Abstract
5-Hydroxytryptamine 1A (5-HT1A) receptor agonists reverse the hypotensive and sympathoinhibitory responses to severe hemorrhage in rats. To determine whether 5-HT1A receptor-mediated pressor responses in hypovolemic animals are due to sympathoexcitation and/or direct vasoconstriction, blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) responses to the partial 5-HT1A receptor agonist buspirone or the more selective, full 5-HT1A receptor agonist (+)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) were compared in intact and ganglionic blocked, hemorrhaged Sprague-Dawley rats. Buspirone produced dose-dependent increases in BP (110 ± 4**, 86 ± 4**, 65 ± 7 mm Hg), HR [369 ± 10**, 337 ± 14, 277 ± 16 beats per minute (bpm)], and RSNA (114 ± 36**, 34 ± 21, -23 ± 25% baseline for 0.2, 0.1, and 0 mg/kg; **p < 0.01 versus 0 mg/kg, 3 min after injection). Ganglionic blockade with hexamethonium chloride blocked the pressor effect of 9.9 μg/kg 8-OH-DPAT and attenuated, but did not block, the pressor response to 0.2 mg/kg buspirone (85 ± 7 versus 46 ± 6 mm Hg for buspirone + ganglionic blockade versus saline + ganglionic blockade; p < 0.01). In subsequent tests, rats treated with the selective α1-adrenergic receptor antagonist prazosin (25 μg/kg) continued to show extensive tachycardic (+73 ± 26 bpm) and sympathoexcitatory (128 ± 55% baseline) responses to 0.2 mg/kg buspirone. Ganglionic blockade combined with prazosin completely blocked all responses to buspirone. Buspirone (0.2 mg/kg) produced significant bradycardic (-89 ± 12 bpm; p < 0.01) and sympathoinhibitory (-72 ± 7% baseline; p < 0.01) responses in euvolemic rats 3 min after injection. It is concluded that the pressor effect of buspirone is unique to hypovolemic animals and is mediated by sympathetic activation as well as direct activation of vascular α1-adrenergic receptors.
Footnotes
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This work was supported by American Heart Association Grants 0310026Z and 9930104N (to P.O.-O. and K.S.).
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DOI: 10.1124/jpet.103.064626.
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ABBREVIATIONS: 5-HT1A, 5-hydroxytryptamine 1A receptor; 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin; BP, blood pressure; HR, heart rate; RSNA, renal sympathetic nerve activity; PE, polyethylene; MAP, mean arterial pressure; ANOVA, analysis of variance; bpm, beats per minute; WAY-100,635, [O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride.
- Received December 18, 2003.
- Accepted February 6, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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