Does chronic ketanserin treatment enhance bradycardia in old rats by serotonergic blockade?

To determine if the cardiovascular effects of chronic treatment with ketanserin would vary with increasing age, ketanserin was given by daily gavage for 14 days to male Sprague-Dawley rats at ages 4, 14, or 24 months. Before treatment, 24-month-old rats had higher blood pressures and weaker reflex heart rate responses than younger rats. Treatment with ketanserin caused hypotension, enhanced bradycardia, attenuated reflex tachycardia, and reversed serotonin (5-HT) responses, with all effects being more pronounced in 24-month-old rats than in younger rats. None of the age-related effects can be attributed to alpha-adrenergic blockade because they occurred even while cardiovascular responses to phenylephrine, an alpha 1-adrenergic agonist, were unaltered at any age. On the other hand, serotonergic blockade seems a more likely explanation because reversal or enhancement by ketanserin of cardiovascular responses to serotonin was age-related, being more marked in 14- and 24- than in 4-month-old rats. Our results suggest that as the cardiovascular effects of ketanserin become more pronounced with advancing age, 5-HT blockade intensifies and bradycardia becomes augmented until the ensuing cardiac inhibition eventually accentuates the hypotensive effects in older rats.

Hypotensive and reflex bradycardic effects of ketanserin, but not of prazosin, enhanced selectively in aging conscious rats.

To determine whether cardiovascular effects of ketanserin are altered differently with aging as compared with those of prazosin, we recorded blood pressure (BP) and heart rate (HR) changes produced by treatment with either drug in three age groups of conscious Sprague-Dawley rats. BP was decreased more by ketanserin in 24-month than in 4- or 14-month-old rats, but was decreased equally by prazosin in all age groups. Pressor responses to phenylephrine (PE) were consistently abolished by both drugs, indicating that the greater hypotensive effects of ketanserin in 24-month-old rats were not due simply to alpha 1-adrenergic blockade. By contrast, baroreflex sensitivity, determined from reflex HR responses to infused angiotensin or sodium nitroprusside (SNP), was altered differently in old rats by ketanserin but not by prazosin. Whereas enhancement of reflex bradycardia by prazosin occurred at all ages, it was demonstrable only with ketanserin in older rats. Moreover, reflex tachycardia was unaffected by prazosin but was reversed to bradycardia by ketanserin in older rats. Because these differences persisted even after the data had been normalized to compensate for differences in baseline pressures, effects on HR reflexes were considered age dependent for ketanserin but not for prazosin. Although the underlying mechanisms are not clear, the selective enhancement of reflex bradycardia and reversal of reflex tachycardia in old rats by ketanserin, but not by prazosin, could explain why hypotensive responses to ketanserin increase with age whereas those to prazosin do not.

Aging impairs heart rate reflexes earlier in female than in male Sprague-Dawley rats.

We compared heart rate reflexes in conscious male or female Sprague-Dawley rats at ages of 4, 14, or 24 months to determine whether, with advancing age, baroreflex sensitivity diminishes uniformly in both sexes. Phenylephrine or sodium nitroprusside was infused intravenously to elevate or lower systemic arterial pressure and thereby elicit reflex changes in heart rate. Ensuing blood pressure responses to either drug were smaller at 24 months than at 4 or 14 months in males but did not differ between age groups in females. By contrast, reductions in reflex tachycardia or bradycardia were significant at 14 and 24 months in females but only at 24 months in males. Regression slopes from 4 to 14 months of age, though unaltered in males, fell significantly in females (from 2.35 +/- 0.2 to 1.28 +/- 0.2 for tachycardia, and from -2.17 +/- 0.1 to -1.46 +/- 0.1 for bradycardia). Thus, heart rate reflexes though eventually impaired in both sexes, were impaired earlier in females than in males.

Aging enhances serotonergic cardiovascular blockade by ketanserin in conscious rats.

We recorded cardiovascular responses to serotonin (5-HT) and to two selective serotonergic agonists following ketanserin treatment in 3 groups of conscious rats aged 4, 14 or 24 months. The selective agonists were DOI (5-HT2 agonist), and phenylbiguanide (5-HT3 agonist). Before ketanserin treatment, pressor responses to 5-HT or DOI were larger while reflex bradycardic responses to 5-HT or phenylbiguanide were smaller in 14- and 24-month than in 4-month-old rats. Ketanserin treatment lowered blood pressure consistently, and the ensuing hypotension was more pronounced in 14- and 24-month than in 4-month-old rats. Pressor responses to DOI were attenuated similarly in all rats, but those to 5-HT were reversed to depressor responses whose magnitude was smaller in 14- and 24-month than in 4-month-old rats. On the other hand, bradycardic responses to 5-HT and phenylbiguanide were enhanced in 14- and 24- but not in 4-month-old rats. Our results indicate that even before ketanserin was given, old rats had enhanced pressor responses to 5-HT2 agonists together with weakened bradycardic responses to 5-HT3 agonists. Following ketanserin treatment, 5-HT2 pressor responses were blocked while 5-HT3 bradycardic responses were enhanced but only in old rats. These results are compatible with the interpretation that the more pronounced hypotension produced in old rats by ketanserin is due to two complementary effects on serotonergic receptors: blockade of 5-HT2 pressor responses coupled with selective enhancement of 5-HT3 bradycardic responses.