Haemodynamic effects of losartan and the endothelin antagonist, SB 209670, in conscious, transgenic ((mRen‐2)27), hypertensive rats

• Published in: British journal of pharmacology 1995-10, Vol.116 (4), p.2237-2244
• Main Authors: Gardiner, S.M., March, J.E., Kemp, P.A., Mullins, J.J., Bennett, T.
• Format: Article
• Language: English
• Subjects: Angiotensin II - metabolism; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Animals; Animals, Genetically Modified; Antihypertensive Agents - pharmacology; Biphenyl Compounds - pharmacology; endothelin; Endothelin Receptor Antagonists; Endothelins - antagonists & inhibitors; Endothelins - metabolism; Hemodynamics - drug effects; Hypertension - genetics; Hypertension - physiopathology; Imidazoles - pharmacology; Indans - pharmacology; Losartan; Male; Rats; Rats, Sprague-Dawley; Receptors, Endothelin - drug effects; Regional Blood Flow - drug effects; SB 209670; Tetrazoles - pharmacology; Transgenic rats; vasoconstriction
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.1995.tb15059.x

1 Hypertensive transgenic (TGR(mRen‐2)27) (abbreviated to TG) rats (n = 6) and their normotensive Sprague‐Dawley (SD) control strain (n = 7) were chronically instrumented for the measurement of cardiac haemodynamics. 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 μl min−1 mmHg−1 100g−1) since 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 hindquarters vascular beds in the TG rats (reduction in vascular conductance relative to SD rats = 42%, 46% and 49%, respectively). 3 During an 8 h observation period with saline infusion, or following injection of losartan (10 mg kg−') in SD rats there was no hypotension or regional vasodilatation. With infusion of the endothelin antagonist, SB 209670 (10 μg kg−1 min−), there was a slight hypotension, but no significant vasodilatation; co‐administration of losartan and SB 209670 caused a similar profile of effect, although the hypotension was increased 4 With the same experimental protocol in TG rats, losartan caused a biphasic, progressive fall in mean arterial blood pressure accompanied by renal, mesenteric and hindquarters vasodilatation. Although the response to SB 209670 was not biphasic, its hypotensive and vasodilator effects were not different from those of losartan after 8 h. In the combined presence of losartan and SB 209670, mean arterial blood pressure (116 ± 5 mmHg) was significantly lower than with SB 209670 (132±4mmHg) or losartan (136 ± 6 mmHg) alone, and renal, mesenteric and hindquarters vascular conductances (61 + 3, 90+14 and 52+4 [kHz mmHg−1]103, respectively) were higher than the corresponding values following either SB 209670 (49±4, 52±4 and 34±3 [kHz mmHg−1]103, respectively) or losartan (43±5, 59±3 and 35±4 [kHz mmHg−1]103, respectively) alone. These results indicate the maintenance of hypertension in TG rats is dependent upon renal, mesenteric and hindquarters vasoconstriction, mediated by angiotensin II (AII) and endothelin (ET). Since we found that plasma ET‐1 levels in TG rats (12.06±2.87 pmol 1−1) were lower than in SD rats (21.53±3.94 pmol 1−1), then it is possible that locally‐generated, rather than circulating ET‐1 contributes to the widespread vasocon