Effects of Ridogrel, a Thromboxane Synthase Inhibitor and Receptor Antagonist, on Blood Pressure in the Spontaneously Hypertensive Rat

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Ridogrel is a dual acting thromboxane synthase inhibitor/TP receptor antagonist. We examined the effects of single and multiple doses on systolic blood pressure in stroke-prone spontaneously hypertensive rats. Single doses of ridogrel (5 to 125 mg/kg) did not affect systolic blood pressure or furosemide-stimulated excretion rates of thromboxane B₂ or 6-keto-prostaglandin F_1α, although ex vivo serum thromboxane B₂ was dose-dependently reduced up to 95%. In contrast, repeated dosing (7 days) with ridogrel (3 to 25 mg/kg/day), had an antihypertensive effect in 12-week-old stroke-prone spontaneously hypertensive rats. At 25 mg/kg/day, ridogrel reduced systolic blood pressure from 200±6.1 to 173±6.7 mmHg (n=12, P<0.01). Ridogrel dose-dependently reduced serum thromboxane B₂ and increased plasma renin activity. Unlike single doses, repeated dosing reduced urinary thromboxane B₂ excretion (from 103±7 ng/day to 49±10 ng/day, P<0.01) while preserving 6-keto-prostaglandin F_1α excretion. Ketoprofen, a cyclo-oxygenase inhibitor, (10 mg/kg/day for 7 days), depressed urine 6-keto-prostaglandin F_1α in addition to attenuating serum and urine thromboxane B₂. Ketoprofen prevented the antihypertensive effects of ridogrel. Ridogrel did not lower systolic blood pressure in Sprague-Dawley rats. We conclude that the antihypertensive effect of ridogrel involves preserving renal prostaglandin synthesis during thromboxane attenuation.