HEMODYNAMIC-EFFECTS OF LOSARTAN AND THE ENDOTHELIN ANTAGONIST, SB-209670, IN CONSCIOUS, TRANSGENIC ((MREN-2)27), HYPERTENSIVE RATS

1 Hypertensive transgenic (TGR(mRen-2)27) (abbreviated to TG) rats (n= 6) and their normotensive Sprague-Dawley (SD) control strain (n=7) wer e chronically instrumented for the measurement of cardiac haemodynamic s. The hypertension in TG rats (mean blood pressure 181+/-9 mmHg) was entirely attributable to a reduction in total peripheral conductance ( TG rats=169+/-7, SD rats=292+/-15 mu l min(-1) mmHg(-1) 100g(-1)) sinc e cardiac index was not different in the two strains (TG rats = 30.5 /- 1.2, SD rats = 29.5+/-1.6 ml min(-)1 100g(-1)). 2 In other animals instrumented for the assessment of regional haemodynamics, the extent of peripheral vasoconstriction was similar in renal, mesenteric and hi ndquarters vascular beds in the TG rats (reduction in vascular conduct ance relative to SD rats=42%, 46% and 49%, respectively). 3 During an 8h observation period with saline infusion, or following injection of losartan (10 mg kg(-1)) in SD rats there was no hypotension or regiona l vasodilatation. With infusion of the endothelin antagonist, SE 20967 0 (10 mu g kg(-1) min(-1)), there was a slight hypotension, but no sig nificant vasodilatation; co-administration of losartan and SE 209670 c aused a similar profile of effect, although the hypotension was increa sed. 4 With the same experimental protocol in TG rats, losartan caused a biphasic, progressive fall in mean arterial blood pressure accompan ied by renal, mesenteric and hindquarters vasodilatation. Although the response to SE 209670 was not biphasic, its hypotensive and vasodilat or effects were not different from those of losartan after 8 h. In the combined presence of losartan and SE 209670, mean arterial blood pres sure (116+/-5 mmHg) was significantly lower than with SE 209670 (132+/ -4 mmHg) or losartan (136+/-6 mmHg) alone, and renal, mesenteric and h indquarters vascular conductances (61+/-3, 90+/-14 and 52+/-4 [kHz mmH g(-1)]10(3), respectively) were higher than the corresponding values f ollowing either SE 209670 (49+/-4, 52+/-4 and 34+/-3 [kHz mmHg(-1)]10( 3), respectively) or losartan (43+/-5, 59+/-13 and 35+/-4[kHz mmHg(-1) ]10(3), respectively) alone. These results indicate the maintenance of hypertension in TG rats is dependent upon renal, mesenteric and hindq uarters vasoconstriction, mediated by angiotensin II (AII) and endothe lin (ET). Since we found that plasma ET-1 levels in TG rats (12.06+/-2 .87 pmol l(-1)) were lower than in SD rats (21.53+/-3.94 pmol l(-1)), then it is possible that locally-generated, rather than circulating ET -1 contributes to the widespread vasoconstriction in TG rats.