Central thromboxane receptors: mRNA expression and mediation of pressor responses

These studies tested whether activation of central thromboxane (Tx) A(2)/prostaglandin (PG) H-2 receptors raises blood pressure (BP). Messenger RNA for TxA(2)/PGH(2) receptors was detected in normal Sprague-Dawley rat brain and in rat neuronal and astroglial brain cells in culture. The mean arterial blood pressure (MAP) was recorded in conscious rats during graded administration of the TxA(2)/PGH(2) receptor agonist U-46,619 given intracerebroventricularly or intravenously. Because the presser responses to intracerebroventricular (but not intravenous) U-46,619 were significantly greater in high-salt compared with low-salt rats, high-salt rats were used for subsequent studies. The rise in MAP with intracerebroventricular administration of U-46,619 was greater than with intravenous administration and was more sustained. A comparison of plasma radioactivity after intracerebroventricular or intravenous injection of [H-3]U-46,619 demonstrated that similar to 35% of the drug reached the systemic circulation by 5-15 min after intracerebroventricular administration. Coadministration of a TxA(2)/PGH(2) antagonist, ifetroban, by intravenous or intracerebroventricular routes blocked the presser responses induced by U-46,619. The half-maximal inhibition for blockade of responses was substantially lower for intracerebroventricular than for intravenous responses (intracerebroventricular: 0.03 +/- 0.01 vs. intravenous: 3.1 +/- 0.6 mu g/kg; P < 0.001). The intravenous administration of ifetroban (10 mu g/kg) caused a greater (P < 0.02) inhibition of presser responses to U-46,619 (1 mu g/kg) given intravenously (81 +/- 3%) compared with U-46,619 given intracerebroventricularly (40 +/- 13%). In conclusion, TxA(2)/PGH(2) receptor mRNA is expressed in neurons, glial, and brain stem of normal rats. The central administration of a TxA(2)/PGH(2) mimetic raises blood pressure by interaction with specific central and peripheral receptors. This response is augmented in rats fed a high-salt compared with a low-salt diet.