Blockade of the renin-angiotensin system in heart failure in conscious dogs.
OBJECTIVE
To study the different cardiac and renal hemodynamic effects of an angiotensin converting enzyme inhibitor and an angiotensin II receptor antagonist in experimental heart failure in conscious dogs.


METHODS
We compared the effects of the angiotensin converting enzyme inhibitor, captopril, with those of the angiotensin II (Ang II) subtype-1 receptor antagonist, losartan, on hemodynamics and hormonal changes in congestive heart failure by rapid ventricular pacing on conscious dogs. Furthermore, we characterized the Ang II receptors in canine heart, using the canine cardiac membrane fraction in heart failure.


RESULTS
Acute intravenous administration of captopril improved the cardiac output by 19% (P < 0.01) but losartan did not, although blockade of the renin-angiotensin system by losartan (1.1 mumol/kg) or captopril (0.69 mumol/kg) induced similar changes in the plasma renin activity, norepinephrine and arginine vasopressin, and a similar decrease in mean arterial pressure (-10 mmHg). Renal blood flow was increased by either losartan or captopril. In the binding study, losartan produced a single displacement curve (IC50 = 0.25 mumol/l), while the Ang II subtype-2 (AT2) receptor antagonist PD123319 did not, indicating that the predominant Ang II receptor is type-1 (AT1) in canine heart. Neither the ratio of AT1 to AT2 receptors nor the receptor density changed with the development of heart failure.


CONCLUSIONS
The lack of effect of losartan on cardiac output may be the result of its inability to block non-AT1 receptor-mediated Ang II activities adequately. Captopril may improve cardiac output by means of mechanisms not mediated by Ang II, such as locally increasing bradykinin.
Murakami
M
M
Department of Internal Medicine, Keio University, Tokyo, Japan.
Suzuki
H
H
Naitoh
M
M
Matsumoto
A
A
Kageyama
Y
Y
Tsujimoto
G
G
Saruta
T
T
D000804:Angiotensin II / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001713:Biphenyl Compounds / Q000378:metabolism / Q000494:pharmacology*; D002216:Captopril / Q000494:pharmacology*; D004285:Dogs; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism; D012016:Reference Values; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013777:Tetrazoles / Q000378:metabolism / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D007093:Imidazoles; D011725:Pyridines; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; D002216:Captopril; D019808:Losartan