ENHANCED INVOLVEMENT OF ENDOTHELIN IN THE HEMODYNAMIC SEQUELAE OF ENDOTOXEMIA IN CONSCIOUS, HYPERTENSIVE, TRANSGENIC ((MREN-2)27) RATS

1 Age-matched (3-4 months old) male, heterozygous, hypertensive, trans genic ((mRen-2)27) rats (abbreviated to TG rats) and the normotensive control animals (homozygous, Hannover Sprague-Dawley rats (abbreviated to SD rats), were chronically instrumented for the assessment of regi onal haemodynamic responses to continuous lipopolysaccharide (LPS) inf usion (150 mu g kg(-1) h(-1), i.v.) 2 The early (1-2 h) hypotension in SD rats (-11+/-3 mmHg; n=7) was significantly less than that in TG ra ts (-35+/-3 mmHg; n = 8), but by 24 h mean arterial blood pressure (MA P) in both strains of rat was not different from the pre-LPS value (SD rats: baseline, 108+/-3 mmHg; 24 h LPS, 112+/-4 mmHg; TG rats: baseli ne, 171+/-2 mmHg; 24 h LPS, 169+/-3 mmHg). At this stage in the SD rat s there was a renal vasodilatation (Delta vascular conductance, 29+/-1 0 [kHz mmHg(-1)]10(3)) but not in TG rats (Delta vascular conductance 2+/-3[kHz mmHg(-1)]10(3)). 3 Co-infusion of LPS and the non-selective endothelin receptor antagonist, SE 209670 (600 mu g kg(-1) bolus, 600 mu g kg(-1) h(-1)) between 24 and 31 h in SD rats caused a fall in MAP of 16+/-2 mmHg accompanied by hindquarters vasodilatation (Delta vasc ular conductance 11+/-3 (kHz mmHg(-1))10(3)). In TG rats, under the sa me conditions, the fall in MAP was -60+/-6 mmHg, and there were renal, mesenteric and hindquarters vasodilatations (Delta vascular conductan ce, 23+/-5, 32+/-7, and 14+/-4 (kHz mmHg(-1))10(3), respectively). All effects, except the hindquarters vasodilatation, were greater in TG t han in SD rats. 4 In TG rats infused with LPS alone for 31 h, between 24 and 31 h the fall in MAP was -17+/-4 mmHg, and the changes in renal , mesenteric and hindquarters vascular conductances were 5+/-3, -4+/-5 , and 12+/-4 (kHz mmHg(-1))10(3), respectively. 5 Administration of th e angiotensin (AT(1))-receptor antagonist, losartan (10 mg kg(-1), i.v .) following coinfusion of LPS and SE 209670 between 24 and 31 h cause d similar falls in MAP in SD and TG rats (-12+/-3 and -14+/-4 mmHg, re spectively). 6 These results, together with previous findings, are con sistent with a relative enhancement of the contribution of endothelin to the maintenance of cardiovascular status in endotoxaemic TG rats, p articularly through a mesenteric vasoconstrictor action.