Activation of the central cholinergic system mediates the reversal of hypotension by centrally administrated U-46619, a thromboxane A2 analog, in hemorrhaged rats.

Abstract

In the present study, we investigated the role of the central cholinergic system in mediating the pressor effect of intracerebroventricularly administrated U-46619, a thromboxane A2 (TxA2) analog, in hemorrhaged hypotensive rats. Hemorrhage was performed by withdrawing a total volume of 2.1 ml of blood per 100 g body weight over a period of 10 min. Intracerebroventricular (i.c.v.) injection of U-46619 (0.5, 1, 2 micro g) produced a dose- and time-dependent increase in arterial pressure and reversed the hypotension of this condition. Hemorrhage caused small increases in extracellular hypothalamic acetylcholine and choline levels. Intracerebroventricular administration of U-46619 (1 micro g) further increased the levels of extracellular acetylcholine and choline by 57% and 41%, respectively. Pretreatment with SQ-29548 (8 mug; i.c.v.), a selective TxA2 receptor antagonist, completely abrogated the effects of subsequent injection of U-46619 (1 mug; i.c.v.) on arterial pressure and extracellular acetylcholine and choline levels. Pretreatment with mecamylamine (50 micro g; i.c.v.), a cholinergic nonselective nicotinic receptor antagonist, attenuated the pressor effect of U-46619 (1 micro g, i.c.v.) in hemorrhaged rats whereas pretreatment with atropine (10 micro g; i.c.v.), a cholinergic nonselective muscarinic receptor antagonist, had no effect. Interestingly, pretreatment of rats with methyllycaconitine (10 micro g; i.c.v.) or alpha-bungarotoxin (10 micro g; i.c.v.), selective antagonists of alpha-7 subtype nicotinic acetylcholine receptors (alpha7nAChRs), partially abolished the pressor effect of U-46619 (1 micro g; i.c.v.) in the hypotensive condition. Pretreatment with a combination of mecamylamine plus methyllycaconitine or mecamylamine plus alpha-bungarotoxin attenuated the reversal effect of U-46619, but only to the same extent as pretreatment with either antagonist alone. In conclusion, i.c.v. administration of U-46619 restores arterial pressure and increases posterior hypothalamic acetylcholine and choline levels by activating central TxA2 receptors in hemorrhaged hypotensive rats. The activation of central nicotinic cholinergic receptors, predominantly alpha7nAChRs, partially acts as a mediator in the pressor responses to i.c.v. injection of U-46619 under these conditions.

• Authors: Murat Yalcin, Sinan Cavun, M Sertac Yilmaz, Vahide Savci
• Journal: Brain research (Brain Res) Vol. 1118 Issue 1 Pg. 43-51 (Nov 06 2006) ISSN: 0006-8993 [Print] Netherlands
• PMID: 16962568 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bridged Bicyclo Compounds, Heterocyclic
• Chrna7 protein, rat
• Fatty Acids, Unsaturated
• Hydrazines
• Nicotinic Antagonists
• Receptors, Nicotinic
• Receptors, Thromboxane A2, Prostaglandin H2
• Vasoconstrictor Agents
• alpha7 Nicotinic Acetylcholine Receptor
• Thromboxane A2
• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
• SQ 29548
• Acetylcholine

Topics

• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid (pharmacology)
• Acetylcholine (metabolism)
• Animals
• Blood Pressure (drug effects, physiology)
• Bridged Bicyclo Compounds, Heterocyclic
• Cholinergic Fibers (drug effects, metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Extracellular Fluid (drug effects, metabolism)
• Fatty Acids, Unsaturated
• Hemorrhage (complications, physiopathology)
• Hydrazines (pharmacology)
• Hypotension (drug therapy, etiology, physiopathology)
• Hypothalamus, Posterior (drug effects, metabolism)
• Injections, Intraventricular
• Male
• Neural Pathways (drug effects, metabolism)
• Nicotinic Antagonists (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Nicotinic (drug effects, metabolism)
• Receptors, Thromboxane A2, Prostaglandin H2 (antagonists & inhibitors, metabolism)
• Thromboxane A2 (analogs & derivatives)
• Time Factors
• Vasoconstrictor Agents (pharmacology)
• alpha7 Nicotinic Acetylcholine Receptor