title: Acute effects of E-3174, a human active metabolite of losartan, on the cardiovascular system in tachycardia-induced canine heart failure.
abstract: The aim of this study was to evaluate the acute effects of E-3174, a human active metabolite of the AT1 receptor antagonist, losartan, on hemodynamic functions in dogs with severe heart failure (HF). In dogs, insignificant plasma levels of E-3174 are present following administration of losartan, and therefore, the effects of these two drugs can be studied independently in the dog. HF was established by rapid pacing of the right ventricle (250-270 beats/min) for 4 weeks. We examined changes in cardiovascular functions after acute intravenous administration of losartan (1 mg/kg) and E-3174 (0.3 and 1 mg/kg), as well as an ACE inhibitor, enalapril (0.3 and 1 mg/kg), under condition of HF. The HF before treatment was characterized by increases in pre- and after-load of the left ventricle (LV), consequent low cardiac output, and LV dilatation. E-3174 at 0.3 and 1 mg/kg reduced pulmonary artery pressure (-13+/-6% and -22+/-3% from baseline, respectively, p<0.05), pulmonary capillary wedge pressure (-18+/-4% and -36+/-10%, p<0.05) and mean arterial pressure (-24+/-2% and -36+/-7%, p<0.05), increased stroke volume (SV: +12+/-7% p>0.05; +36 +/-19%, p<0.05), and reduced peripheral resistance (-23+/-5% and -41+/-9%, p<0.05), but had no effect on the first derivative of left ventricular pressure (dP/dt/P) or the time constant for relaxation. Effects of losartan at 1 mg/kg were similar to those of 0.3 mg/kg of E-3174. Enalapril at 1 mg/kg caused changes comparable to those seen after E-3174 administration (1 mg/kg), except that the increase in SV (+16+/-8%, p<0.05) with enalapril was not as great as that with E-3174. Both losartan at 1 mg/kg and E-3174 at 0.3 and 1 mg/kg increased fractional shortening to a similar extent (FS: +52+/-12%, +47+/-8% and +56+/-8%), while enalapril at 0.3 and 1 mg/kg had no significant effects on FS. Reflex elevation of plasma renin activity induced by 1 mg/kg of E-3174 was similar to that caused by 1 mg/kg of enalapril, suggesting that the two drugs achieved similar inhibition of the endogenous renin angiotensin system. Our study demonstrated that acute blockade of the AT1 receptor with E-3174 reduced elevated pre- and after-load and consequently increased stroke volume in a canine HF model. With the exception of changes in stroke volume, these effects of E-3174 were comparable to those produced by enalapril, and were 3 times stronger than those by losartan.
authors.affiliation: Pharmacology, Tsukuba Research Institute, Banyu Pharmaceutical, Co., Ltd., Japan.
authors.forename: J
authors.initials: J
authors.lastname: Suzuki
authors.forename: H
authors.initials: H
authors.lastname: Ohta
authors.forename: K
authors.initials: K
authors.lastname: Hanada
authors.forename: N
authors.initials: N
authors.lastname: Kawai
authors.forename: T
authors.initials: T
authors.lastname: Ikeda
authors.forename: M
authors.initials: M
authors.lastname: Nakao
authors.forename: F
authors.initials: F
authors.lastname: Ikemoto
authors.forename: M
authors.initials: M
authors.lastname: Nishikibe
mesh_terms: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects*; D004285:Dogs; D004452:Echocardiography; D004558:Electric Stimulation; D004656:Enalapril / Q000494:pharmacology; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects*; D006728:Hormones / Q000097:blood; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects; D013610:Tachycardia / Q000150:complications / Q000503:physiopathology*; D013777:Tetrazoles / Q000494:pharmacology*; D016276:Ventricular Function
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D006728:Hormones; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D004656:Enalapril; D012083:Renin; C066026:losartan carboxylic acid; D019808:Losartan