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.

Short-term lisinopril treatment in old rats worsens impairment of angiotensin-induced reflex bradycardia.

To determine how short-term treatment with an angiotensin-converting enzyme (ACE) inhibitor affects drug-induced reflex bradycardia at different ages in conscious rats, we compared the magnitude of drug-induced reflex bradycardia before and after injecting bolus intravenous doses of lisinopril, 1 mg/100 g, in male Sprague-Dawley rats aged 4 (young) or 19 (old) months. Anesthetic artifacts were avoided by recording all drug-induced cardiovascular responses from femoral arterial cannulas implanted 1 week earlier. For eliciting reflex bradycardia, blood pressure was increased by graded intravenous infusion of angiotensin or phenylephrine. Impairment of reflex bradycardia in old rats occurred only during pressor responses to angiotensin but not when blood pressure was equally increased with phenylephrine. Subsequent administration of lisinopril affected neither pressor and reflex bradycardic responses to phenylephrine nor pressor responses to angiotensin. However, contrary to the baroreflex enhancement described previously by others, the reflex bradycardia induced by angiotensin was reduced by lisinopril treatment but only in old and not in young rats. Thus our results indicate that whereas angiotensin-induced reflex bradycardia was already impaired in old rats before lisinopril was given, it was reduced further after short-term lisinopril treatment.

Conscious obese rats have impaired reflex bradycardia and enhanced norepinephrine sensitivity.

Male Sprague-Dawley rats fed a condensed milk diet were classified as either "obesity susceptible" (OS) or "obesity resistant" (OR) based on body weight increases attained after 12 wk. Overall caloric intake in OS rats was higher than in chow-fed controls, and OS rats were heavier than chow-fed controls or OR rats. There were no significant differences in blood glucose, serum insulin, ventricular weight, basal blood pressure, or heart rate. Pressor responses recorded after combined blockade with atropine and propranolol to eliminate reflex effects were identical for vasopressin, but those to norepinephrine were larger in OS than in OR rats, whereas those to angiotensin were larger in OS than in control rats. When baroreflex sensitivity was assessed using intravenously infused sodium nitroprusside or phenylephrine to alter systemic arterial pressure, differences in reflex tachycardia were equivocal, but reflex bradycardia was clearly inhibited in OS rats. These results show that, although basal blood pressure was unaffected in OS rats, their impaired reflex bradycardia along with enhanced pressor responsiveness to norepinephrine could predispose them to subsequent development of hypertension.

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.

Contrasting baroreflex effects of muscimol versus bicuculline injected into the nucleus tractus solitarius in anesthetized rats.

To examine how the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) affects baroreflex regulation, reflex heart rate and renal nerve responses were recorded in anesthetized rats after bilateral injections of muscimol or bicuculline into the nucleus tractus solitarius (NTS). Blood pressure, heart rate, and renal nerve activity were increased by the GABA agonist muscimol and decreased by the GABA antagonist bicuculline. Control injections of the vehicle alone were ineffective. More importantly, all reflex responses later induced by infusing phenylephrine or sodium nitroprusside intravenously were reduced by muscimol. The magnitude of the reflex bradycardia and sympathoinhibition caused by phenylephrine, as well as that of the reflex tachycardia and sympathoexcitation caused by sodium nitroprusside, diminished after NTS injections of muscimol. By contrast, the same reflex responses tended to be enhanced after NTS injections of bicuculline, but most changes were not significant. If GABA acts on receptors located on second-order neurons in the NTS, then muscimol would inhibit those neurons, whereas bicuculline would prevent endogenous GABA from reaching them. Thus muscimol would reduce reflex responsiveness by inhibiting all second-order neurons, whereas bicuculline would enhance it by protecting the same neurons from inhibition by endogenous GABA.

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.

Insulin acts centrally to enhance reflex tachycardia in conscious rats.

Systemic and central insulin treatment for 10 days were compared in conscious rats given insulin either by daily subcutaneous injection or by continuous intracerebroventricular infusion. To measure changes in baroreflex sensitivity, heart rate responses elicited reflexly by elevating blood pressure with phenylephrine or lowering it with sodium nitroprusside were recorded before and after insulin treatment. Although reflex bradycardia and basal mean pressures and heart rates were unaffected, reflex tachycardia was consistently more pronounced in rats treated with insulin (whether given systemically or centrally) than in vehicle-treated controls. Plasma glucose was reduced and plasma insulin was elevated but only in insulin-treated rats injected subcutaneously and not in those infused intracerebroventricularly. Inasmuch as reflex tachycardia was still enhanced when insulin was infused intracerebroventricularly despite the absence of hypoglycemia and hyperinsulinemia, our results are compatible with the interpretation that insulin acts directly on the brain to enhance reflex tachycardia. This interpretation furthermore implies that insulin, even after chronic systemic treatment, could reach the brain and alter baroreflex regulation.

Selective enhancement in SHR of hypotension and bradycardia caused by NTS-injected serotonin.

To examine whether serotonergic mechanisms in the nucleus tractus solitarius (NTS) become altered by hypertension, responses to serotonin (5-HT) or L-glutamate injected into the NTS were compared in anesthetized rats. Because isotonic saline had appreciable effects whereas artificial cerebrospinal fluid did not, artificial cerebrospinal fluid was routinely used as the vehicle. Microinjections of 5-HT or L-glutamate always reduced mean pressure, heart rate, and renal nerve activity. Depressor and bradycardic responses to 5-HT were consistently more pronounced in spontaneously hypertensive rats than in either regular Wistar or Wistar-Kyoto rats, but similar responses elicited with L-glutamate did not differ between rat groups. By contrast, attendant inhibition of renal nerve activity was the same in all rats, thereby suggesting that it either is not a good indicator of sympathetic activity or does not contribute to the hypotensive effects of 5-HT. Our results are compatible with the interpretation that hypotensive responses to 5-HT were enhanced because serotonergic mechanisms for cardiovascular regulation in the NTS were sensitized in spontaneously hypertensive rats.

Age-related reduction of reflex bradycardia in conscious rats by catecholaminergic nucleus tractus solitarius lesions.

To determine whether catecholaminergic lesions in the nucleus tractus solitarius (NTS) have age-related baroreflex effects, we compared conscious 3-month- and 14-month-old rats pretreated with either 6-hydroxydopamine (6-OHDA) or vehicle injected into the NTS. Body weights fell immediately in both age groups, but after 2 weeks the weight loss persisted only in 14-month-old rats. Mean pressures and heart rates, though diminished after 3 days, were later elevated slightly in 3-month- but not in 14-month-old rats. Two weeks after 6-OHDA pretreatment, reflex tachycardia was reduced in both age groups, but reflex bradycardia was reduced only in 3-month-old and not in 14-month-old rats. Corresponding changes in vehicle-treated rats were not significant. Because 6-OHDA induced lesions in the NTS inhibited reflex bradycardia selectively at 3 but not at 14 months of age, our results suggest that catecholaminergic mechanisms in the NTS for regulating reflex bradycardia become impaired with age.

Catecholaminergic nucleus tractus solitarius lesions in anesthetized rats alter baroreflexes differently with age.

To explore whether catecholaminergic lesions produced chemically in the nucleus tractus solitarius (NTS) would alter the baroreflex impairment that normally occurs with age, we compared baroreflex responses in 3- and 14-month-old rats given bilateral microinjections of 6-hydroxydopamine (6-OHDA) or its vehicle into the NTS. After 2 weeks, basal pressures were unaffected but heart rates were lower in 14- than in 3-month-old rats. Sympathetic nerve inhibition elicited reflexly during intravenous infusions of sodium nitroprusside was reduced in 3-month-old rats, but increased in 14-month-old rats. Depressor, bradycardiac, and sympatho-inhibitory responses to afferent aortic nerve stimulation were likewise reduced in 3-month-old rats and oppositely enhanced in 14-month-old rats. Enhanced bradycardia probably does not depend on increased parasympathetic sensitivity because responses to vagal stimulation did not differ between age groups. Although underlying mechanisms remain uncertain, by showing that baroreflex responses become altered differently in 3- and 14-month-old rats by 6-OHDA these results suggest that the baroreflex changes normally occurring with age may be due, at least in part, to modified catecholaminergic mechanisms in the NTS.

Baroreflex changes produced by serotonergic or catecholaminergic lesions in the rat nucleus tractus solitarius.

To distinguish between catecholaminergic and serotonergic mechanisms for baroreflex regulation in the medulla, we compared rats with chemical lesions produced by injecting 6-hydroxydopamine (6-OHDA) or 5,7-dihydroxytryptamine (5,7-DHT) into the nucleus tractus solitarius (NTS) bilaterally at the caudal tip of the area postrema. After 2 weeks, basal blood pressure and heart rate were unaltered, but blood pressure lability, instead of being increased, was slightly reduced. Baroreflex tests in conscious rats showed that although phenylephrine-induced reflex bradycardia was unaffected, nitroprusside-induced reflex tachycardia was enhanced by 5,7-DHT. In anesthetized rats, drug-induced reflex chronotropic responses no longer differed between groups, but attendant decreases or increases in renal nerve activity were consistently reduced by 6-OHDA. On the other hand, upon afferent aortic nerve stimulation, particularly with low current frequencies, bradycardic and sympathoinhibitory responses were enhanced by 5,7-DHT, but the sympathoinhibitory responses were reduced by 6-OHDA. Despite the absence of demonstrable necrosis or cell loss at NTS injection sites, 6-OHDA reduced norepinephrine mainly and serotonin partly, whereas 5-7-DHT reduced serotonin content alone, thereby indicating that chemical lesions had indeed been produced. Because these cardiovascular changes probably reflect differences in catecholaminergic vs. serotonergic baroreflex regulation, our results are generally compatible with the interpretation that baroreflex modulation in the NTS involves catecholaminergic facilitation and serotonergic inhibition.

Age-related delay in recovery of beta-adrenergic sensitivity after abrupt propranolol withdrawal in rats.

We compared cardiovascular responses to various adrenergic agonists in conscious 3-month and 12-month old rats that had been treated with propranolol daily for 7 days, to determine whether changes in beta-adrenergic hypersensitivity induced by abrupt propranolol withdrawal would differ with age. Depressor and tachycardic responses elicited by beta-adrenergic stimulation with isoproterenol were still reduced during the first 3 days following propranolol withdrawal, but were restored to pretreatment levels, more slowly in 12-month than in 3-month-old rats. Opposite pressor and bradycardic responses to alpha-adrenergic stimulation with phenylephrine did not differ between age groups, either before or after propranolol withdrawal. By contrast, pressor and bradycardic responses produced by combined alpha- and beta-adrenergic stimulation with epinephrine after propranolol withdrawal, though unaltered in 3-month-old rats, were enhanced in 12-month-old rats. Hence after sudden propranolol withdrawal beta-adrenergic sensitivity in conscious rats was gradually restored, rather than being enhanced, but more slowly at 12 than at 3 months of age. These results suggest that following abrupt cessation of prolonged propranolol treatment, restoration of normal beta-adrenergic sensitivity becomes delayed in older rats.

Aging reduces cardiovascular and sympathetic responses to NTS injections of serotonin in rats.

Serotonergic mechanisms for baroreflex modulation could become altered with age. This possibility was explored by comparing cardiovascular and sympathetic effects elicited in 2-month- and 24-month-old rats by injecting serotonin (5-HT) directly into the nucleus tractus solitarius (NTS) which is the primary baroreflex relay station in the medulla. Ensuing decreases in mean pressure, heart rate, and renal nerve firing were significantly smaller in 24-month-old than in 2-month-old rats. By contrast, similar injections into the NTS of the vehicle alone were ineffective in both age groups. Postmortem examination of brain sections showed that NTS injection sites were equally distributed in both age groups, thereby indicating that the brain areas affected by 5-HT were identical regardless of age. Reduced sensitivity of peripheral myocardial beta-adrenergic and vascular alpha-adrenergic receptors was considered partly responsible because 5-HT injected into the NTS lowers blood pressure by decreasing sympathetic vasomotor tone and slows the heart by increasing vagal tone with reciprocal sympatho-inhibition. But since reduced adrenergic sensitivity would not account for the concurrent decrease in renal nerve firing, a more logical explanation is that the sensitivity of serotonergic mechanisms in the NTS for inhibiting blood pressure, heart rate, and renal nerve activity decreases with age.

Waning cardiovascular responses to adrenergic drugs in conscious ageing rats.

Blood pressure and heart rate responses to various drugs were recorded in three groups of conscious rats at ages 3-, 12- and 26-months to determine whether cardiovascular responsiveness changes selectively with age. Basal mean pressures were higher while heart rates were lower in 26-month-old rats than in others. Phenylephrine, as an alpha-adrenergic agonist, produced significantly smaller pressor and bradycardic responses in 26-month-old than in younger rats. By contrast, pressor and bradycardic responses to angiotensin did not differ between age groups. Depressor responses produced by isoproterenol, as a beta-adrenergic agonist, were unaffected by age, but the accompanying tachycardia was significantly weaker in 26-month-old than in younger rats. On the other hand, combined alpha- and beta-adrenergic stimulation with epinephrine elicited pressor and bradycardic responses that were significantly smaller in 12- and 26-month-old rats than in 3-month-old rats. Thus, our results show that while vascular alpha-adrenergic and myocardial beta-adrenergic responses diminished with age, cardiovascular responses to angiotensin were essentially unaltered. Considered collectively these results suggest that ageing impairs responsiveness to alpha- and beta-adrenergic stimuli selectively without affecting that to other vasoactive drugs probably because as endogenous catecholamines increase with age, receptor occupancy also increases and the respective vascular and myocardial receptors become saturated.

Normotensive diabetic BB/W rats show enhanced reflex tachycardia.

Spontaneously diabetic BB/W rats were compared with age-matched regular Wistar and nondiabetic BB/W rats to determine whether the presence of diabetes would alter cardiovascular regulation appreciably. Systolic and mean blood pressures measured with the tail-cuff method from 12 to 26 wk of age tended to be slightly higher in diabetic than nondiabetic BB/W rats, but the differences were not significant. Mean pressures recorded from indwelling catheters in the same rats at 28 wk of age also did not differ significantly, thereby verifying that the diabetic rats were not hypertensive. To measure baroreflex sensitivity, heart-rate responses were elicited reflexly by elevating blood pressure with phenylephrine or lowering it with sodium nitroprusside. Although reflex bradycardia elicited with phenylephrine was the same, reflex tachycardia elicited with sodium nitroprusside was more pronounced in diabetic BB/W than other rats. Underlying autonomic mechanisms were then assessed by repeating the baroreflex tests after either cholinergic blockade with methylatropine or beta-adrenergic blockade with propranolol. Magnitude of reflex bradycardia after inhibition by either cholinergic or beta-adrenergic blockade still did not differ between rat groups but that of reflex tachycardia remained significantly stronger in diabetic BB/W than other rats. These results collectively show that, although diabetic BB/W rats remained normotensive, they had enhanced reflex tachycardia that persisted even after efferent autonomic blockade. The failure to develop higher pressures with time further indicates that without additional manipulation, these rats cannot be used experimentally to simulate the simultaneous presence of hypertension in diabetic patients.

Sympathetic activation by chronic insulin treatment in conscious rats.

Normal male Wistar rats pretreated with insulin for 12 days were studied to determine if chronic insulin treatment would reproduce the cardiovascular changes occurring in obese rats with hyperinsulinemia. After 12 days, plasma insulin rose while plasma glucose fell, but basal pressures recorded while the rats were awake remained unchanged. Depressor and tachycardic responses to isoproterenol were enhanced, thereby suggesting that beta adrenergic responsiveness had been increased. By contrast, cardiovascular responses to angiotensin were unaltered. The same rats were then anesthetized with urethane-chloralose, and reflex responses, elicited by elevating blood pressure with phenylephrine or lowering it with sodium nitroprusside, were compared with those from control rats that had not been treated with insulin. Reflex inhibition of splanchnic nerve activity during phenylephrine infusion was weaker, whereas reflex tachycardia during nitroprusside infusion was stronger in insulin-treated rats. However, cardiovascular and sympathetic responses elicited by electrical stimulation of the posterior hypothalamus were the same whether the rats had been treated with insulin or not. Although these differences imply that hyperinsulinemia cannot be solely responsible for the cardiovascular dysfunction in obesity, our results nonetheless suggest that by increasing beta adrenergic responsiveness and reducing sympathetic inhibition, excess insulin can cause sympathetic predominance even without elevating blood pressure.

Tail-cuff detection of systolic hypertension in different strains of ageing rats.

To identify rat strains suitable for studying age-related development of hypertension we compared pressures measured with the tail-cuff method in different groups of ageing Fischer 344, Wistar, or Sprague-Dawley rats. Preliminary experiments to establish optimal frequency of chronic blood pressure measurement in ageing rats showed that tail-cuff systolic pressures did not differ significantly whether taken weekly or monthly. Repeated tail-cuff measurements were comparable even when a common cuff size was used in different groups of rats with varying tail diameters. Additional studies were then carried out in 1-year old male Wistar and Sprague-Dawley rats to measure tail-cuff pressures monthly during the second year of age. Systolic and mean pressures increased progressively with age in both strains, as did body weight and heart rate, but the incidence of hypertension was higher in Sprague-Dawley than in Wistar rats. Elevations in mean pressures were sometimes more pronounced than those in systolic pressure. Two months after the last tail-cuff measurement, the presence of hypertension in Wistar rats was verified by the elevated mean pressures that were recorded from femoral artery catheters. Our results overall suggest that the predisposition to hypertension was higher in Sprague-Dawley than in Wistar or Fischer 344 rats of the same age, and also in males than in females of the same strain. Of all the different strains and sexes we compared, therefore, male Sprague-Dawley rats from 20 to 24 months of age may be the best model for studying the development of systolic hypertension with age.

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.

Strain differences in baroreflex inhibition by centrally infused enalapril in old rats.

To determine whether inhibition of the brain renin-angiotensin system would affect baroreflexes similarly in old rats of different strains, we compared 24-month-old male Fischer 344 and Sprague-Dawley rats. Baroreflex sensitivity was tested while the rats were awake by recording reflex heart rate responses elicited as blood pressure was elevated with phenylephrine or lowered with sodium nitroprusside. Sprague-Dawley rats had higher blood pressures and lower heart rates initially. Chronic infusion of enalapril, a converting enzyme inhibitor, into a lateral cerebral ventricle (ICV) for two weeks lowered blood pressure in Sprague-Dawley but not in Fischer 344 rats. Furthermore, reflex bradycardia was unaffected in either rat strain, but reflex tachycardia was selectively suppressed in Fischer 344 rats. Thus, although time controls were not done to rule out spontaneous changes during the 14-day infusion period, these results suggest that central cardiovascular regulation does not change similarly with age in these two rat strains. As removal of the brain renin-angiotensin system lowered blood pressure in one strain and inhibited reflex tachycardia in the other, the divergence could mean that the brain renin-angiotensin system acts differently to keep blood pressure elevated in Sprague-Dawley rats and modulate reflex tachycardia in Fischer 344 rats.