Angiotensin antagonists with increased specificity for the renal vasculature.

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Abstract

This study was designed to ascertain whether renal vascular angiotensin receptors differ from other systemic angiotensin receptors and whether, on that basis, antagonists with greater specificity for the renal vasculature can be defined. Femoral and renal blood flow and their responses to angiotensin II (AII) and its heptapeptide analogue, 1-des Asp AII (AIII), were measured with an electromagnetic flowmeter in 26 dogs. For the kidney, the threshold doses of AII and AIII were identical (2.5+/-0.27 vs. 2.3+/-0.35 pmol/100 ml renal blood flow, with similar dose-response curves. In contrast, AII had a greater pressor effect (P less than 0.001) and produced more femoral vasoconstriction (P less than 0.001) than AIII. All four antagonists studied (1-Sar, 8-Ala AII [P113]; 8-Ala AII; 1-des Asp, 8-Ala AII; 1-des Asp, 8-Ile AII) induced parallel shifts in the renal blood flow response to AII and AIII. P113 induced greater blockade than 8-Ala AII (P less than 0.001) which, in turn, was more effective than 1-des Asp, 8-Ala AII (P less than 0.001). 1-des Asp, 8-Ile AII was as effective as P113. Each analogue induced an identical inhibition of the renal vascular response to AII and AIII. In addition, AII and AIII induced cross-tachyphylaxis. All lines of evidence suggested that AII and AIII act on a single receptor in the kidney, which differs at least functionally from other systemic vascular receptors. The possibility that heptapeptide analogues represent angiotensin antagonists with greater specificity for the renal vasculature was pursued in a model in which the renin-angiotensin system is activated. Acute, partial thoracic inferior vena caval occlusion was induced in an additional 16 dogs. P113 induced progressive, dose-related hypotension and a limited increase in renal blood flow in this model. The 1-des Asp, 8-Ile AII analogue, conversely, induced a consistent, larger, dose-related renal blood flow increase, with significantly less hypotension over a wide dose range. We conclude that the renal vascular receptor differs sufficiently from systemic angiotensin receptors that heptapeptide analogues of AII will be useful in exploring angiotensin's role in states characterized by disordered renal perfusion and function.

Authors

K J Taub, W J Caldicott, N K Hollenberg