Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT₁‐receptor subtype

Abstract

1 The pharmacological profile of valsartan, (S)-N-valeryl-N-([2'-(lH-tetrazol-5-yl) (p.o.). The antihypertensive effect lasted for at least 24 h after either route of administration. After repeated oral administration for 4 days (3 and 10 mg kg-' daily), in 2K1C renal hypertensive rats, systolic blood pressure was consistently decreased, but heart rate was not significantly affected. 7 In conscious, normotensive, sodium-depleted marmosets, valsartan decreased mean arterial pressure, measured by telemetry, after oral doses of 1-30 mg kg'. The hypotensive effect persisted up to 12 h after 3 and l0mgkg-' and up to 24h after 30mgkg-'.8 In sodium-depleted marmosets, the hypotensive effect of valsartan lasted longer than that of losartan (DuP 753). In renal hypertensive rats, both agents had a similar duration (24 h), but a different onset of action (valsartan at 1 h, losartan between 2 h and 24 h). 9 These results demonstrate that valsartan is a potent, specific, highly selective antagonist of AII at the AT,-receptor subtype and does not possess agonistic activity. Furthermore, it is an efficacious, orally active, blood pressure-lowering agent in conscious renal hypertensive rats and in conscious normotensive, sodium-depleted primates.

Angiotensin II receptor pharmacology and AT1-receptor blockers

“…The K i for the AT 1 receptor in smooth-muscle cells is 2.4 nmol/L, the one for the AT 2 receptor in human myometrium membranes is 57.7 mol/L, therefore, the selectivity for the AT 1 over the AT 2 receptor is about 30 000-fold. 21 In human adrenal glands, the IC 50 was determined to be 2.6 nmol/L, a value comparable to the other mentioned AT 1 antagonists. 22 After oral administration, valsartan is absorbed quickly, with a T max at 2 h. Bioavailability is 25%, and is reduced by 46% with concomitant food intake.…”

“…19 Despite the fact that losartan binding to the AT 1 receptor is sufficient to result in an effective receptor blockade, it is lower when compared to some other AT 1 antagonists, whose IC 50 values range from 1.5 to 4 nmol/L. 21,26,93,94 However, the binding affinity of EXP3174 ( IC 50 of 3.7 nmol/L), 19 is substantially higher, and is within the range of other AT 1 antagonists. The affinity of EXP3174 for the AT 1 receptor is 30 000-fold higher than that for the AT 2 receptor.…”

“…This was the basis for the further development of highly specific and selective angiotensin AT 1 -receptor binding substances such as losartan, [16][17][18][19] valsartan, [20][21][22][23] irbesartan, [24][25][26][27] candesartan, 28 eprosartan, 29 telmisartan, 30 and others (overview 31 ), and AT 2 -receptor ligands/antagonists, for example, PD123177, PD123319, and CGP42112. 32,33 Ang II receptor subtypes…”

“…Some, as for example candesartan, valsartan, irbesartan, and EXP3174, achieve AT 1 -receptor blockade with an antagonism that has been designated 'insurmountable', 21,92,93 meaning that they cannot be readily displaced, even by very high concentrations of Ang II, while others, such as losartan and eprosartan, are strong competitive antagonists for Ang II at the AT 1 receptor, and, therefore, can be more readily displaced by high concentrations of Ang II at their binding sites.…”

Pharmacologic properties of candesartan cilexetil—possible mechanisms of long-acting antihypertensive action

“…EXP3174, the active metabolite of losartan, showed a mixed-inhibiting profile. It has been reported eprosartan produced surmountable (competitive) inhibition, 22 but valsartan, 23 and irbesartan 24 produced insurmountable inhibitions. In these reports, irbesartan and valsartan showed insurmountable inhibition, but they had a mixed type of competitive and non-competitive inhibition, and were not totally non-competitive.…”