Differences in the acute and chronic antihypertensive mechanism of action of ketanserin in spontaneously hypertensive rats.
The antihypertensive mode of action of the 5HT2 receptor antagonist, ketanserin (KET), is still a subject of controversy and has been evaluated predominantly in acute studies. Acute i.v. administration of KET (3.0 or 6.0 mg/kg) in spontaneously hypertensive rats resulted in dose-dependent reductions in mean arterial pressure accompanied by concomitant bradycardia. In these studies, the responses to single i.v. doses of the alpha-1 adrenoceptor agonist phenylephrine (10.0 micrograms/kg) and to the 5HT2 receptor agonist alpha-methyl-5-hydroxytryptamine (125.0 micrograms/kg) 30 min after injection of KET were blocked. In spontaneously hypertensive rats treated with KET infusions (3.0 mg/kg/day i.v., n = 9, or 6.0 mg/kg/day i.v., n = 8) for 7 days via osmotic minipumps, significant dose-dependent falls in systolic blood pressure were observed during the period of infusion. Heart rate did not change over the period of observation in both vehicle- and KET-treated groups. On day 7 of infusion, KET dose-dependently reduced responses to the 5HT2 agonist alpha-methyl-5-hydroxytryptamine (5.0-125.0 micrograms/kg i.v.) but did not affect responses to phenylephrine (1.0-10.0 micrograms/kg i.v.). Baroreflex sensitivity on day 7 was significantly greater in KET-infused rats as compared with control rats. These data confirm that the acute antihypertensive effects of KET are due to a combination of alpha-1 and 5HT2 receptor blockade. During chronic administration, however, the alpha-1 blocking effects of KET are compensated for, and the reduction in blood pressure by day 7 of KET chronic administration is maintained predominantly by persistent blockade of 5HT2 receptors.
Balasubramaniam
G
G
Department of Pharmacology, Faculty of Medicine, National University of Singapore, Kent Ridge.
Lee
H S
HS
Mah
S C
SC
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007262:Infusions, Intravenous; D007650:Ketanserin / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR / Q000502:physiology*; D012680:Sensitivity and Specificity; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013997:Time Factors
D000317:Adrenergic alpha-Antagonists; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C042390:alpha-methylserotonin; D012701:Serotonin; D007650:Ketanserin