BLOOD PRESSURE EFFECTS OF THROMBOXANE A₂ BLOCKADE IN SPONTANEOUSLY HYPERTENSIVE RATS

Abstract

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-dependent 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Endothelium-Derived Contracting Factor in Carotid Artery of Hypertensive Dahl Rats

“…It has been reported that blockage of TXA 2 synthetase induced a significant antihypertensive effect in SHR. 21,22 The antihypertensive effect may be due to improvement of renal function and due to decrease in the pressor effects of TXA 2 and of noradrenaline. In contrast to SHR, the depressor effect is not obtained in hypertensive Dahl rats, although blockage of TXA 2 synthetase ameliorates renal functional and structural lesions.…”

Delayed Hypotensive Effect Of The Thromboxane A2/Prostaglandin H2 Receptor Antagonist S‐1452 in Spontaneously Hypertensive Rats

“…Thromboxane A2 elevates BP through several mechanisms, such as salt and water retention, 18 activation of the sympathetic nervous system, 19 enhancement of the vasoconstrictor effects of angiotensin (Ang)II, 20 noradrenaline, 18 endothelin-1, 21 5-hydroxytryptamine and vasopressin. [11][12][13][14][15][16]23 However, some results suggest that TxA2 synthase inhibitors, but not TxA2/PGH2 receptor antagonists, have the ability to lower BP in SHR. [5][6][7][8][9] If TxA2 is profoundly involved in the development of hypertension in SHR, inhibition of TxA2 synthesis or blockade of TxA2/PGH2 receptors could lower BP in these animals.…”

“…Previous findings on the effects of a TxA2 synthase inhibitor and TxA2/PGH2 receptor antagonist on BP in SHR have been conflicting. [11][12][13][14][15][16]23 However, some results suggest that TxA2 synthase inhibitors, but not TxA2/PGH2 receptor antagonists, have the ability to lower BP in SHR.…”

“…A large oral dose of OKY-046, a TxA2 synthase inhibitor, decreased blood pressure (BP) in SHR. Boussairi et al 15 reported significant reductions of BP using CGS 22652, a TxA2/PGH2 receptor antagonist with TxA2 synthase inhibitory activity, in SHR, while Johnson et al 16 did not observe such a reduction using ifetroban, another TxA2/PGH2 receptor antagonist. 12 In contrast, short-term studies with TxA2/PGH2 receptor antagonists did not show significant BP reductions in SHR.…”

“…13,14 However, long-term treatment with these agents provided apparently controversial effects. Boussairi et al 15 reported significant reductions of BP using CGS 22652, a TxA2/PGH2 receptor antagonist with TxA2 synthase inhibitory activity, in SHR, while Johnson et al 16 did not observe such a reduction using ifetroban, another TxA2/PGH2 receptor antagonist. Thus, to understand more clearly the role of TxA2 in the development and maintenance of hypertension in SHR, further studies involving long-term treatment with other TxA2/PGH2 receptor antagonists is needed.…”