Ruben D. Buñag

Sympathetic hyperactivity elevates blood pressure during acute cerebroventricular infusions of hypertonic salt in rats

Hypertonic solutions of 0.3 M sodium chloride (NaCl) infused into the third ventricle (ICV) for 20 min in urethaneanesthetized rats consistently elevated mean aortic pressure by ∼10 mm Hg. Heart rate and sympathetic nerve activity diminished slightly during the first few minutes but then accelerated to attain higher than preinfusion levels. By contrast, ICV infusions of either artificial cerebrospinal fluid alone or 0.6 M sucrose were ineffective, those of 0.6 M urea were slightly depressor, while those of 0.3 M ammonium chloride elevated blood pressure without affecting sympathetic nerve activity. In rats pretreated with a vasopressin antagonist, the early pressor effects of hypertonic NaCl were inhibited, while sympathetic nerve firing, instead of being initially inhibited, increased from the onset. Consequently, the blood pressure elevation occurring during the first 5 min of ICV infusion was considered partly due to vasoconstriction caused by increased secretion of endogenous vasopressin, and subsequent maintenance of the blood pressure elevation after the first 10 min was attributed to sympathetic overactivity. Because pressor and sympathetic nerve responses were substantially enhanced following bilateral vagotomy or sinoaortic denervation, it was considered likely that responsiveness to hypertonic NaCl in intact rats is inhibited by both cardiopulmonary and sinoaortic baroreceptor afferents. Augmentation of pressor responsiveness following interruption of baroreceptor afferent pathways suggests that increases in sympathetic activity and blood pressure produced by hypertonic NaCl could contribute to saltinduced hypertension, particularly when baroreceptor buffering becomes deficient.

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.) in-fusions of phenylephrine or sodium nitroprusside in rats that were either awake or anesthetized (with pentobarbital, urethane, or cholralose). 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.

Reduced Cardiovascular Responsiveness to Hypothalamic Stimulation during Urethane and Amobarbital Anesthesia

Graded pressor responses to electrical stimulation of the posterior hypothalamus were accompanied by variable changes in heart rate. Tachycardia caused by weak currents was prevented by propranolol while reflex bradycardia associated with pressor responses to strong currents was abolished by atropine. Rats anesthetized with urethane were generally more responsive to hypo thalamic stimulation than those anesthetized with amobarbital. Stimulation thresholds were significantly lower when rats were awake than when they were anesthetized with either anesthetic. In some experiments, responses that were initially depressor during amobarbital anesthesia, later became pressor when the rats were awake or anesthetized with urethane. Our findings indicate that general anesthesia alters cardiovascular responsiveness to hypothalamic stimulation qualitatively as well as quantitatively.

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

Summary: To examine how the inhibitory neurotransmitter γ-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.

Pancreatic hormones in streptozotocin-diabetic rats

SummaryPancreatic polypeptide (PP) levels of plasma and pancreas were studied in the rat after streptozotocin (STZ) injection. In 4 weeks of observation, plasma PP was elevated up to 4 times the control values with marked hyperglycemia and insulinopenia. At 4 weeks, intravenous (i.v.) glucose tolerance tests and i.v. insulin tolerance tests were performed. In the glucose tolerance test, control rats responded with a 10-fold increase in plasma insulin and 15% decrease in plasma PP levels, whereas STZ-diabetic rats produced no increase of plasma insulin and an approximately 50% reduction of plasma PP levels with marked hyperglycemia. In the insulin tolerance test, diabetic rats showed a marked increase in plasma PP levels and less increase in plasma insulin levels than the controls. In diabetic rats, pancreatic insulin levels were reduced to about 3.5% of control, whereas those of somatostatin (SRIF), PP and glucagon were elevated to 8.3, 2.7 and 1.4 times control, respectively. In a morphometric study, islet areas of diabetic rats were seen to be reduced to about 10% of control. With in vitro perfused pancreatic slices, STZ-diabetic pancreas released much more glucagon and PP than control pancreas. Thus, STZ injection in the rat caused marked β-cell damage as well as hyperplasia of SRIF, PP and glucagon cells, with glucagon and PP hypersecretion.

In vitro inhibition by synthetic phospholipids of pressor responses to renin

Incubation mixtures containing kidney extracts and standard doses of renin or angiotensin were injected i.v. into awake rats. Pressor responses to injected renin were reduced while those to angiotensin were unaffected. 2 of 5 synthetic phospholipids had the same effects as the kidney extracts; the oleyl and palmityl derivatives were effective while the stearyl, lauryl, and myristyl derivatives were not. By contrast, the prostaglandins E1 and F2α both inhibited responsiveness not only to renin but also to angiotensin and norepinephrine. Neither blockade of vascular angiotensin receptors nor suppression of endogenous converting enzyme explains selective inhibition of response to renin. An enzymatic inhibition of renin also appears unlikely since degree of reduction in response was unaffected by duration of incubation. Our results may be due to the formation of micelles on renin molecules in vitro.

Selective suppression of pressor and sympathetic responses to centrally infused TRH in hypothyroid rats.

To determine whether hypothyroidism alters responsiveness to centrally infused thyrotropin-releasing hormone (TRH), blood pressure and sympathetic nerve responses to various stimuli were recorded in urethane-anesthetized rats. Four weeks after thyroidectomy or treatment with propylthiouracil, pressor responses elicited by intracerebroventricular- (ICV)-infused TRH or by electrical stimulation of the posterior or ventromedial hypothalamus were always accompanied by increased sympathetic nerve activity in all rats. When serum thyroxine levels were lowered in hypothyroid rats, pressor responses to most stimuli, including intravenous injections of norepinephrine, angiotensin, and vasopressin, were inhibited, indicating that peripheral pressor responsiveness had been reduced. For centrally acting stimuli, pressor inhibition was also considered partly caused by a selective decrease in sympathetic vasomotor tone because sympathetic excitation was reduced only during ICV infusions of TRH, but not during posterior hypothalamic stimulation. On the other hand, there was no obvious explanation why both pressor and sympathetic responses to ventromedial hypothalamic stimulation were spared from inhibition. Because sympathetic nerve responses to ICV-infused TRH were reduced by thyroid suppression, these results imply that sympathetic activation by TRH in intact rats is mediated, at least in part, indirectly by way of TRH stimulation of thyroid activity.

THE CARDIOVASCULAR EFFECTS OF SUBSTANCE P IN THE CHICKEN

In 1931, Euler and Gaddum‘ reported the presence of an unidentified depressor substance in extracts of various tissues, particularly those of the brain and intestine. This depressor agent was referred to as “substance P” and it was suggested that the fall in arterial pressure produced by substance P in the atropinized rabbit is due to peripheral vasodilatation.‘. 2. Subsequent investigations have shown that intraarterial injections of substance P cause a pronounced dilatation of the vessels in the perfused, chronically-denervated rabbit The depressor activity of substance P has also been demonstrated in other mammals and its hypotensive effect has been found to be unaffected by atropine, antihistaminics or ganglionic-blocking agents.6 In cats and rabbits, intracisternal or intraventricular injections of substance P have been observed to produce prominent respiratory manifestations with very slight and variable hemodynamic effects.’ In healthy human subjects, it has been reported that intravenous infusions of substance P produce facial flushing, increased blood flow in the muscles and skin, hypotension and tachycardia.*, 9. lo These various observations indicate that in mammals, the predominant factor responsible for the depressor response to substance P is a peripheral vasodilatation. The present experiments were conducted to investigate the cardiovascular effects of substance P in the chicken.

Sympathetic inhibition and vasopressin mediation during centrally induced responses to serotonin in rats

Summary: To study mechanisms underlying the cardiovascular effects of centrally administered serotonin, we recorded responses to intracerebroventricular (i.c.v.) injections of serotonin in urethane-anesthetized rats. Doserelated increases in blood pressure accompanied by reductions in heart rate and sympathetic nerve firing were elicited consistently. The diminution in sympathetic nerve activity implies that while sympathetic inhibition could contribute to the bradycardia, sympathetic activation alone cannot account for the pressor response. Pressor and bradycardic responses must have been caused by activation of specific serotonergic receptors in the brain because both responses were inhibited following serotonin blockade produced by i.c.v. injection of methysergide. By contrast, intravenous injection of a vasopressin antagonist inhibited the pressor response selectively, thereby suggesting that peripheral mediation of the pressor (but not the bradycardic) response involves release of endogenous vasopressin. Collectively, our results are compatible with the interpretation that i.c.v.-injected serotonin acts on serotonergic brain receptors to elevate blood pressure by releasing endogenous vasopressin, and slow the heart through sympathetic inhibition.

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. (Aging Clin. Exp. Res. 6: 239–248, 1994)