Haemodynamic 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) 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 microliters 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-1) in SD rats there was no hypotension or regional vasodilation. With infusion of the endothelin antagonist, SB 209670 (10 micrograms kg-1 min-1), there was a slight hypotension, but no significant vasodilation; 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 vasodilation. 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+/-4 mmHg) or losartan(136 +/- 6 mmHg) alone, and renal, mesenteric and hindquarters vascular conductances (61 +/- 3, 90+/-14 and 52+/-4 [kHz nmHg-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 +/- 13 and 35+/-4 [kHz mmHg-1]103, respectively) alone. These results indicate the maintenance of hypertension inTG rats is dependent upon renal, mesenteric and hindquarters vasoconstriction, mediated by angiotensinII (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-l contributes to the widespread vasoconstriction in TG rats.
Gardiner
S M
SM
Department of Physiology & Pharmacology, University of Nottingham Medical School, Queen's Medical Centre, Nottingham.
March
J E
JE
Kemp
P A
PA
Mullins
J J
JJ
Bennett
T
T
D000804:Angiotensin II / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology*; D007189:Indans / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007093:Imidazoles; D007189:Indans; D017466:Receptors, Endothelin; D013777:Tetrazoles; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-; D000804:Angiotensin II; D019808:Losartan