Dale W. Quest and Thomas W. Wilson (*)
Cardiovascular Risk Factor Reduction Unit (C.R.F.R.U.), Department of
Medicine, Division of Clinical Pharmacology, Royal University Hospital,
103 Hospital Drive, Saskatoon, SK, Canada, S7N OW8
(*) To whom correspondence should be addressed.
Abstract: 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 F1alpha 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+/-1O ng/day, P<0.01) while preserving 6-keto-prostaglandin
F1alpha excretion. Ketoprofen, a cyclo-oxygenase inhibitor, (10
mg/kg/day for 7 days), depressed urine 6-keto-prostaglandin F1alpha
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.
Keywords: Blood pressure, Renal prostanoid, Ridogrel, Thromboxane