T R A C T Acetylation of platelet cyclooxygenase by oral aspirin is dose dependent and cumulative with repeated administration. However, no single dose of aspirin has been found to be completely selective of platelet thromboxane (TX) synthesis inhibition in man. We determined the dose dependence, cumulative nature and selectivity of aspirin effects on platelet TXB2 and renal prostaglandin (PG) and prostacyclin (PGI2) production. We measured, by radioimmunoassay, serum TXB2 levels after whole blood clotting and urinary excretion of PGE2, PGF2a, and 6-keto-PGF,a, before and after single or repeated oral aspirin doses given to 46 healthy subjects. Single doses of 6-100 mg aspirin resulted in a linear (r = 0.92, P < 0.01) inhibition of platelet TXB2 production, ranging from 12 to 95% after 24 h. A daily dose of 0.45 mg/kg given for 7 d produced a cumulative and virtually complete inhibition of platelet TXB2 production, without significantly reducing the urinary excretion of PGE2, PGF2a, and 6-keto-PGF,a in both healthy men and women. The platelet inhibitory effect of this regimen was maintained unaltered throughout 1 mo of therapy, with no evidence of cumulative inhibition of renal PGsynthesis. Moreover, furosemide-induced renal PGI2 synthesis and renin release were unaffected by chronic low-dose aspirin. Following cessation of aspirin therapy, platelet TXB2 production returned toward control values at a similar rate as after a single higher dose. We conclude that in healthy subjects: (a) aspirin causes a dose-dependent inhibition of platelet TXA2 production, with no obvious sex-related difference; (b) the inhibitory effect of daily low-dose aspirin is cumulative on platelet TXA2 but not on renal PG-synthesis; (c) during chronic low-dose aspirin therapy, renal PGI2-producing cells are readily activable by furosemide at a time of virtually complete suppression of platelet cyclooxygenase activity.

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Selective Cumulative Inhibition of Platelet Thromboxane Production by Low-dose Aspirin in Healthy Subjects

Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome.

Recent studies have indicated that acute inhibition of nitric oxide biosynthesis in the rat promotes arterial hypertension and renal vasoconstriction. We evaluated the renal and systemic effects of 4-6 weeks of nitric oxide blockade in Munich-Wistar rats receiving the nitric oxide inhibitor nitro-L-arginine orally. Age-matched untreated rats were used as controls. In an additional seven rats, nitric oxide blockade was carried out in conjunction with oral administration of the novel angiotensin II antagonist losartan potassium. Tail-cuff pressure rose progressively in nitro-L-arginine-treated rats, reaching 164 +/- 6 mm Hg at 4-6 weeks, compared with 108 +/- 3 mm Hg in controls. In rats concomitantly receiving losartan, tail-cuff pressure reached 125 +/- 6 mm Hg, still elevated compared with rats receiving losartan alone (98 +/- 3 mm Hg). Nitro-L-arginine-treated rats presented marked renal vasoconstriction and hypoperfusion, as well as a 30% fall in glomerular filtration rate and a 39% increase in filtration fraction. Treatment with Losartan normalized glomerular filtration rate, but not filtration fraction or renal vascular resistance. Plasma renin activity was elevated after nitro-L-arginine treatment. Renal histological examination revealed widespread arteriolar narrowing, focal arteriolar obliteration, and segmental fibrinoid necrosis in the glomeruli. In a separate group of rats, nitro-L-arginine administered for 1 week induced hypertension that was partially reversed by acute L-arginine, but not D-arginine or L-glycine, infusions. We conclude that chronic nitric oxide blockade may constitute a new model of severe arterial hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension.

A radioimmunoassay for angiotensin I and its application to the determination of renin activity is described. The assay employs antibodies raised to copolymers of angiotensin I and succinylated poly-l-lysine. Angiotensin labeled with 125I and purified by high voltage paper electrophoresis is employed as a tracer. Incubation is carried out in plasma in the presence of 3 metal binding reagents which serve to inhibit effectively proteolytic attack on angiotensin I. Immunoassay of generated angiotensin I is carried out directly on plasma diluted 1:20. Fifteen normal volunteers were studied on a metabolic ward at 2 levels of Na intake, during recumbency and upright posture, and following the administration of furosemide. Renin activity increased with Na restriction, was significantly higher on upright activity during both normal and restricted Na intake, and was most markedly elevated following the diuretic. Renin values obtained by immunoassay of angiotensin I correspond closely to those observed by ...

Application of a radioimmunoassay for angiotensin I to the physiologic measurements of plasma renin activity in normal human subjects

Double isotope derivative assay of aldosterone in biological extracts.

. In 60 patients with pituitary adenomas, the serum concentration of the alpha subunit of the glycoprotein hormones (serum alpha) was measured by a sensitive and specific radioimmunoassay. Five patients had markedly elevated serum alpha prior to therapy (range 14.5–23.0 ng/ml). These 5 patients included 2 hyperthyroid men with inappropriately high serum thyrotropin, one of whom also had acromegaly, a man with hyperprolactinemia and elevated cerebrospinal fluid alpha, a postmenopausal woman with low serum gonadotropins and hyperprolactinemia, and a man with central hypothyroidism and hypogonadism. Three of the 5 were restudied after therapy; serum alpha in these three decreased from 19.5 to 10.6, 23.0 to 2.0, and 17.0 to 12.0 ng/ml. Alpha in these 3 patients' serum eluted similarly to normal pituitary alpha by gel chromatography. The other 55 patients, including twenty with acromegaly, fifteen with galactorrhea, and two with Nelson's syndrome, had serum alpha <0.5–5.0 ng/ml. In addition, 22 patient...

Secretion of Alpha Subunit of Glycoprotein Hormones by Pituitary Adenomas

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Evidence that a humoral agent stimulates the adrenal cortex to secrete aldosterone in experimental secondary hyperaldosteronism

/pdf/impaired-aldosterone-production-in-salt-losing-congenital-lggwn2ix7k.pdf

Bernard Kliman

Papers

Application of a radioimmunoassay for angiotensin I to the physiologic measurements of plasma renin activity in normal human subjects

Double isotope derivative assay of aldosterone in biological extracts.

Secretion of Alpha Subunit of Glycoprotein Hormones by Pituitary Adenomas

Evidence that a humoral agent stimulates the adrenal cortex to secrete aldosterone in experimental secondary hyperaldosteronism

Impaired Aldosterone Production in “Salt-losing” Congenital Adrenal Hyperplasia