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Diverse effects of AT1 receptor antagonists on normal blood pressure and regulatory system
Y Hashimoto1, H Yabana, H Narita
1Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Japan.
Insights
A novel AT1 receptor antagonist, TA-606, does not affect normal blood pressure or its regulatory system, unlike losartan. TA-606 and its metabolite 606A did not impact baroreceptor-heart rate reflex or L-glutamate receptor binding.
Area of Science:
- Pharmacology
- Cardiovascular Research
- Neuroscience
Background:
- Angiotensin II type 1 (AT1) receptor antagonists, like losartan, benefit heart failure patients.
- A potential drawback of AT1 antagonists is their effect on normal blood pressure.
- Normotensive patients may experience adverse effects if blood pressure is lowered.
Purpose of the Study:
- To compare the effects of a novel AT1 receptor antagonist, TA-606, with losartan on normal blood pressure and its regulatory mechanisms.
- To investigate the impact of TA-606 and its active metabolite (606A) on the baroreceptor-heart rate reflex and L-glutamate receptor binding.
- To determine if TA-606 offers an advantage over losartan by not affecting normal blood pressure.
Main Methods:
- Administration of TA-606 (30 and 100 mg/kg, p.o.) and losartan (100 mg/kg, p.o.) to assess effects on normal blood pressure.
- Intravenous administration of active metabolites EXP3174 (losartan's metabolite) and 606A (TA-606's metabolite) to evaluate baroreceptor-heart rate reflex suppression.
- In vitro assessment of 606A and EXP3174 binding to the L-glutamate receptor.
Main Results:
- TA-606 did not alter normal blood pressure, while losartan showed a tendency to decrease it.
- EXP3174 suppressed the baroreceptor-heart rate reflex, but 606A did not.
- EXP3174 inhibited L-glutamate receptor binding (IC50 = 13.3 microM), whereas 606A did not.
Conclusions:
- TA-606, a potent AT1 receptor antagonist, does not negatively impact normal blood pressure.
- Unlike losartan's metabolite, TA-606's metabolite (606A) does not affect central blood pressure regulatory systems (baroreceptor reflex, L-glutamate receptors).
- TA-606 represents a potentially safer AT1 receptor antagonist for managing conditions like heart failure, especially in normotensive individuals.
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 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.