Thromboxane A2 is a
prostanoid having potent platelet aggregatory and
vasoconstrictor properties. To determine a possible role for
thromboxane A2 in the development of severe
hypertension and
stroke, we chronically administered the selective
thromboxane A2 synthase inhibitor
UK-38,485 (
Dazmegrel) to
stroke-prone spontaneously hypertensive rats (SHRSP). Serum
thromboxane B2 (the stable hydrolysis product of
thromboxane A2) generation was significantly greater in incubates of whole blood from SHRSP than in those from normotensive control Wistar-Kyoto rats and was inhibited greater than 89% by
UK-38,485 administered in vivo. In 10 male SHRSP fed a Japanese-style rat chow and given 1% NaCl in
drinking water to accelerate the occurrence of
stroke, treatment with 100 mg/kg/day
UK-38,485 by gavage starting at 8.6 weeks of age diminished systolic blood pressure elevation
at 10 (205 +/- 2 vs. 220 +/- 4 mm Hg, p less than 0.01) and 11 weeks of age (210 +/- 4 vs. 239 +/- 7 mm Hg, p less than 0.01) compared with 10 untreated SHRSP. The ultimate establishment of severe
hypertension was not prevented by
UK-38,485.
Stroke-related mortality was 70% in both UK-38,485-treated and control SHRSP at 14 weeks of age. Histologic examination revealed cerebrovascular lesions consistent with the occurrence of
stroke in both control and UK-38,485-treated SHRSP. Our results support a possible role for
thromboxane A2 in the elevation of blood pressure in SHRSP but do not support a possible role for the prevention of
stroke by
thromboxane A2 synthase inhibition in these rats.