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Enhanced involvement of endothelin in the haemodynamic sequelae of endotoxaemia in conscious, hypertensive, transgenic ((mRen‐2)27) rats
Author(s) -
Gardiner S. M.,
Kemp P. A.,
March J. E.,
Bennett T.
Publication year - 1998
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0701762
Subject(s) - endocrinology , medicine , hemodynamics , vasodilation , endothelin receptor , blood pressure , vascular resistance , mean arterial pressure , endothelin 1 , endothelins , bolus (digestion) , receptor , heart rate
Age‐matched (3–4 months old) male, heterozygous, hypertensive, transgenic ((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 regional haemodynamic responses to continuous lipopolysaccharide (LPS) infusion (150 μg kg −1 h −1 , i.v.) The early (1–2 h) hypotension in SD rats (−11±3 mmHg; n =7) was significantly less than that in TG rats (−35±3 mmHg; n =8), but by 24 h mean arterial blood pressure (MAP) 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: baseline, 171±2 mmHg; 24 h LPS, 169±3 mmHg). At this stage in the SD rats there was a renal vasodilatation (Δ vascular conductance, 29±10 [kHz mmHg −1 ]10 3 ) but not in TG rats (Δ vascular conductance 2±3[kHz mmHg −1 ]10 3 ). Co‐infusion of LPS and the non‐selective endothelin receptor antagonist, SB 209670 (600 μg kg −1 bolus, 600 μg 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 (Δ vascular conductance 11±3 (kHz mmHg −1 )10 3 ). In TG rats, under the same conditions, the fall in MAP was −60±6 mmHg, and there were renal, mesenteric and hindquarters vasodilatations (Δ vascular conductance, 23±5, 32±7, and 14±4 (kHz mmHg −1 )10 3 , respectively). All effects, except the hindquarters vasodilatation, were greater in TG than in SD rats. 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. Administration of the angiotensin (AT 1 )‐receptor antagonist, losartan (10 mg kg −1 , i.v.) following co‐infusion of LPS and SB 209670 between 24 and 31 h caused similar falls in MAP in SD and TG rats (−12±3 and −14±4 mmHg, respectively). These results, together with previous findings, are consistent with a relative enhancement of the contribution of endothelin to the maintenance of cardiovascular status in endotoxaemic TG rats, particularly through a mesenteric vasoconstrictor action.British Journal of Pharmacology (1998) 123 , 1403–1408; doi: 10.1038/sj.bjp.0701762