ozagrel and bunazosin

We investigated the influence of the vascular and renal thromboxane system on the antihypertensive effects of the alpha 1 adrenoceptor antagonist (alpha 1 blocker) bunazosin in spontaneously hypertensive rats (SHR). SHR were treated for 2 weeks with the alpha 1, blocker bunazosin (0.5 mg/kg body weight/day). The systolic blood pressure immediately declined with bunazosin treatment, and then rose toward the level observed in untreated SHR. This antihypertensive effect was accompanied by a decrease in the ratio of prostacyclin to thromboxane A2 in the vascular wall and the kidney. A subdepressor dose of the thromboxane synthase inhibitor OKY-046 lessened the thromboxane generation during bunazosin treatment, and synergistically potentiated the antihypertensive action of the alpha 1 blocker. Such synergy was also observed between OKY-046 and prazosin, an alternative alpha 1 blocker, but not with amosulalol, an alpha 1 blocker having no quinazoline moiety. alpha 1 blockers with a quinazoline moiety dose-dependently stimulate thromboxane generation in cultured smooth muscle cells from SHR. These data indicate that alpha 1 blockers enhance thromboxane generation in the arterial wall and kidney, thereby contributing to the lessening of the antihypertensive effects observed during alpha 1 blocker treatment.

Topics: Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Body Weight; Cells, Cultured; Drug Synergism; Eicosanoids; Ethanolamines; Kidney; Methacrylates; Muscle, Smooth, Vascular; Prazosin; Quinazolines; Rats; Rats, Inbred SHR; Sodium; Thromboxane-A Synthase; Thromboxanes

In order to assess the roles of vasoconstrictor thromboxane in the antihypertensive action of alpha 1 adrenoceptor antagonist, we explored the influences of OKY-046, a selective thromboxane inhibitor, on the antihypertensive effects of bunazosin in spontaneously hypertensive rats (SHR). 2-week antihypertensive treatment with bunazosin (0.5 mg/kg/day) did not produce a significant decrease of systolic blood pressure in SHR, as compared to untreated controls. The blood pressure reduction was associated with a decrease of PGI2/TXA2 in vascular eicosanoids generation (p less than 0.02) and an increase of TXA2 excretion in urine (p less than 0.05). A combination treatment with OKY-046 almost completely abolished the enhanced TXA2 generation in the vascular wall and kidney, which was strikingly associated with a potentiation of the blood pressure reduction by bunazosin treatment (176 vs 186 mmHg, p less than 0.01). Bunazosin directly stimulated TXA2 biosynthesis in vascular smooth muscle cells in culture in a dose-dependent manner. Thus, these data clearly indicate that bunazosin, a quinazoline derivative, enhances vasoconstrictor TXA2 system in the vascular wall and kidney possibly through direct actions, which would attenuate the antihypertensive effects of alpha 1 adrenoceptor antagonism by bunazosin treatment.

Topics: Adrenergic alpha-Antagonists; Animals; Blood Vessels; Hypertension; Kidney; Male; Methacrylates; Quinazolines; Rats; Rats, Inbred SHR; Thromboxane A2; Thromboxane-A Synthase