Baroreceptor-denervated Animals Research Articles

Responses of rat postganglionic sympathetic vasoconstrictor neurons following blockade of nitric oxide synthesis in vivo

The hypothesis was tested that the activation of postganglionic sympathetic neurons contributes to the peripheral vasoconstriction and the blood pressure increase which are observed in rats after systemic blockade of nitric oxide synthase by substituted l-arginine analogues. Single and multifibre postganglionic sympathetic activity supplying hindlimb hairy skin and the activity in the caudal lumbar sympathetic trunk supplying mainly hindlimb skeletal muscle were recorded in anaesthetized, paralysed and artificially ventilated Wistar rats before, during and up to 1 h after intravenous injection of a supramaximal dose (10 or 35 mg/kg) of N G-nitro- l-arginine methyl ester. This elicited a sustained rise of arterial blood pressure, a long-lasting decrease in heart rate and vasoconstriction in hindlimb skin and skeletal muscle as measured by laser Doppler flowmetry. With intact buffer nerves all sympathetic neurons analysed responded with a decrease in their ongoing activity in parallel with the vasoconstriction and the increased blood pressure, except for one neuron which was unresponsive. These responses were probably mediated by the arterial baroreceptors, since it was shown that N G-nitro- l-arginine methyl ester did not impair the function of both the afferent and the efferent limb of the reflex. Furthermore, baroreceptor denervation almost abolished the inhibitory responses in sympathetic neurons. In baroreceptor denervated animals, with a latency of about 15 min after N G-nitro- l-arginine methyl ester there was an increase in sympathetic activity without a further increase in blood pressure. It was concluded that sympathetic vasoconstrictor neurons which supply the rat hindlimb do not contribute by neurogenic means to the vasoconstriction and the blood pressure increase occurring after blockade of the nitric oxide synthase. Instead, the results suggest that sympathetic vasoconstrictor neurons, via the baroreceptor loop, counteract the vasoconstriction caused by the blockade of endothelium-derived nitric oxide. Therefore nitric oxide does not seem to play a role in the central regulation of activity in the sympathetic vasoconstrictor pathways studied here. The long latency increase in sympathetic activity observed after N G-nitro- l-arginine methyl ester in baroreceptor-denervated animals may be due to an impairment of blood flow in the brainstem.

Baroreflexes influence autoregulation of cerebral blood flow during hypertension

Cerebral blood flow (CBF) is autoregulated at mean arterial pressures (MAP) ranging from approximately 50 to 150 mmHg. When MAP exceeds the upper limit, autoregulation breaks through, vasodilatation occurs, and CBF increases rapidly. Earlier studies have shown that the arterial baroreflex does not influence autoregulation. However, CBF may rise to a lesser degree during abrupt hypertension immediately after interruption of the baroreceptor reflex than it would at comparable levels of blood pressure in intact animals. Generally this shift of the breakthrough point has been attributed to an increase in sympathetic nerve activity immediately after sinoaortic denervation. We hypothesized that denervation of arterial baroreceptors would blunt vasodilatation during slow controlled increases of arterial pressure, and we sought to determine whether sympathetic nerves contributed to regulation of CBF during hypertension in baroreceptor-denervated animals. Thirty-eight rats were studied to determine whether sinoaortic denervation affected autoregulation or breakthrough during acute hypertension. In five intact rats, when arterial pressure was raised by phenylephrine to 155 +/- 4 mmHg, cerebrovascular resistance fell by 60% and CBF increased by 434%. After interruption of the baroreflex in six rats, such dramatic increases in CBF with breakthrough did not occur despite greater increases in MAP (to 185 +/- 2 mmHg). Similar results were obtained when arterial pressure was raised by infusion of arginine vasopressin in four intact and three denervated rats. The effects of baroreceptor reflex interruption were not significantly affected by bilateral removal of the superior cervical ganglia. Rates of rise of MAP and increases of pulse pressure were equivalent between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of the spinal cord in generating the 2- to 6-Hz rhythm in rat sympathetic outflow.

In baroreceptor-denervated animals, sympathetic nerve discharge (SND) displays a 2- to 6-Hz rhythm. Current theories suggest that this rhythm is generated by a neural oscillator in the medulla. In urethan-anesthetized rats, we have examined the effect on the 2- to 6-Hz rhythm of lumbar SND produced by 1) altering the firing pattern of a major output of this medullary network [the rostral ventrolateral medulla (RVLM)] and 2) disrupting the interactions between medulla and spinal cord (SC). Microinjection of muscimol [gamma-aminobutyric acid (GABA) agonist] unilaterally or a mixture of kynurenic acid (KYN; broad spectrum, excitatory amino acid antagonist) and bicuculline (GABAA antagonist) bilaterally into RVLM produced little effect on the 2- to 6-Hz rhythm. Intrathecal injection of KYN or transection of the cervical SC also had little effect once SND had been restored by intrathecal injection of kainic acid (excitatory amino acid agonist). Thus, whereas an excitatory input to the spinal cord is required for the generation of basal SND, patterning of this input is not critical for production of the 2- to 6-Hz SND rhythm that, in this species, may be essentially of spinal origin.

The effects of 8-OH-DPAT on medulllary 5-HT neurons and sympathetic activity in baroreceptor-denervated animals

The effects of the 5HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on medullary 5-hydroxytryptamine (5-HT) neuronal firing and inferior cardiac sympathetic nerve activity were simultaneously determined in baroreceptor-denervated cats. 5-HT neuronal firing was inhibited by 50% at a 1 μg/kg i.v. dose of 8-OH-DPAT in the baroreceptor-denervated animal. Unit firing was completely inhibited by a 3 μg/kg dose. In contrast, 8-OH-DPAT inhibited inferior cardiac nerve activity between 10 and 100 μg/kg i.v. A similar relationship between the 8-OH-DPAT-induced inhibition of 5-HT unit activity and sympathetic nerve activity was observed in sham-operated control animals. These data suggest that the sympatholytic effects of 8-OH-DPAT cannot be explained on the basis of an autoreceptor effect of the drug.

Desipramine inhibits sympathetic nerve activity in the rabbit

The aim of the study was to determine the sites of action of intravenously administered desipramine on the sympathetic nervous system in anaesthetized rabbits (alfadolone + alfaxalone). Renal postganglionic sympathetic nerve activity was measured in order to determine central nervous and ganglionic effects. The clearance of noradrenaline from the plasma was determined with an isotope tracer method. From the noradrenaline clearance and the plasma concentration of noradrenaline the noradrenaline spillover rate was calculated. These parameters as well as blood pressure and heart rate were measured before (basal values) and at the end of 20-min infusions of sodium nitroprusside, which was given in order to modulate efferent sympathetic nerve activity through the baroreceptors. Desipramine 0.5 mg kg-1 + 0.05 mg kg-1 h-1 (bolus injection followed by infusion) and 2 mg kg-1 + 0.2 mg kg-1 h-1 dose-dependently inhibited basal sympathetic nerve activity and the noradrenaline clearance. Desipramine had no effect on basal blood pressure, noradrenaline spillover rate or heart rate. Nitroprusside produced hypotension and simultaneously increased sympathetic nerve activity, noradrenaline spillover rate and heart rate; the clearance of noradrenaline was reduced with decreasing blood pressure. The relationship between sympathetic nerve activity and blood pressure was shifted by desipramine in a manner indicating central sympathoinhibition. Desipramine had no effect on the relationship of the noradrenaline spillover rate to blood pressure, whereas it shifted the heart rate-blood pressure relationship in a manner indicating an enhancement of reflex cardioacceleration. In a separate series of experiments, desipramine also inhibited sympathetic nerve activity in baroreceptor-denervated animals. The results show that desipramine centrally inhibits sympathetic outflow in the rabbit.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular effects of posterior hypothalamic stimulation in baroreflex-denervated rats

The overall purpose of this study was to examine the effect of sinoaortic baroreceptor denervation (SAD) on the cardiovascular and sympathetic outflow responses to electrical stimulation of the posterior hypothalamus. In anesthetized rats that had undergone SAD 7-10 days before experimentation, electrical stimulation of the posterior hypothalamus elicited greater increases in mean arterial pressure, iliac vascular resistance, mesenteric vascular resistance, and lumbar sympathetic nerve activity than in sham-operated baroreceptor-intact animals. Similarly, the pressor effects of intravenous norepinephrine were also augmented in the baroreceptor-denervated group compared with the baroreceptor-intact group. When posterior hypothalamic and intravenous norepinephrine pressor stimuli, which produced equivalent pressor responses in sham-operated baroreceptor-intact animals, were compared in baroreceptor-denervated animals, the pressor effects of the central hypothalamic stimulus were enhanced to a greater degree than the norepinephrine pressor effects. These data provide evidence that arterial baroreceptor reflexes exert greater buffering of pressor stimuli initiated from the central nervous system compared with pressor responses due to peripheral vascular vasoconstrictor agents.

Posterior hypothalamic influences on cardiovascular effects of aortic nerve stimulation.

The purpose of this study was to examine the influence of stimulation of the posterior hypothalamus on the baroreflex responses produced by stimulation of the aortic depressor nerve. Animals were initially anesthetized and implanted with a bipolar electrode in the posterior hypothalamus. Three to 5 days later, animals were anesthetized with urethan, and the left aortic depressor nerve was dissected and placed on a bipolar platinum-iridium electrode. The effects of electrical stimulation of the posterior hypothalamus (0, 160, and 280 microA) were examined in baroreflex-intact and acutely sinoaortic baroreceptor-denervated animals, and the responses to aortic nerve stimulation (2, 8, 16, and 32 Hz) were examined during each level of hypothalamic stimulation. The first set of experiments was performed in baroreceptor-intact animals; e.g., in animals with arterial baroreceptor inputs intact from both carotid sinus regions in addition to intact right aortic baroreceptor afferent pathways. In that group, stimulation of the posterior hypothalamus attenuated the bradycardia and depressor effects of aortic nerve stimulation. When influences from other baroreceptor inputs were removed with acute sinoaortic baroreceptor denervation, posterior hypothalamic stimulation interrupted the reflex bradycardia due to aortic nerve stimulation; however, the depressor response to aortic nerve stimulation was not attenuated. Similar to the arterial pressure response, hypothalamic stimulation did not attenuate the decreases in mesenteric and iliac vascular resistance produced by aortic nerve stimulation in the baroreflex-denervated group. We conclude that posterior hypothalamic stimulation attenuates baroreflex-mediated bradycardia but does not alter baroreflex control of arterial pressure and peripheral vascular resistance.

Central and peripheral mechanisms of arterial pressure lability following baroreceptor denervation

Deafferentation of sinoaortic baroreceptors produces a marked increase in the lability of arterial pressure that is sustained chronically. Studies reviewed in this paper were designed to determine the mechanisms responsible for generating arterial pressure lability. Pharmacological interruption of the humoral vasopressin and angiotensin systems failed to alter arterial pressure lability. In contrast, blockade of sympathetic nervous system transmission at both ganglionic and alpha-adrenergic receptor levels significantly attenuated lability. A similar effect was observed with the peripheral neurotoxin, 6-hydroxydopamine. After blockade of sympathetic transmission, a further reduction in lability was produced by blocking the renin-angiotensin or vasopressin systems. The dissociation of the level of arterial pressure from lability was achieved with parachloroamphetamine which raised arterial pressure but reduced lability. A substantial peripheral contribution to lability was obtained in experiments in which the alpha-adrenergic agonist, phenylephrine, produced a marked increase in lability in both normal and baroreceptor-denervated animals in which humoral and neural transmission were blocked. These data demonstrate that following baroreceptor deafferentation, arterial pressure lability is produced primarily by the sympathetic nervous system and secondarily by circulating humoral factors that appear to act on vascular smooth muscle to induce fluctuations in the level of arterial pressure.

Analysis of hemodynamic variability after sinoaortic denervation in the conscious rat.

The present study was undertaken to determine the regional hemodynamic basis for increased mean arterial pressure (MAP) variability produced by sinoaortic baroreceptor denervation (SAD) in the conscious rat. Sinoaortic-denervated and intact rats were instrumented chronically with a catheter placed in the femoral artery and pulsed-Doppler flow probes positioned on the renal and superior mesenteric arteries and the lower abdominal aorta to determine MAP, heart rate, and regional vascular resistance. Each cardiovascular variable was sampled once per minute during a 1-h recording period. Compared with control animals, baroreceptor-denervated animals exhibited greater variability of MAP and mesenteric, renal, and hindquarter resistances 7-9 days after SAD. The variability of heart rate was similar when animals from the two groups were compared. The pattern of significant correlation for the relationship of MAP to vascular resistance in the different beds was not consistent for individual SAD and intact animals. Finally, a wider distribution of mean values was observed for the individuals within the SAD group for MAP, heart rate, and hindquarter and renal vascular resistances. We conclude that SAD produces greater fluctuation of vascular resistance in several beds which contributes to the increased lability of MAP; however, there is no predictable pattern of vascular resistance lability which underlies the variability of arterial pressure.

Reflex changes in sympatho-adrenal medullary functions in response to baroreceptor stimulation in anesthetized rats

Effects of increased and decreased blood pressure on adrenal sympathetic nerve activity and catecholamine secretion were examined in anesthetized Wistar rats. Efferent nerve impulses were counted and adrenal venous plasma was collected just before and 30 s after the onset of hypotensive stimulation induced by bleeding (average decrease in systolic blood pressure over the stimulation period was 38 mm Hg) or a hypertensive stimulation induced by phenylephrine administration (average increase in systolic blood pressure over the stimulation period was 41 mm Hg). While nerve activity and epinephrine and norepinephrine secretion were not significantly altered by the change in blood pressure in baroreceptor denervated animals, there were increases in these variables (131.1% of control levels for epinephrine, 117.5% for norepinephrine, and 127.1% for nerve activity) in response to bleeding and a marked decrease (to 63.0% of control levels for epinephrine, 53.9% for norepinephrine, and 54.0% for nerve activity) in response to phenylephrine administration with baroreceptors intact. These changes were significant both with respect to control blood pressure levels and with regard to the effect of stimulation in the baroreceptor-denervated animals. The reflex responses in adrenal nerve and catecholamine secretion were generally proportional in magnitude. The present results are discussed with regard to the effects of somatic stimulation on nerve activity and catecholamine secretion.

Cerebrovascular response to hypoxia in baroreceptor- and chemoreceptor-denervated dogs.

Cerebral hemodynamic responses to arterial hypoxemia were studied in anesthetized paralyzed dogs that were or that had undergone carotid baroreceptor denervation, carotid chemoreceptor denervation, vagotomy, or both vagotomy and carotid sinus nerve section. Arterial O2 content was lowered from control (19.0 vol%) to 9.6 vol% by either decreasing arterial O2 tension [hypoxic hypoxemia (HH)] or increasing carboxyhemoglobin saturation[carbon-monoxide hypoxemia (COH)] at normal O2 tension. In intact animals (composite control values from all groups) HH and COH resulted in similar increases in cerebral blood flow (to 205 and 197% of control, respectively). Cerebral vascular resistance decreased more with COH than with HH (to 42 vs. 60% of control). The response from carotid baroreceptor-denervated animals and from vagotomized animals did not differ from that of the intact animals. After carotid chemoreceptor denervation and combined carotid sinus nerve section and vagotomy, both HH and COH increased cerebral blood flow to 194% of control (same increase as in intact animals, carotid baroreceptor-denervated animals, and vagotomized animals) and produced equal reductions in cerebral vascular resistance (to 34% of control). These data show that the carotid and aortic chemoreceptors are not necessary for the increase in cerebral blood flow provoked by hypoxemia and that this response is not modified by the carotid and aortic baroreceptors.

The role of the baroreceptor reflex in the cardiovascular effects of propranolol in the conscious spontaneously hypertensive rat.

1. The role of baroreceptors in the cardiovascular mechanism of action of DL-propranolol has been studied by comparing the acute effects of subcutaneous injection of 1 and 5 mg/kg (3.3 x 10(-6) and 16.5 x 10(-6) mol/kg) of this drug in conscious baroreceptor-denervated spontaneously hypertensive (SH) rats with those in sham-operated control SH rats. 2. At 5 mg/kg (16.5 x 10(-6) mol/kg) propranolol caused a small, but significant, increase in blood pressure in sham-operated SH rats, whereas both after 1 and 5 mg/kg (3.3 x 10(-6) and 16.5 x 10(-6) mol/kg) immediate hypotension was observed in baroreceptor-denervated animals. 3. Heart rate dropped rapidly after injection of 1 or 5 mg/kg (3.3 x 10(-6) and 16.5 x 10(-6) mol/kg) propranolol both in the baroreceptor-denervated and sham-operated SH rats. Bradycardia was significantly larger in the baroreceptor-denervated animals after an injection of 5 mg/kg (16.5 x 10(-6) mol/kg). 4. It is concluded that the lack of an early hypotensive effect of propranolol in intact animals is caused by an increased baroreceptor reflex activity as a consequence of the fall in cardiac output.

The effects of etomidate on arterial pressure, pulse rate and preganglionic sympathetic activity in cats.

We have studied the effects of etomidate on preganglionic cervical sympathetic activity, arterial pressure, and pulse rate. Normal and baroreceptor-denervated animals were studied. On the basis of findings it is concluded that etomidate exerts a minimal direct depressant action on the cardiovascular system. A profound depression of sympathetic tone was observed in spite of unaffected arterial pressure. Etomidate was also shown to possess a mild vagolytic action.

Mechanism of effect of thoracic inferior vena cava constriction on renal water excretion.

Persistent secretion of vasopressin and/ or diminished distal fluid delivery have been proposed to explain the impaired water excretion associated with low-output cardiac failure. In the present investigation cardiac output (CO) was diminished in anesthetized dogs undergoing a water diuresis by constriction of the thoracic inferior vena cava (TIVC). In intact animals (group I) acute TIVC constriction decreased CO from 3.5 to 2.2 liters/min (P < 0.005) as urinary osmolality (U(osm)) increased from 103 to 543 mosmols/ kg (P < 0.001) and free water clearance (C(H2o)) decreased from 2.1 to -0.6 ml/min (P < 0.001). This antidiuretic effect was disassociated from changes in renal arterial and venous pressures, glomerular filtration rate, solute excretion, and renal innervation. To examine the role of vasopressin in this antidiuresis, studies (group II) were performed in acutely hypophysectomized, steroid-replaced animals. In these animals TIVC constriction decreased CO to a similar degree from 3.4 to 2.1 liters/min (P < 0.001). However, the effects on U(osm) (87-104 mosmols/kg) and C(H2o) (2.1-1.6 ml/min) were significantly less than in intact dogs. In another group of hypophysectomized animals, (group III) renal arterial and venous pressures were not controlled, and the effect of TIVC constriction on U(osm) was not significant (65-79 mosmols/kg) although C(H2o) decreased from 3.3 to 1.9 ml/min (P < 0.001). In both the group II and III studies, there were linear correlations between the changes in C(H2o) and the urine flow. Studies were also performed in baroreceptor-denervated animals with intact hypothalamo-neurohypophyseal tracts, and acute TIVC constriction altered neither U(osm) nor C(H2o) when renal arterial pressure was controlled. These results therefore indicate that the effect of TIVC constriction on U(osm) is primarily vasopressin mediated while the effect on C(H2o) is mediated both by vasopressin release and diminished distal fluid delivery. A decrease in renal arterial pressure, or some consequence thereof, seems to be an important determinant of the latter effect.