Cardiac haemodynamic effects of the non-peptide, angiotensin II-receptor antagonist, DuP 753, in conscious Long Evans and Brattleboro rats.
1. In previous experiments in conscious, water-replete Long Evans and Brattleboro rats the non-peptide angiotensin II-receptor antagonist, DuP 753, caused only slight hypotension and peripheral (particularly renal) vasodilatations. However in water-deprived (i.e. renin-dependent) Brattleboro rats, DuP 753 caused marked hypotension and regional vasodilatations. The major objective of the present study was to determine if the hypotensive effects of DuP 753 under any of the experimental conditions studied previously were contributed to by negative effects on cardiac haemodynamics. 2. Male, Long Evans and Brattleboro rats were chronically instrumented with electromagnetic flow probes on the ascending aorta and with intravascular catheters. Data were collected by use of a microcomputer-based system that provided digitised print-out of instantaneous heart rate, mean arterial blood pressure, cardiac output, stroke volume, peak aortic flow, maximum positive slope of the aortic flow signal (+ dF/dtmax), total peripheral conductance and central venous pressure. 3. Incremental i.v. bolus doses (0.1-10 mg kg-1, at 15 min intervals) of DuP 753 were administered to water-replete Long Evans (n = 8) and Brattleboro (n = 8) rats, and to water-deprived (14 h) Brattleboro rats (n = 9) (the latter animals show marked activation of the renin-angiotensin system). In all groups, 15 min after the highest dose of DuP 753 had been given, a supramaximal dose of captopril (2 mg kg-1) was injected to determine if it had any additional effects. 4. In water-replete, Long Evans and Brattleboro rats, DuP 753 (0.1-1 mg kg-1) caused slight, transient hypotension, with rises in total peripheral conductance; increases in cardiac output, peak aortic flow, + dF/dtmax and stroke volume were inconsistent and central venous pressure did not change. Higher doses of DuP 753 (3 and 10mgkg-') caused modest, sustained hypotension that was due entirely to an increase in total peripheral conductance, since cardiac output, peak aortic flow and + dF/dtmax showed transient elevations; captopril had no additional hypotensive or vasodilator effects. 5. Under resting conditions, water-deprived Brattleboro rats showed an increase in mean arterial blood pressure, but there were reductions in total peripheral conductance, cardiac output and + dF/dtmax. DuP 753 (0.1-10 mg kg- 1, i.v., boluses at 15 min intervals) caused incremental hypotension and tachycardia and dose-dependent rises in total peripheral conductance that were accompanied by transient increases in cardiac output, peak aortic flow and + dF/dtmax; captopril had no additional hypotensive or vasodilator effects. 6. Under no conditions were there any negative effects of DuP 753 on myocardial function; moreover, it is likely the transient increases in cardiac function following DuP 753 were indirect and due to the reduction in afterload. Thus, it appears the haemodynamic effects of DuP 753 can be explained by its vasodilator action.
Batin
P
P
Department of Medicine, Queen's Medical Centre, Nottingham.
Gardiner
S M
SM
Compton
A M
AM
Kemp
P A
PA
Bennett
T
T
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D002496:Central Venous Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D051381:Rats; D011910:Rats, Brattleboro; D013045:Species Specificity; D013777:Tetrazoles / Q000494:pharmacology*; D014868:Water Deprivation / Q000502:physiology
D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D019808:Losartan