Pharmacologic Effects of Wy 27569

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Summary: Wy 27569 (1,4 dihydro-2-[imidazol-1-yl-methyl]-6-methyl-4-[3-nitrophenyl] pyridine-3,5, dicarboxylic acid 3-ethyl 5-methyl diester) is a combined calcium channel blocker and thromboxane synthetase inhibitor. This article reports the in vivo and in vitro pharmacological studies demonstrating these properties. Wy 27569 evoked rightward shifts and depressed the maximum of calcium dose response curves in potassium depolarised rat aortas [concentration required to inhibit the response by 50% (IC50) = 7.3 nM]. The calcium channel blocker nitrendipine exhibited a similar profile to, although more potent than, Wy 27569 (IC50 = 0.28 nM). Comparison of the data obtained in aortas with the effects of these compounds in electrically stimulated isolated ventricle strips (IC50 for Wy 27569 = 8.3 μM, IC50 for nitrendipine = 0.41 μM) suggests that Wy 27569, like nitrendipine, is a vascular selective calcium channel blocker. Wy 27569 and the thromboxane synthetase inhibitor dazoxiben inhibited the collagen -stimulated production of thromboxane B2 (TXB2, IC50 = 3.9 and 2.8 μM, respectively) and, over the same concentration range, enhanced the production of immunoreactive 6 keto prostaglandin F1α (6 keto-PGF1α) by human platelet rich plasma. Single doses of Wy 27569 (0.3-10 mg kg−1 p.o.) or dazoxiben (3-10 mg kg−1 p.o.) evoked a dose-related reduction of TXB2 and enhancement of immunoreactive 6 keto PGF1α levels in rat plasma and serum. Nitrendipine (0.3-10 mg kg−1 p.o.) had no significant effect on either eicosanoid. Wy 27569 (0.1-30 mg kg−1 p.o. or 0.03-1 mg kg−1 i.v.) evoked a dose-related reduction in mean arterial blood pressure (MABP) in spontaneously hypertensive rats (SHR). Oral administration of 10 mg kg−1 Wy 27569 reduced MABP in 1 kidney-1 clip and 2 kidney-1 clip Goldblatt hypertensive rats and, to a lesser extent, in normotensive rats. Nitrendipine was approximately threefold more potent than Wy 27569. Dazoxiben had no significant effect on MABP. In conclusion, Wy 27569 reduced TXB2 production and enhanced immunoreactive 6 keto PGF1α levels in vivo and in vitro and lowered blood pressure in rats. Both these effects occurred over the same dose range and with similar durations of action.

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