Central thromboxane receptors: mRNA expression and mediation of pressor responses.
These studies tested whether activation of central thromboxane (Tx)A2/prostaglandin (PG) H2 receptors raises blood pressure (BP). Messenger RNA for TxA2/PGH2 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 TxA2/PGH2 receptor agonist U-46,619 given intracerebroventricularly or intravenously. Because the pressor 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 [3H]U-46,619 demonstrated that approximately 35% of the drug reached the systemic circulation by 5-15 min after intracerebroventricular administration. Coadministration of a TxA2/PGH2 antagonist, ifetroban, by intravenous or intracerebroventricular routes blocked the pressor 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 micrograms/kg; P < 0.001). The intravenous administration of ifetroban (10 micrograms/kg) caused a greater (P < 0.02) inhibition of pressor responses to U-46,619 (1 microgram/kg) given intravenously (81 +/- 3%) compared with U-46,619 given intracerebroventricularly (40 +/- 13%). In conclusion, TxA2/PGH2 receptor mRNA is expressed in neurons, glial, and brain stem of normal rats. The central administration of a TxA2/PGH2 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.
Gao
H
H
Division of Nephrology and Hypertension, Georgetown University Medical Center, Washington, District of Columbia 20007, USA.
Peng
B
B
Welch
W J
WJ
Wilcox
C S
CS
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D001794:Blood Pressure; D001933:Brain Stem / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D015870:Gene Expression; D008297:Male; D010080:Oxazoles / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000502:physiology*; D017673:Sodium Chloride, Dietary; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology
D019086:Bridged Bicyclo Compounds, Heterocyclic; D010080:Oxazoles; D011450:Prostaglandin Endoperoxides, Synthetic; D012333:RNA, Messenger; D017482:Receptors, Thromboxane; D017673:Sodium Chloride, Dietary; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C078904:ifetroban