Differential age-dependent attenuation of reflex tachycardia by verapamil in rats.

To determine if verapamil alters baroreflex function differently depending on age, reflex heart rate responses to intravenous infusions of phenylephrine or sodium nitroprusside were compared in conscious 5- and 14-month-old rats before and after daily oral administration of verapamil (100 mg/kg) for 6 days. The effects of verapamil on parasympathetic and sympathetic mediation of heart rate were also assessed by repeating baroreflex tests after treatment with either propranolol or atropine. All reflex heart rate responses were initially smaller in 14- than in 5-month-old rats. Regardless of age, magnitude of reflex bradycardia or the effects on it of either cholinergic or beta-adrenergic blockade, were unaffected by verapamil. By contrast, reflex tachycardia which was attenuated in both age groups, was decreased further by subsequent cholinergic or beta-adrenergic blockade in 5-month-old rats, but only by cholinergic blockade in 14-month-old rats. These findings suggest that while verapamil did not affect autonomic mediation of reflex bradycardia, it reduced that of reflex tachycardia differently depending on age. Whereas it attenuated both sympathetic and parasympathetic mediation of reflex tachycardia in 5-month-old rats, it attenuated only sympathetic mediation in 14-month-old rats.

Autonomic regulation of reflex bradycardia in rats declines with age.

Heart rate responses, elicited reflexly by elevating blood pressure with phenylephrine or lowering it with sodium nitroprusside, were compared in groups of rats aged 4 and 14 months. All tests were done while the rats were awake to avoid artefacts due to anesthesia. Parasympathetic and sympathetic contributions were assessed by repeating baroreflex tests after cholinergic blockade with atropine or beta-adrenergic blockade with propranolol. Magnitude of reflex bradycardia and tachycardia was initially smaller in the 14-month-old rats than in the younger rats thereby indicating that baroreflex sensitivity had diminished with age. After beta-adrenergic or cholinergic blockade, adjusted means (obtained by covariance analysis) for reflex tachycardia did not differ significantly between rat groups, but those for reflex bradycardia were significantly smaller in the 14-month-old rats than in the younger rats. Selective attenuation of reflex bradycardia after either cholinergic or beta-adrenergic blockade indicates that concurrent parasympathetic activation and sympathetic withdrawal during reflex bradycardia were also reduced in 14-month-old rats. These results suggest that as autonomic mediation of reflex bradycardia diminishes with age, old rats may no longer be able to slow the heart as easily whenever blood pressure rises, but they can still accelerate it whenever blood pressure falls.

Age-dependent baroreflex attenuation by centrally infused verapamil in rats.

Because oral administration of verapamil for 6 days reduces reflex tachycardia without affecting reflex bradycardia, we tested chronotropic baroreflexes in conscious rats aged 5 or 15 months before and after verapamil was infused intracerebroventricularly for 6 days to determine whether a central action contributes to the reflex attenuation. Baroreflex responses consisted of reflex bradycardia elicited during pressor responses to methoxamine and reflex tachycardia during depressor responses to sodium nitroprusside. As we have shown previously, all reflex heart rate responses were initially smaller in 15-month-old than in 5-month old rats. Osmotic minipumps filled with saline or verapamil (100 micrograms/kg/day) were connected to cannulas in a lateral ventricle or femoral vein and, after 6 days, baroreflexes were recorded again. Control infusions of either saline intracerebroventricularly or verapamil intravenously were ineffective. In contrast, intracerebroventricular infusions of verapamil attenuated reflex heart rate responses to methoxamine or sodium nitroprusside differently in the two age groups: both reflex tachycardia and bradycardia were attenuated in 5-month-old rats; however, in 15-month-old rats only reflex bradycardia was reduced, whereas reflex tachycardia was unaffected. The selective reduction of reflex tachycardia in 5-month-old, but not in 15-month-old, rats suggests that intracerebroventricularly infused verapamil affects central baroreflex regulation differently depending on age.

Differential anesthetic depression of chronotropic baroreflexes in rats.

To assess anesthetic alteration of chronotropic baroreflexes, arterial pressure and heart rate (HR) were monitored continuously during intravenous (i.v.) infusions of phenylephrine or sodium nitroprusside in rats that were either awake or anesthetized (with pentobarbital, urethane, or chloralose). Ensuing reflex HR responses during each drug infusion were determined in two ways: (a) at 10-s intervals (time analysis), and (b) with every 5-mm Hg change in pressure (pressure analysis). Results were less variable with pressure than with time analysis. With responses from awake rats as a basis for comparison, pressure analysis showed that pentobarbital greatly attenuated both reflex tachycardia and bradycardia, whereas urethane and chloralose reduced only reflex tachycardia. Depression by pentobarbital of both reflex tachycardia and bradycardia suggests severe attenuation of both sympathetic and parasympathetic tone. In contrast, preferential alteration of reflex tachycardia by chloralose and urethane implies a greater attenuation of sympathetic than parasympathetic tone.

Uneven blunting of chronotropic baroreflexes in obese Zucker rats.

We compared reflex chronotropic responses to intravenously infused drugs in three groups of age-matched normotensive female rats, namely, Sprague-Dawley, lean Zucker, and obese Zucker. Initial mean pressures did not differ between rat groups, but heart rates tended to be lower in obese Zucker rats. Baroreflex impairment was already evident, because heart rate responses to infused phenylephrine (reflex bradycardia) or sodium nitroprusside (reflex tachycardia) were consistently weaker in obese Zucker than in other rats. Regardless of rat grouping, subsequent cholinergic blockade with atropine elevated, whereas beta-adrenergic blockade with propranolol lowered, basal heart rates without affecting mean pressure. Reflex heart rate responses were all appreciably reduced after either type of autonomic blockade, and although the extent of inhibition varied between rat groups, the residual heart rate responses remaining after blockade were nonetheless always smaller in obese than in lean rats. This difference suggests that efferent sympathetic and parasympathetic mechanisms normally responsible for mediating heart rate reflexes were unevenly blunted in obese Zucker rats.

Obese Zucker rats, though still normotensive, already have impaired chronotropic baroreflexes.

We compared reflex chronotropic responses to intravenously-infused drugs in 3 groups of age-matched female rats, namely: Sprague-Dawley, lean Zucker, and obese Zucker. Initial baselines for mean arterial pressure and heart rate did not differ between rat groups. However, baroreflex sensitivity was evidently attenuated in obese Zucker rats because their heart rate responses to infused phenylephrine or sodium nitroprusside were consistently weaker than those of other rats. Should these rats eventually become hypertensive, their blunted baroreflexes could contribute importantly to initiate the blood pressure elevation.