Diverse effects of AT1 receptor antagonists on normal blood pressure and regulatory system.
An AT1 receptor antagonist, losartan, has been reported to improve survival and quality of life in patients with congestive heart failure as angiotensin converting enzyme inhibitors do. Since many of the patients are normotensive, it may be a drawback if the compound decreases normal blood pressure. In this study, we investigated whether a novel AT1 receptor antagonist, TA-606, which is more potent than losartan, affects normal blood pressure and its regulatory system in comparison with losartan. TA-606 (30 and 100 mg/kg, p.o.) did not change normal blood pressure, whereas losartan (100 mg/kg, p.o.) tended to decrease it. Although EXP3174 (1 and 10 mg/kg, i.v.), an active metabolite of losartan, suppressed the baroreceptor-heart rate (HR) reflex, 606A (1 and 10 mg/kg, i.v.), an active metabolite of TA-606, did not affect it. Since losartan is known to affect the L-glutamate receptor which is part of the central blood pressure regulatory system, we also investigated whether 606A affects L-glutamate receptor binding. We found that 606A did not affect the binding of the L-glutamate receptor, but EXP3174 inhibited the binding with IC50 values of 13.3 microM. These findings suggest that, even having the same AT1 receptor antagonist properties as losartan and EXP3174, TA-606 and its active metabolite do not influence normal blood pressure or its regulatory system.
Hashimoto
Y
Y
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Japan.
Yabana
H
H
Narita
H
H
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan; D008297:Male; D011311:Pressoreceptors / Q000187:drug effects; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D017470:Receptors, Glutamate / Q000187:drug effects; D012018:Reflex / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology
C106452:606A compound; D057911:Angiotensin Receptor Antagonists; D000889:Anti-Arrhythmia Agents; D000959:Antihypertensive Agents; D007093:Imidazoles; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D017470:Receptors, Glutamate; D013777:Tetrazoles; D011433:Propranolol; C066026:losartan carboxylic acid; D019808:Losartan