Tolerance development to the vagal-mediated bradycardia produced by 5-HT1A receptor agonists.
The purpose of this study was to characterize the bradycardic effects of 5-hydroxytryptamine (5-HT)1A receptor agonists in the chloralose-anesthetized spinal cat and to determine if tolerance develops to the bradycardia produced by these drugs. 5-HT1A receptor agonists studied included 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), buspirone, gepirone, flesinoxan and U-93385E (cis-(3aR)-(-)-2,3,3a,4,5,9b-hexahydro-3-propyl-1H-benz[e]indole-9 - carboxamide). These compounds reduced heart rate by 20 to 30% in the spinal cat and lowered arterial blood pressure. The hypotension resulted from a decrease in cardiac output. Atropine reversed and vagotomy prevented the bradycardia produced by a single dose of U-93385E. The decrease in heart rate produced by i.v. bolus doses of flesinoxan or U-93385 was reversed by administration of the 5-HT1A receptor antagonists spiperone or WAY 100135. Administration of a single dose of U-93385E (either 0.3, 1.0 or 3.0 mg/kg i.v.) resulted in a 20 to 30% decrease in heart rate. In contrast, cumulative dosing of U-93385E (0.01-3.0 mg/kg i.v.) failed to lower heart rate in the spinal cat. Similarly, infusion of 1 mg/kg of U-93385E over a 2-hr period failed to lower heart rate and prevented a bradycardic effect of a single bolus dose of U-93385E or flesinoxan. In contrast, the alpha-2 receptor agonist clonidine decreased heart rate in animals receiving the U-93385E infusion. Finally, single bolus doses of flesinoxan or U-93385E failed to decrease heart rate in cats treated for 7 days with U-93385E and then saline for 3 days.(ABSTRACT TRUNCATED AT 250 WORDS)
McCall
R B
RB
Upjohn Company, Kalamazoo, Michigan.
Escandon
N A
NA
Harris
L T
LT
Clement
M E
ME
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D002065:Buspirone / Q000494:pharmacology; D002415:Cats; D004361:Drug Tolerance; D006339:Heart Rate / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology*
D007211:Indoles; D011743:Pyrimidines; D017366:Serotonin Receptor Agonists; C082409:U 93385; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C039979:gepirone; D002065:Buspirone