BLOOD-PRESSURE EFFECTS OF THROMBOXANE-A(2) BLOCKADE IN SPONTANEOUSLY HYPERTENSIVE RATS

1. The effects of CGS 22652, a thromboxane (Tx) A2 synthase inhibitor and TxA2/prostaglandin (PG) H2 receptor antagonist, on blood pressure (BP) were studied in conscious freely moving spontaneously hypertensive rats (SHR). 2. Three groups of 13 male SHR were subcutaneously infused from 5 to 11 weeks of age via osmotic minipumps with CGS 22652 at doses of 5 (SHRa) or 10 (SHRb) mg/kg per 24 h or with the vehicle only (SHRc). A fourth group (SHRd, n = 13) was orally treated from 3 to 11 weeks of age with CGS 22652 (30 mg/kg) given by gavage once a day. 3. CGS 22652 dose-dependently reduced the age-related increase in systolic BP. The pressor response to noradrenaline (200 ng/kg, i.v.) but not to angiotensin I or II was slightly (P < 0.05) diminished in 11 week old SHRb and SHRd compared to SHRc. Acute ganglionic blockade by trimethaphan (10 mg/kg, i.v.), as well as angiotensin converting enzyme inhibition by perindopril (2 mg/kg, i.v.) decreased BP to a similar extent in the four groups. After combined blockade of vasopressin receptors and of the autonomic nervous system and the administration of a direct vasodilator (hydralazine, 3 mg/kg, i.v.), the residual mean BP was identical in the four groups of rats. 4. Chronic treatment with CGS 22652 dose-dependently antagonized the TxA2/PGH2 receptors but did not modify the TxA2 synthesis. The urinary sodium excretion did not differ between groups. 5. In conclusion, at the doses used, CGS 22652 given either orally or subcutaneously exhibited only TxA2/PGH2 receptor blocking properties in SHR. Chronic treatment modestly prevented the development of hypertension in SHR, probably through a decrease in the pressor effects of TxA2 and of noradrenaline.