PubMed · 7016423
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D L Horwitz. 1981. Renin.. https://pubmed.ncbi.nlm.nih.gov/7016423/
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Antagonists of the type 1 (AT1) angiotensin II (Ang II) receptor increase renin secretion and plasma Ang II levels, and the increased Ang II levels may counteract the effects of the antagonist. Moreover, other investigators have suggested that the reactive increase in Ang II levels may increase bradykinin (BK) levels through stimulation of the type 2 Ang II receptor (AT2). We investigated the acute effects of the AT1 receptor antagonist losartan (intraarterial injection of 10 mg/kg every 12 h) in male Sprague Dawley rats by measuring circulating angiotensin and BK peptides at 6, 12, and 24 h. Whereas acute losartan administration increased blood angiotensin levels four- to sixfold, blood BK levels were unchanged. We also investigated the effects of losartan administered for 8 days (10 mg/kg every 12 hours, by intraperitoneal injection) on circulating and tissue levels of angiotensin and BK peptides, and angiotensin-converting enzyme (ACE). Losartan increased plasma renin levels 100-fold; plasma angiotensinogen levels decreased to 24% of control; and plasma aldosterone levels were unchanged. Ang II levels in plasma, adrenal, lung, heart, and aorta were increased 25-, 8-, 3.5-, 2.4-, and 14-fold, respectively, by losartan administration. By contrast, kidney Ang II levels decreased to 71% of control, accompanied by a decrease in kidney levels of BK-(1-7) and BK-(1-9). No other tissue showed a change in BK peptide levels, except for a reduction in blood levels of BK-(1-8) to 43% of control. Plasma ACE increased by 13-50%, but tissue ACE levels were unchanged. These data demonstrate that losartan has tissue-specific effects on endogenous levels of angiotensin and BK peptides and indicate that increased BK levels do not contribute to the actions of losartan. The absence of a reactive increase in endogenous kidney levels of Ang II indicates that this tissue is likely to be the most sensitive to AT1 receptor antagonism.
A new technique for noninvasive measurement of intrarenal blood flow distribution over cortex and medulla is proposed. The technique involves analysis of 123I-labeled hippuran renography, according to a kinetic model that describes the flow of 123I-hippuran from the heart (input) through the renal cortex and medulla to the bladder (output). The method is validated and compared with the standard microsphere injection technique in anesthetized dogs. Changes in intrarenal blood flow distribution were induced by infusion of placebo (n = 6), angiotensin I (n = 5), or atrial natriuretic factor (n = 5). Baseline percentage medullary blood flow in the left kidney was 12 +/- 1% of total renal blood flow measured with microspheres and 15 +/- 1% with renography. During infusion of the placebo, medullary blood flow decreased slightly compared with baseline, as measured with both methods, by 2 +/- 6 (microspheres) and 1 +/- 8% (renography). Infusion of angiotensin I caused a marked fall in medullary blood flow by 42 +/- 11 (microspheres) and 57 +/- 8% (renography). In contrast, infusion of atrial natriuretic factor caused a small rise in medullary blood flow as measured with both methods (9 +/- 3 and 12 +/- 11%, respectively). The absolute and percent changes in medullary blood flow measured with renography correlated with those measured with microspheres (left kidney: r = 0.67, P = 0.005; r = 0.71, P = 0.003, respectively; right kidney: r = 0.62, P = 0.01; r = 0.68, P = 0.004, respectively). We conclude that the proposed kinetic model of renal 123I-hippuran handling can be used to measure changes in intrarenal blood flow distribution and, because of its noninvasive character, may be of use in clinical studies.