Delayed hypotensive effect of the thromboxane A2/prostaglandin H2 receptor antagonist S-1452 in spontaneously hypertensive rats

1. Several lines of evidence indicate that thromboxane (Tx) A(2) may contribute to the development and maintenance of hypertension. The present study was undertaken to evaluate the role of TxA(2) in the development of hypertension in spontaneously hypertensive rats (SHR) by using an orally active, highly specific TxA(2)/prostaglandin H-2 receptor antagonist S-1452. 2. Vehicle (1% arabic gum solution) alone was given orally to Wistar-Kyoto (WKY) rats (n = 15) and SHR (n = 14), while S-1452 (10 mg/kg per day, twice daily) was administered orally to SHR (n = 16) for 18 weeks (from 5 to 23 weeks of age). 3. No significant difference was observed in tail-cuff blood pressure (BP) between vehicle- and S-1452-treated SHR before and at 5 and 11 weeks after treatment. Thereafter, BP was further elevated in vehicle-treated SHR, but was significantly blunted in SHR treated with S-1452 at 15 (224 +/- 8 vs 211 +/- 13 mmHg; P < 0.01) and 18 weeks (227 +/- 9 vs 206 +/- 10 mmHg; P < 0.001); this was associated with reduced proteinuria. 4. Urinary TxB(2) in vehicle-treated SHR, especially during the early period, was significantly greater than that in WKY rats, while no significant difference was observed in urinary 6-keto-prostaglandin F-1 alpha (6-keto-PGF(1 alpha)) between the two groups. Treatment with S-1452 reduced urinary excretion of TxB(2) at 18 weeks. 5. The present study shows that S-1452, at the dose used, does not reduce BP during the early period of the development of hypertension. These results suggest that the role of enhanced TxA(2) production in the development of hypertension is small, if any, in SHR. Delayed response of BP may be independent of the direct pharmacological effects of S-1452.