Diverse Effects of AT1 Receptor Antagonists on Normal Blood Pressure and Regulatory System.

Abstract

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 tuM. 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. (Hypertens Res 1999; 22: 121-127) Key Words: TA-606, losartan, AT1 receptor antagonist, baroreceptor-heart rate reflex, blood pressure regulation An AT1 receptor antagonist, losartan, has been reported to improve survival and quality of life of patients with congestive heart failure (1) as angiotensin converting enzyme inhibitors (2, 3) do, which are considered to be good treatments for patients with hypertension. However, hypotensive action of these agents may limit their usage in heart failure patients. Excessively low blood pressure may induce ischemia in multiple organs, and it was reported that blood pressure excessively lowered by antihypertensive agents (< 85 mmHg in diastolic blood pressure) was related to poor prognosis in patients with ischemic heart disease; i. e. , J curve phenomenon (4).Losartan is known as the first nonpeptide AT1 receptor antagonist developed for clinical use (5), and was reported to affect normal blood pressure; by lowering it even at regular clinical doses (6, 7) . In addition to AT1 receptor antagonism, losartan was reported to affect the glutamate receptor which is involved in the central blood pressure regulatory system, including the baroreflex (8, 16). L-glutamate is known as an important neurotransmitter in the medulla oblongata in the central blood pressure regulatory system (9-11). It is also known that this area lacks a blood-brain barrier despite dense vascular supply (12,16). Therefore, humoral factors in blood can be detected by this area, and it is considered to be ideally suited to the integration of both neural and humoral signals essential for normal autonomic regulation (13,14) . It is possible that the low...