Physical exercise-induced cardiovascular adjustments are modulated by muscarinic cholinoceptors within the ventromedial hypothalamic nucleus.

The effects of blocking ventromedial hypothalamic nucleus (VMH) muscarinic cholinoceptors on cardiovascular responses were investigated in running rats. Animals were anesthetized with pentobarbital sodium and fitted with bilateral cannulae into the VMH. After recovering from surgery, the rats were familiarized to running on a treadmill. The animals then had a polyethylene catheter implanted into the left carotid artery to measure blood pressure. Tail skin temperature (T(tail)), heart rate, and systolic, diastolic and mean arterial pressure were measured after bilateral injections of 0.2 microl of 5 x 10(-9) mol methylatropine or 0.15 M NaCl solution into the hypothalamus. Cholinergic blockade of the VMH reduced time to fatigue by 31 % and modified the temporal profile of cardiovascular and T(tail) adjustments without altering their maximal responses. Mean arterial pressure peak was achieved earlier in methylatropine-treated rats, which also showed a 2-min delay in induction of tail skin vasodilation, suggesting a higher sympathetic tonus to peripheral vessels. In conclusion, muscarinic cholinoceptors within the VMH are involved in a neuronal pathway that controls exercise-induced cardiovascular adjustments. Furthermore, blocking of cholinergic transmission increases sympathetic outflow during the initial minutes of exercise, and this higher sympathetic activity may be responsible for the decreased performance.

Effects of low-protein diet on the baroreflex and Bezold-Jarisch reflex in conscious rats.

The present study evaluated the effects of a low-protein diet (LP, 6% protein) on cardiovascular reflexes of Male Fisher rats. Three experimental groups, and their respective controls (15% protein), were used: (1) Baroreceptor reflex (BAR); (2) Bezold-Jarisch reflex (BJR); and (3) Prazosin treated. Dietary restriction began after weaning (three weeks) and lasted for a period of five weeks, after which animals were subjected to the experimental protocols. The BAR group was evaluated through injections of phenylephrine (0.5-5.0 microgram/Kg, i.v.) and sodium nitroprusside (0.7-7.0 microgram/Kg, i.v.) while the BJR was evaluated through injections of serotonin (2.5-10 microgram/Kg, i.v.). Our results showed an increased baroreflex gain bradycardia for the LP group (-0.96+/-0.34 vs. -2.12+/-1.06 bpm/mmHg) and a larger bradycardia for the BJR the LP group (160+/-18% greater than controls). Basal cardiovascular parameters were not different between LP and control rats, however LP animals treated with prazosin resulted in a larger fall of blood pressure (-19+/-3 vs. -28+/-5 mmHg). In conclusion, LP rats present an increased responsiveness of BAR and BJR, which could contribute to their normal levels of cardiovascular parameters, in spite of the possible increase in the sympathetic vasomotor tonus observed with the prazosin protocol.

Role of carbon monoxide in L-glutamate-induced cardiovascular responses in nucleus tractus solitarius of conscious rats.

Heme oxygenase degrades heme to form carbon monoxide. It has been reported that heme oxygenase-derived carbon monoxide may interact with L-glutamate (L-Glu) receptors in the nucleus tractus solitarius (NTS). Integrative studies suggest that heme oxygenase inhibitors raise blood pressure, in part, by inhibiting carbon monoxide formation in the NTS. The currents studies were designed to determine if heme oxygenase inhibitors affect the cardiovascular actions of L-Glu in the NTS. Accordingly, MAP and HR responses to unilateral microinjections of L-Glu (5 nmol/100 nl) into the NTS were measured before and after ipsilateral microinjections of zinc deuteroporphyrin 2,4-bis glycol (ZnDPBG, 4.5 nmol/100 nl) or chromium mesoporphyrin (CrMP, 1.5 nmol/100 nl) in awake rats chronically instrumented with NTS guide cannulaes and arterial catheters. With respect to non-treatment (+36+/-5 mmHg, -107 bpm, n=10), ZnDPBG pre-treatment attenuated the pressor and bradycardic responses to L-Glu (+7+/-3 mmHg, -10+/-6 bpm, P<0.05). CrMP similarly attenuated cardiovascular responses to L-Glu (+47+/-3 mmHg, -68+/-8 bpm vs. +20+/-5 mmHg, -40+/-9 bpm; before vs. after, n=10, P<0.05). Matched series yielded no vehicle- or time-related effects. Our findings suggest that a heme oxygenase product, such as carbon monoxide, may affect NTS glutamatergic neurotransmission to participate in cardiovascular control.

Sympathoexcitatory neurotransmission of the chemoreflex in the NTS of awake rats.

Cardiovascular responses to chemoreflex activation by potassium cyanide (KCN, 20 microgram/rat iv) were analyzed before and after the blockade of ionotropic or metabotropic receptors into the nucleus of the solitary tract (NTS) of awake rats. Microinjection of ionotropic antagonists [6,7-dinitroquinoxaline-2,3-dione or kynurenic acid (Kyn)] into the lateral commissural NTS (NTSlat), the midline commissural NTS (NTSmid), or into both (NTSlat+mid), produced a significant increase in basal mean arterial pressure, and the pressor response to chemoreflex activation was only partially reduced, whereas microinjection of Kyn into the NTSmid produced no changes in the pressor response to the chemoreflex. The bradycardic response to chemoreflex activation was abolished by microinjection of Kyn into the NTSlat or into NTSlat+mid but not by Kyn microinjection into the NTSmid. Microinjection of alpha-methyl-4-carboxyphenylglycine, a metabotropic receptor antagonist, into the NTSlat or NTSmid produced no changes in baseline mean arterial pressure or heart rate or in the chemoreflex responses. These results indicate that 1) the processing of the parasympathetic component (bradycardia) of the chemoreflex seems to be restricted to the NTSlat and was blocked by ionotropic antagonists and 2) the pressor response of the chemoreflex was only partially reduced by microinjection of ionotropic antagonists and not affected by injection of metabotropic antagonists into the NTSlat or NTSmid or into NTSlat+mid in awake rats.

Autonomic processing of the cardiovascular reflexes in the nucleus tractus solitarii.

The nucleus tractus solitarii (NTS) receives afferent projections from the arterial baroreceptors, carotid chemoreceptors and cardiopulmonary receptors and as a function of this information produces autonomic adjustments in order to maintain arterial blood pressure within a narrow range of variation. The activation of each of these cardiovascular afferents produces a specific autonomic response by the excitation of neuronal projections from the NTS to the ventrolateral areas of the medulla (nucleus ambiguous, caudal and rostal ventrolateral medulla). The neurotransmitters at the NTS level as well as the excitatory amino acid (EAA) receptors involved in the processing of the autonomic responses in the NTS, although extensively studied, remain to be completely elucidated. In the present review we discuss the role of the EAA L-glutamate and its different receptor subtypes in the processing of the cardiovascular reflexes in the NTS. The data presented in this review related to the neurotransmission in the NTS are based on experimental evidence obtained in our laboratory in unanesthetized rats. The two major conclusions of the present review are that a) the excitation of the cardiovagal component by cardiovascular reflex activation (chemo- and Bezold-Jarisch reflexes) or by L-glutamate microinjection into the NTS is mediated by N-methyl-D-aspartate (NMDA) receptors, and b) the sympatho-excitatory component of the chemoreflex and the pressor response to L-glutamate microinjected into the NTS are not affected by the NMDA receptors antagonist, suggesting that the sympatho-excitatory component of these responses is mediated by non-NMDA receptors.

Autonomic processing of the cardiovascular reflexes in the nucleus tractus solitarii

The nucleus tractus solitarii (NTS) receives afferent projections from the arterial baroreceptors, carotid chemoreceptors and cardiopulmonary receptors and as a function of this information produces autonomic adjustments in order to maintain arterial blood pressure within a narrow range of variation.The activation of each of these cardiovascular afferents produces a specific autonomic response by the excitation of neuronal projections from the NTS to the ventrolateral areas of the medulla (nucleus ambiguus, caudal and rostral ventrolateral medulla). The neurotransmitters at the NTS level as well as the excitatory amino acid (EAA) receptors involved in the processing of the autonomic responses in the NTS, although extensively studied, remain to be completely elucidated. In the present review we discuss the role of the EAA L-glutamate and its different receptor subtypes in the processing of the cardiovascular reflexes in the NTS. The data presented in this review related to the neurotransmission in the NTS are based on experimental evidence obtained in our laboratory in unanesthetized rats. The two major conclusions of the present review are that a) the excitation of the cardiovagal component by cardiovascular relfex activation (chemo- and Bezold-Jarisch reflexes) or by L-glutamatae microinjection into the NTS is mediated by N-methyl-D-aspartate (NMDA) receptors, and b) the sympatho-excitatory componente of the chemoreflex and the pressor response to L-glutamate microinjected into the NTS are not affected by an NMDA receptor antagonist, suggesting that the sympatho-excitatory component of these responses is mediated by non-NMDA receptors.

NMDA receptors in NTS are involved in bradycardic but not in pressor response of chemoreflex.

Activation of carotid chemoreceptors with intravenous potassium cyanide (KCN) produces increases in arterial pressure, bradycardia, and tachypnea. In the present study, we activated carotid chemoreceptors with KCN and the neurotransmission of the chemoreceptor reflex into the commissural nucleus tractus solitarii (NTS) was blocked with phosphonovaleric acid (AP-5), an N-methyl-D-aspartate (NMDA)-selective antagonist. The aim of this study was to evaluate the involvement of NMDA receptors in the cardiovascular and respiratory responses produced by chemoreceptor activation in unanesthetized rats. The pressor response to KCN was not changed after microinjection of three different doses of AP-5 into the NTS, whereas the bradycardic response was reduced in a dose-dependent manner. The increase in respiratory frequency in response to carotid chemoreceptor activation was also not affected by AP-5 microinjected into the NTS. The data indicate that the activation of the cardiovagal component of the chemoreflex in the commissural NTS is mediated by NMDA receptors, whereas pressor and ventilatory responses are not.

Role of lateral hypothalamus on fluid, electrolyte, and cardiovascular responses to activation of the MSA.

In this study we investigated the influence of electrolytic lesion or of opioid agonist injections into the lateral hypothalamus (LH) on the dipsogenic, natriuretic, kaliuretic, antidiuretic, pressor, and bradycardiac effects of cholinergic stimulation of the medial septal area (MSA) in rats. Sham- and LH-lesioned male Holtzman rats received a stainless steel cannula implanted into the LH. Other groups of rats had cannulas implanted simultaneously into the MSA and LH. Carbachol (2 nmol) injection into the MSA induced water intake, pressor, and bradycardic responses. LH lesion reduced all of these effects (1-3 and 15-18 days). Previous injection of synthetic opiate agonist, FK-33824 (100 ng), into the LH reduced the water intake, natriuresis, kaliuresis, and pressor responses induced by carbachol injected into the MSA. These data show that both electrolytic lesion or injection of an opiate agonist in the LH reduces the fluid-electrolyte and cardiovascular responses to cholinergic activation of the MSA. The involvement of LH with central excitatory and inhibitory mechanisms related to fluid-electrolytic and cardiovascular control is suggested.

Role of the medial septal area on the cardiovascular, fluid and electrolytic responses to angiotensin II and cholinergic activation into the subfornical organ in rats.

In the present study we investigated the effect of electrolytic lesion of the medial septal area (MSA) on the pressor and dipsogenic response to cholinergic activation and angiotensin II (ANGII) injection into the subfornical organ (SFO) in rats. In addition the effect of MSA lesion on the natriuresis, kaliuresis and diuresis after cholinergic activation of the SFO was also investigated. Sham- and MSA-lesioned rats with a stainless steel cannula implanted into the SFO was used. The injection of ANGII (12 ng) into the SFO in sham rats produced pressor (24 +/- 2 mmHg) and dipsogenic (9.6 +/- 1.1 ml/h) responses. MSA lesion, both acute (2-6 days) and chronic (15-19 days), reduced the pressor (14 +/- 2 mmHg) and dipsogenic (2.7 +/- 1 ml/h) responses to ANGII into SFO. The injection of the cholinergic agonist carbachol (2 nmol) into the SFO in sham rats produced pressor (48 +/- 4 mmHg), dipsogenic (10 +/- 1.2 ml/h), natriuretic (457 +/- 58 microEq/2 h) and kaliuretic (249 +/- 16 microEq/2 h) responses. Acute, but not chronic MSA lesion reduced the pressor (27 +/- 3 mmHg), natriuretic (198 +/- 55 microEq/2 h) and kaliuretic (128 +/- 16 microEq/2 h) responses to carbachol into SFO. No change in the dipsogenic response to carbachol into the SFO was observed in MSA-lesioned rats. Antidiuresis after carbachol was observed only in MSA-lesioned rats. The present results show that the MSA plays a role on the pressor, natriuretic and kaliuretic responses to cholinergic activation of the SFO in rats and on the pressor and dipsogenic responses to ANGII into the same area.(ABSTRACT TRUNCATED AT 250 WORDS)

Opiate activation suppresses the drinking, pressor and natriuretic responses induced by cholinergic stimulation of the medial septal area.

The present study investigates the participation and interaction between cholinergic and opiate receptors of the medial septal area (MSA) in the regulation of Na+, K+ and water excretion, drinking and blood pressure regulation. Male Holtzman rats were implanted with stainless steel cannulae opening into the MSA. Na+, K+ and water excretion, water intake and blood pressure were measured after injection of carbachol (cholinergic agonist), FK-33824 (an opiate agonist) + carbachol or naloxone (an opiate antagonist) + carbachol into MSA. Carbachol (0.5 or 2.0 nmol) induced an increase in Na+ and K+ excretion, water intake and blood pressure and reduced the urinary volume. FK-33824 reduced the urinary volume and Na+ and K+ excretion. Previous injection of FK-33824 (100 ng) into the MSA blocked the increases in Na+ and K+ excretion, water intake and blood pressure induced by carbachol. Naloxone (10 micrograms) produced no changes in the effect of 2.0 nmol carbachol, but potentiated the natriuretic effect induced by 0.5 nmol dose of carbachol. These data show an inhibitory effect of opiate receptors on the changes in cardiovascular, fluid and electrolyte balance induced by cholinergic stimulation of the MSA in rats.

Lesions of the lateral hypothalamus impair the pressor response to clonidine injected into the medial septal area of conscious rats.

The central injection of clonidine (an alpha 2-adrenoceptor agonist) in conscious normotensive rats produces hypertensive responses and bradycardia. The present study was performed to investigate the effect of electrolytic lesions of the lateral hypothalamus (LH) on the pressor and bradycardic responses induced by clonidine injected into the medial septal area (MSA) in conscious and unrestrained rats. Male Holtzman rats weighing 250-300 g were used. Mean arterial pressure and heart rate were recorded in sham- or bilateral LH-lesioned rats with a cerebral stainless steel cannula implanted into the MSA. The injection of clonidine (40 nmol/microliter) into the MSA of sham rats (N = 8) produced a pressor response (36 +/- 7 mmHg, P < 0.05) and bradycardia (-70 +/- 13 bpm, P < 0.05) compared to saline. Fourteen days after LH-lesion (N = 9) the pressor response was reduced (9 +/- 10 mmHg, P < 0.05) but no change was observed in the bradycardia (-107 +/- 24 bpm). These results show that LH is an important area involved in the pressor response to clonidine injected into the MSA of rats.

Lesions of the lateral hypothalamus impair the pressor response to clonidine injected into the medial septal area of conscious rats

The central injection of clonidine (an alpha2-adrenoceptor agonist) in conscious normotensive rats produces hypertensive responses and breadycardia. The present study performed was performed to investigate the effect of electrolytic lesions of the lateral hypothalamus (LH) on the pressor and bradycardiac responses induced by clonidine injected into the medial septal area (MSA) in conscious and unrestrained rats. Male Holtzman rats weighing 250-300 g were used. Mean arterial pressure and heart rate were recorded in sham- or bilateral LH-lesioned rats with a cerebral stainless steel cannula implanted into the MSA. The injection of clonidine (40 nmol/ul) into the MSDA of sham rats (N=8) produced a pressor response (36 ñ 7 mmHg, P<0.05) and bradycardia (-70 ñ 13 bpmm, P<0.05) compared to saline. Fourteen days after LH-lesion (N=9) the pressor response was reduced (9 ñ 10 mmHg, P<0.05) but no change was observed in the bradycardia (-107 ñ 24 bpm). These results show that LH is an important area involved in the pressor response to clonidine injected into the MSA of rats

Effect of dehydration on the increase of arterial pressure and renal electrolyte excretion produced by central cholinergic stimulation in rats.

Natriuresis, kaliuresis, diuresis, arterial pressure and heart rate were studied in rats following dehydration and cholinergic stimulation of the medial septal area (MSA). The increase in renal Na+ and K+ excretion produced by the injection of carbachol (2 nmol) into the MSA in normal hydrated rats was abolished in 48-h water-deprived rats. Urinary volume was also reduced. Cholinergic stimulation of the MSA produced a smaller increase in arterial pressure in 48-h water-deprived rats compared to normal hydrated animals. No change was observed in heart rate. These results show that hydration state is essential for the central cholinergic control of electrolyte excretion and increase in arterial pressure.

Effect of dehydration on the increase of arterial pressure and renal electrolyte excretion produced by central cholinergic stimulation in rats

Natriuresis, kaliuresis, diuresis, arterial pressure and heart rate were studied in rats following dehydration and cholinergic stimulation of the medial septal area (MSA). The increase in renal NA+ and K+ excretion produced by the injection of carbachol (2nmol) into the MSA in normal hydrated rats was abolished in 48-h water-deprived rats. Urinary volume was also reduced. Cholinergic stimulation of the MSA produced a smaller mincrease in arterial pressure in 48-h-deprived rats compared to normal hydrated animals. No change was observed in heart rate. These reults show that hydration state is essential for the central cholinergic control of electrolyte excretion and increase in arterial pressure