5-Hydroxytryptamine 1A receptor activation reduces cutaneous vasoconstriction and fever associated with the acute inflammatory response in rabbits
Department of Physiology, Centre for Neuroscience, Flinders Medical Centre, Flinders University, 5042 SA, Bedford Park, Australia. Neuroscience
(Impact Factor: 3.36).
02/2004; 123(1):1-4. DOI: 10.1016/j.neuroscience.2003.09.021
5-Hydroxytryptamine1A (5-HT1A) receptor activation reduces body temperature partially by dilating the thermoregulatory cutaneous vascular bed, thereby increasing heat transfer to the environment. Constriction of this vascular bed, with consequent reduction of heat transfer to the environment, contributes to fever associated with the acute inflammatory response. Thus activation of 5-HT1A receptors might inhibit thermoregulatory cutaneous vasoconstriction and reduce the fever associated with the acute inflammatory response. The present study tested this hypothesis in conscious unrestrained rabbits. The acute inflammatory reaction was induced with i.v. lipopolysaccharide (LPS, 0.5 μg/kg). Body temperature was measured with an i.p. telemetric probe, and ear pinna blood flow was measured with a chronically implanted Doppler ultrasonic probe. 5-HT1A receptors were activated with i.v. 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT).
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ABSTRACT: The serotonin (5-hydroxytryptamine, 5-HT) receptors have conventionally been divided into seven subfamilies, most of which have several subtypes. Among them, 5-HT(2A) receptor is associated with the contraction of vascular smooth muscle, platelet aggregation and thrombus formation and coronary artery spasms. Accordingly, selective 5-HT(2A) antagonists may have potential in the treatment of cardiovascular diseases. Sarpogrelate, a selective 5-HT(2A) antagonist, has been introduced clinically as a therapeutic agent for the treatment of ischemic diseases associated with thrombosis. Molecular modeling studies also suggest that sarpogrelate is a 5-HT(2A) selective antagonist and is likely to have pharmacological effects beneficial in the treatment of cardiovascular diseases. This review describes the above findings as well as the signaling linkages of the 5-HT(2A) receptors and the mode of agonist binding to 5-HT(2A) receptor using data derived from molecular modeling and site-directed mutagenesis.
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ABSTRACT: Reduction of body temperature is used as predictor of psychotropic drug action. The cutaneous circulation functions as a heat-loss component of temperature regulation. Clozapine and olanzapine reverse hyperthermia and sympathetically-mediated cutaneous vasoconstriction induced by MDMA (3,4-methylenedioxymethamphetamine, ecstasy), suggesting that these drugs might reverse other forms of sympathetically mediated cutaneous vasoconstriction.
Clozapine and olanzapine were compared with haloperidol with respect to their ability to reverse cold-induced and LPS (lipopolysaccharide)-induced cutaneous vasoconstriction in rabbits.
Cutaneous blood flow was measured in conscious rabbits by Doppler ultrasonic flow probe implanted around the central ear artery, and body temperature was measured telemetrically. After control observations, animals were transferred from 26 to 10 degrees C, or LPS (0.5 microLg/kg IV) was administered. After 30 min, clozapine, olanzapine or haloperidol was administered and ear pinna blood flow and body temperature were measured for another 30 min.
Clozapine, in a dose responsive manner (1, 2.5 and 5 mg/kg IV), substantially reversed cold-induced ear pinna vasoconstriction and reduced body temperature. Clozapine (1 mg/kg IV) reversed LPS-induced cutaneous vasoconstriction and reduced the LPS-induced rise in body temperature. Olanzapine had generally similar effects. Haloperidol (1 mg/kg IV in cold experiments and 0.2 mg/kg IV in LPS experiments) did not reverse ear pinna vasoconstriction, or affect body temperature.
Both clozapine and olanzapine, but not haloperidol, reverse physiologically induced cutaneous sympathetic vasomotor discharge. Because of the close link between psychological function and sympathetic regulation of cutaneous blood flow, similar neuropharmacological mechanisms might underly the cutaneous vasodilating action and the psychotropic actions of atypical antipsychotic drugs.
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