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(Hypertension. 1999;33:1420-1424.)
© 1999 American Heart Association, Inc.

Scientific Contributions

Stimulation of the Renin-Angiotensin System by Endothelin Subtype A Receptor Blockade in Conscious Dogs

Heike Berthold; Klaus Münter; Armin Just; Hartmut R. Kirchheim; Heimo Ehmke

From the I. Physiologisches Institut der Ruprecht-Karls-Universität Heidelberg (H.B., A.J., H.R.K., H.E.), and Knoll AG, Ludwigshafen (K.M.), Germany.

Correspondence to Dr Heimo Ehmke, I. Physiologisches Institut der Ruprecht-Karls Universität, Im Neuenheimer Feld 326, D-69120 Heidelberg, Germany. E-mail ehmke{at}novsrv1.pio1.uni-heidelberg.de

Abstract—Previous studies in dogs have shown additive or even synergistic effects of combined angiotensin-converting enzyme inhibition and either nonselective endothelin subtype A/B (ET_A/B) or selective endothelin subtype A (ET_A) receptor blockade on renal vascular resistance and mean arterial blood pressure. A possible mechanism underlying this interaction may be a stimulation of the renin-angiotensin system during endothelin (ET) receptor blockade. We therefore investigated whether plasma renin activity and renin release are regulated by the ET_A receptor. Experiments were made in conscious, chronically instrumented dogs receiving either saline or the selective ET_A receptor antagonist LU 135252 (10 mg/kg IV). Eighty to 100 minutes after the administration of LU 135252 (n=5), heart rate (99±7 versus 81±6 bpm; P<0.05) and renal blood flow (327±40 versus 278±36 mL/min; P<0.05) were increased significantly, whereas mean arterial blood pressure tended to be lower (93±5 versus 105±7 mm Hg). These changes were associated with a 2-fold increase in plasma renin activity (0.74±0.12 versus 0.37±0.10 ng angiotensin I per milliliter per hour; P<0.05). Measurements of renin release at various renal perfusion pressures (n=5) with the use of a vascular occluder implanted around the left renal artery revealed that ET_A receptor blockade did not alter renin release at resting renal perfusion pressure (78±25 versus 71±39 U/min) but strongly enhanced the sensitivity of pressure-dependent renin release <80 mm Hg 2.2-fold. In conclusion, selective ET_A receptor blockade is associated with a stimulation of the circulating renin-angiotensin system, which results from both a sensitization of pressure-dependent renin release and a larger proportion of blood pressure values falling into the low pressure range, where renin release is stimulated. These find-ings strengthen the view that ET and the renin-angiotensin system closely interact to regulate vascular resistance and provide a physiological basis for synergistic hypotensive effects of a combined blockade of both pressor systems.

Key Words: endothelin • receptors, endothelin • renal blood flow • renin-angiotensin system • renin

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