Comparative Study of TA-606, a Novel Angiotensin II Receptor Antagonist, With Losartan in Terms of Species Difference and Orthostatic Hypotension.

Abstract

Losartan is a prodrug type Angiotensin II (Ang II) AT1-receptor antagonist whose efficacy depends on the oxidase activity of individuals. In addition, losartan affects the normal blood pressure and can potentially cause orthostatic hypotension. In this report, we examined effects of TA-606 [(3-pentyloxy)carbonyloxymethyl-5-acetyl-2-n-propyl-3-[2'(1H -tetrazole-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydro imidazo[4,5-c]pyridine-4-carboxylate hydrochloride], a prodrug type AT1-receptor antagonist, on the Ang II-induced pressor response and hypertension in a dog model, which is known to have lower oxidase activity than other species, and orthostatic hypotension in the rat tilting model. The results indicated that TA-606 was immediately converted to its active form, 606A, after oral administration, and it demonstrated potent inhibition of the Ang II-induced pressor response in conscious normotensive dogs (0.3-3 mg/kg, p.o.). It also had a potent hypotensive effect in conscious 2K,1C-renal hypertensive dogs (0.3-10 mg/kg, p.o.). These effects of TA-606 were 32 and 30 times more potent than those of losartan, respectively. In addition, EXP3174 (1, 10 mg/kg, i.v.), an active metabolite of losartan, but not 606A (1-30 mg/kg, i.v.) showed an orthostatic hypotensive effect in the rat tilting model. These results suggest that TA-606 is an effective Ang II receptor antagonist without the drawbacks of losartan.

Evidence for a functional cardiac interaction between losartan and angiotensin‐(1–7) receptors revealed by orthostatic tilting test in rats

“…Candesartan is a highly selective AT 1 antagonist, 48 times more potent than losartan (Shibouta et al, 1993). Therefore, our study supports previous findings showing that the orthostatic effect caused by losartan is beyond antagonism of Ang II AT 1 receptor blockade (Ohlstein et al, 1992;Hashimoto et al, 1999). Previous reports of nonspecificity of losartan for AT 1 receptors provided arguments to the hypothesis that Ang-(1-7) receptors, in the kidney (Chansel et al, 1994;Gironacci et al, 1999) and perhaps in the heart (Gironacci et al, 1994), are sensitive to losartan.…”

“…The same effect is not observed with other Ang II AT 1 receptor antagonists (Ohlstein et al, 1992;Hashimoto et al, 1999), or even with converting enzyme inhibitors (Ohlstein et al, 1992). This suggests that, at least peripherally, the orthostatic hypotensive effect caused by losartan is beyond antagonism of Ang II AT 1 receptor blockade.…”

“…This suggests that, at least peripherally, the orthostatic hypotensive effect caused by losartan is beyond antagonism of Ang II AT 1 receptor blockade. However, the mechanisms involved in mediating the orthostatic hypotensive effect of losartan in rats were not investigated in these previous studies (Ohlstein et al, 1992;Hashimoto et al, 1999).…”

“…Previous studies have shown that, in the rat model of orthostatic challenge, or tilting test, the angiotensin II (Ang II) AT 1 receptor antagonist, losartan, produces a pronounced orthostatic hypotensive response (Ohlstein et al, 1992;Hashimoto et al, 1999). The same effect is not observed with other Ang II AT 1 receptor antagonists (Ohlstein et al, 1992;Hashimoto et al, 1999), or even with converting enzyme inhibitors (Ohlstein et al, 1992).…”

Influência do bloqueador de receptor de angiotensina (Losartana potássica) na função renal e pressão arterial em cães GRMD

“…O protocolo para uso do Losartan foi estabelecido com referência em experimentos previamente feitos em cães e humanos (Wong et al 1991, Goa & Wagstaff 1996, Hashimoto et al 1999, Suzuki et al 2001 Utilizou-se a dose de 50mg de Losartan, administrada via oral, juntamente com a ração triturada e hidratada com água, uma vez ao dia, pela manha durante primeira refeição. Os animais passaram por exames clínicos semanais, de acordo com ficha clínica estipulada pelos médicos veterinários do Canil GRMD-USP, nos quais foram avaliados: temperatura retal, auscultação cardiopulmonar, palpação abdominal, avaliação de mucosas e palpação de linfonodos, de modo a identificar eventuais efeitos adversos do uso da droga e, também, com o objetivo de acompanhar a evolução da doença nos cães tratados.…”