Abstract
Adjuvant treatment of hypovolemic shock with vasoconstrictors is controversial due to their propensity to raise arterial resistance and exacerbate ischemia. A more advantageous therapeutic approach would use agents that also promote venoconstriction to augment perfusion pressure through increased venous return. Recent studies indicate that 5-hydroxytryptophan (5-HT)1A receptor agonists increase blood pressure by stimulating sympathetic drive when administered after acute hypotensive hemorrhage. Given that venous tone is highly dependent upon sympathetic activation of α2-adrenergic receptors, we hypothesized that the 5-HT1A receptor agonist, (+)8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), would increase venous tone in rats subject to hypovolemic shock through sympathetic activation of α2-adrenergic receptors. Systemic administration of 8-OH-DPAT produced a sustained rise in blood pressure (+44 ± 3 mm Hg 35 min after injection, P < 0.01 versus saline) and mean circulatory filling pressure (+4.2 ± 0.7 mm Hg, P < 0.01 versus saline) in conscious rats subjected to hypovolemic shock. An equipressor infusion of epinephrine failed to influence mean circulatory filling pressure (MCFP). Ganglionic blockade, α1-, or peripheral α2-adrenergic receptor blockade prevented the rise in MCFP observed with 8-OH-DPAT, but only α1-adrenergic receptor blockade diminished the pressor effect of the drug (P < 0.01). 8-OH-DPAT raises blood pressure in rats in hypovolemic shock through both direct vascular activation and sympathetic activation of α1-adrenergic receptors. The sympathoexcitatory effect of 8-OH-DPAT contributes to elevated venous tone through concurrent activation of both α1- and α2-adrenergic receptors. The data suggest that 5-HT1A receptor agonists may provide an advantageous alternative to currently therapeutic interventions used to raise perfusion pressure in hypovolemic shock.
Footnotes
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This work was supported by the National Institutes of Health Grants RO1 HL072354 and RO1 HL076162 to K.E.S.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.108944.
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ABBREVIATIONS: 5-HT, 5-hydroxytryptaphan; 8-OH-DPAT, (+)8-hydroxy-2-(di-n-propylamino)-tetralin; MCFP, mean circulatory filling pressure; MAP, mean arterial pressure; L-659,066, (2R-trans)-N-(2-(1,3,4,7,12b-hexahydro-2′-oxo-spiro(2H-benzofuro(2,3-a)quinolizine-2,4′-imidazolidin)-3′-yl)ethyl) methanesulphonamide monohydrochloride; CVP, central venous pressure; HR, heart rate; VPP, venous plateau pressure; ANOVA, analysis of variance; Hex, hexamethonium chloride.
- Received June 2, 2006.
- Accepted August 1, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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