Sinoaortic-denervated Rats Research Articles

Sinoaortic denervation changes catecholamines in caudate-putamen of rats

The 3-day sinoaortic-denervated (SAD) rat has a reduced concentration of dopamine (DA) in caudate-putamen (CP) ( Brain Research), 299 (1984) 380–383). This suggested that the nigrostriatal system processes input from the cardiovascular system via arterial baroreceptor pathways. In this study we compared regional DA levels in CP of SAD and Sham-operated (SO) rats 3 and 7 days after surgery. Bilateral CP samples were obtained by micropunch from consecutive frozen brain sections. Samples were taken throughout the entire lenght of CP from dorsal, lateral and ventral areas. Punches of two consecutive sections were pooled and assayed for DA and norepinephrine (NE). SO rats showed a rostro-caudal gradient of DA in all 3 areas. Three-day SAD rats had significantly lower cumulative DA concentrations in each of the 3 CP areas. The concentration in each region of the 3 areas were also reduced and about half of them achieved statistical significance. SO rats did not show a gradient of NE. Cumulative NE was significantly lower in dorsal and ventral areas of SAD rats. In 7 days SAD rats, DA values were no longer reduced, but were significantly elevated in dorsal but unchanged in ventral areas. These data support evidence of nigrostriatal interaction with baroreceptor pathways.

Sex hormone modulation of ventricular hypertrophy in sinoaortic denervated rats.

The influence of sex hormones on the development of left ventricular hypertrophy was investigated in baroreceptor-denervated rats. A significant increase (p less than 0.01) in the left ventricular weight/body weight ratio was observed in male but not in female rats 15 days after operation, compared to age- and sex-matched sham-operated rats. This differential hypertrophy occurred despite the development of a significant elevation in arterial blood pressure in both sexes. Castration prior to sinoaortic denervation did not change the level of arterial hypertension but caused a significant reduction (p less than 0.01) in left ventricular weight in male rats and a significant increase (p less than 0.01) in female rats. The pretreatment of male and female sinoaortic denervated and castrated rats with testosterone resulted in ventricular hypertrophy similar to that observed in intact male sinoaortic denervated rats. Pretreatment with estradiol, however, suppressed the left ventricular hypertrophy in intact male rats but did not change the normal ventricular mass observed in intact female sinoaortic denervated rats. These results indicate that the development of left ventricular hypertrophy in sinoaortic denervated rats is modulated by sex hormones, and that testosterone exerts a facilitatory and estradiol an inhibitory action.

Striatal dopamine release and metabolism in sinoaortic-denervated rats by in vivo microdialysis

The purpose of this study was to provide new evidence favoring the hypothesis that cardiovascular information from arterial baroreceptors is integrated with the nigrostriatal system that contributes to regulation of motor activity. Samples of extracellular striatal dopamine (DA) and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were collected by the technique of in vivo microdialysis and analyzed by high-performance liquid chromatography-electron capture detection. Rats were prepared with a guide tube placed in the caudate-putamen for subsequent insertion of microdialysis probes. During the 1st wk after sinoaortic denervation (SAD) or sham operation (SO), a microdialysis probe was inserted and perfused with Ringer solution at the rate of 2 microliter/min in the freely moving rats. Samples were collected every 20 min before and after injection of pargyline, 100 mg/kg ip. The results showed that SAD rats have approximately 50% less extracellular striatal DA, DOPAC, and HVA than SO rats (P less than 0.01). After blockade of monoamine oxidase activity with pargyline, striatal DA accumulated three times faster in SO than SAD rats suggesting DA synthesis is reduced in SAD rats. These data provide further evidence that the arterial baroreceptor system affects dopaminergic metabolism in the nigrostriatal system possibly as a means for integration of cardiovascular and motor activity.

Studies on the GABAergic system in cardiovascular control in normotensive and in sinoaortic denervated rats.

The cardiovascular effects of i.v. gamma-amino-beta-hydroxybutyric acid (GABOB) were investigated in rats anaesthetized with urethane. GABOB produced a dose-dependent hypotensive response. Treatment with GABA-A receptor antagonists prevented the GABOB response while the GABA stimulation by diazepam enhanced this response. The beta 1-adrenoceptor antagonist reduced the GABOB-induced hypotension but beta 2-adrenoceptor antagonists did not affect it. Picrotoxin, bicuculline or diazepam produced an increase in basal blood pressure. Fifteen days after sinoaortic denervation in rats the glutamic acid decarboxylase and the aminobutyric acid transaminase (GABA-T) activities were significantly reduced in dorsal pons and in anterior hypothalamus whereas GABA-T activity was increased in ventral medulla oblongata. Our results demonstrate that GABOB stimulates GABA-A receptors in anaesthetized rats and thus exerts a neuromodulatory effect on cardiovascular function. GABAergic neurotransmission participates in the sinoaortic deafferentation in rats.

Central angiotensin alters blood pressure regulation during natural sleep.

Sino-aortic denervation (SAD) in rats alters completely the pattern of pressure changes during sleep: from unchanged to a rise in SS and from slight increase to a market drop in DS. Rats with mild renal hypertension (1K - 1C) behaved like normotensive rats, whereas in those rats with hypertension accompanied by overactivity of RAS, the pattern of MAP changes during sleep was similar to SAD rats. Since acute SAD also produced overactivity of RAS we studied SAD rats treated with Captopril or when RAS was normal at the chronic phase of SAD and we showed that impairment of baroreceptor function per se determines the typical alteration of BP during sleep. Intracerebral infusion of angiotensin modifies the pattern of pressure changes during sleep in a way similar to that produced by impaired baroreceptor function (SAD), probably by altering the central integration of the baroreceptor reflexes. Therefore the pattern of pressure changes during sleep seems to be a sensitive index of the functional integrity of the baroreceptor reflex.

Contractile performance of papillary muscles of renovascular hypertensive and isoproterenol-pretreated rats

Previous studies suggested that left ventricle papillary muscles from neurogenic hypertensive rats with 15 days of sino-aortic denervation (SAD) develop intense depression of their inotropic state. Considering that these animals have an increased cardiac sympathetic tonus that could produce the observed depression of the contractile response we did the present study simulating a cardiac sympathetic hyperactivity pretreating rats, during 15 days, with isoproterenol (IPA, 0.1 mg/kg, i.p., divided in 3 daily doses). Because SAD rats also develop hypertension, the effect of blood pressure overload was studied in rats with 15 days of renovascular hypertension (RHR), Goldblatt 1K1C, to compare, separated, the effects of sympathetic hyperactivity and hemodynamic overload. Results showed that RHR had muscles that developed larger force than their controls (C: 7.31 +/- 0.34 g/mm2, RHR: 12.8 +/- 0.40 g/mm2), meanwhile IPA pretreated rats had muscles developing less force than their respective controls (C: 13.8 +/- 0.37 g/mm2, IPA: 8.61 +/- 0.24 g/mm2). These results are according to the proposition that the contractile state depression is related to the sympathetic hyperactivity, as suggested by the IPA pre-treated group and because the animals with isolated pressure overload showed a better contractile performance when compared to their uninephrectomized controls.

Comparison Between the Effects of MDL 72567 and Nifedipine on Various Cardiovascular Parameters in Conscious Sinoaortic-Denervated Rats and Sham-Operated Controls

In this study the effects of a new calcium entry blocking agent, 2,6-dimethyl-3-methoxycarbonyl-4-(2-nitrophenyl)-5-(2-furoyl)-1, 4-dihydropyridine (MDL 72567), were compared with those of nifedipine on blood pressure, heart rate, ECG, and cardiac contractility indices in conscious sinoaortic baroreceptor-denervated (SA-denervated) rats and their sham-operated controls. In sham-operated rats, the calcium-entry blocking agents (0.1-2 mg/kg i.v.) produced equivalent falls in blood pressure. However, nifedipine caused a much greater reflex tachycardia which was accompanied by a negative inotropic effect, and with the highest dose (2 mg/kg), a prolongation of the PQ interval. MDL 72567 induced an increase in myocardial contractility. In SA-denervated rats, both drugs produced an enhanced fall in blood pressure accompanied by a negative inotropic effect. Nifedipine did not change heart rate in SA-denervated rats, whereas MDL 72567 caused bradycardia. Thus, in these experiments, MDL 72567 caused less reflex tachycardia for a given fall in blood pressure than nifedipine and was less likely to cause myocardial depression. These effects of MDL 72567 may represent valuable, clinically relevant advantages over nifedipine.

Reflex changes in sympathetic nerve activity during mechanical ventilation with PEEP in sino-aortic denervated rats.

The aim of this study was to evaluate the role of cardiopulmonary receptors with vagal afferents in the reflex control of sympathetic nerve activity during mechanical ventilation with positive end-expiratory pressure (PEEP). Experiments were performed on 17 chloralose-anaesthetized rats. Changes in renal sympathetic nerve activity (RSNA), heart rate and mean arterial pressure were studied at zero end-expiratory pressure (ZEEP) and at 5 and 10 cm H2O PEEP in intact animals (n = 8), after sino-aortic denervation (n = 17) and after sino-aortic denervation plus vagotomy (n = 10). In the intact animals, 10 cm H2O PEEP induced a significant increase in RSNA (+66%) and heart rate (+10%) while the mean arterial pressure did not change significantly. Sino-aortic denervation increased baseline levels of RSNA, heart rate and mean arterial pressure. After sino-aortic denervation, 10 cm H2O PEEP still induced a significant increase in RSNA (+22%) and heart rate in 13 animals. In four animals, 10 cm H2O PEEP elicited a depressor reflex with a significant decrease in both RSNA (-32%) and heart rate. Bilateral vagotomy after sino-aortic denervation at ZEEP significantly increased RNSA (+15%) and heart rate, indicating an ongoing tonic inhibitory influence on RSNA from vagal afferents in sino-aortic denervated rats. The PEEP did not induce any significant change in RSNA or heart rate after sino-aortic denervation plus vagotomy. The results indicate that cardiopulmonary receptors with vagal afferents contribute to the reflex excitation of the sympathetic nervous system during mechanical ventilation with PEEP. Under certain circumstances, PEEP may also trigger powerful depressor reflexes, mediated by vagal afferents.

High-NaCl diet reduces cardiac vagal afferent nerve response to volume expansion.

To localize the mechanism by which high dietary NaCl intake decreases the reflex inhibitory effects of intravenous volume expansion on efferent renal sympathetic nerve activity, experiments were performed in anesthetized normal rats prepared for separate examination of the afferent and efferent limbs of the cardiopulmonary baroreceptor reflex. When left ventricular end-diastolic pressure, an index of left heart filling pressure, was progressively increased by intravenous isotonic saline administration in sinoaortic-denervated rats, the increase in cardiac vagal afferent nerve activity was less in rats consuming high compared with normal dietary NaCl intake. During electrical stimulation of the central vagus nerve in sinoaortic-denervated rats, the decreases in efferent renal sympathetic nerve activity were similar in rats consuming high and normal dietary NaCl intake. Thus the effect of high dietary NaCl intake to decrease overall cardiopulmonary baroreceptor reflex gain during intravenous volume expansion is located in the afferent limb of the reflex arc.

Suppressed serum prolactin in sinoaortic-denervated rats.

We investigated the effect of arterial baroreceptor deafferentation on serum and pituitary prolactin (PRL) and on catecholamines in median eminence (ME) and anterior and posterior pituitaries. Male Wistar rats were sinoaortic denervated (SAD) or sham operated (SO). Three days after surgery serum prolactin, measured by radioimmunoassay, was suppressed in SAD rats (-54%, P less than 0.05), and dopamine (DA) and norepinephrine (NE) concentrations, measured by radioenzymatic or high-performance liquid chromatography electron capture methods, were significantly reduced in ME of SAD rats (NE, -54% P less than 0.005 and DA, -56% P less than 0.001). Simultaneously, anterior pituitary of SAD rats had significant increases in both catecholamines, whereas posterior pituitary showed no changes. Four hours after surgery serum PRL was also reduced (-40%, P less than 0.05) in SAD rats, but no changes in ME catecholamines were found. Mean arterial pressure (MAP) and heart rate were measured before and after injection of bromocriptine (0.5 mg/kg ip) in SAD and SO rats 3 days after surgery. Bromocriptine markedly suppressed serum PRL in both groups and reduced MAP from 144 +/- 10 to 84 +/- 5 and from 116 +/- 2 to 99 +/- 3 in SAD and SO rats, respectively; heart rate was reduced in SAD rats. We conclude that the SAD rat is a model of hypertension with suppressed serum PRL and that interruption of arterial baroreceptor nerves suppresses PRL secretion probably by modulating tuberoinfundibular turnover of catecholamines.

Early increase in adrenomedullary catecholamine synthesis in sinoaortic denervated rats

Adrenomedullary catecholamines (dopamine, noradrenaline and adrenaline) and catecholamine synthesizing enzymes (tyrosine hydroxylase and dopamine β-hydroxylase) were elevated within 3 days of sinoaortic denervation in rats with neurogenic hypertension. Conversely, there were no differences in adrenomedullary catecholamines and their related enzymes 21 days after sinoaortic denervation. These results suggest an activation of adrenomedullary catecholamine synthesis at the onset of neurogenic hypertension.

Cardiovascular actions of vasopressin: baroreflex modulation in the conscious rat.

Mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), and total peripheral resistance (TPR) were recorded during graded infusions of arginine vasopressin (AVP), angiotensin II (ANG II), and phenylephrine (PE) in conscious, unrestrained, sinoaortic-denervated (SAD) and normal rats. Base-line MAP, CO, and TPR values before infusion were not different between groups. HR values were significantly higher in SAD rats. Dose-response curves indicated that there was a similar enhancement in pressor sensitivity to AVP, ANG II, and PE in the absence of the baroreceptors. Pressor responses to AVP were buffered by offsetting decreases of CO. Similar elevations in MAP evoked a 50% greater reduction in CO with AVP, and HR decreased 1.5 times as much with AVP than with ANG II or PE. The dose of AVP required to raise MAP by 25 mmHg in control rats resulted in similar falls of CO in SAD rats, whereas HR responses to AVP were attenuated significantly in SAD rats. We conclude that baroreceptor buffering of AVP-induced pressor responses is due principally to reflex reduction of TPR. Furthermore, CO suppression was not baroreflex-mediated, whereas bradycardia was reflex dependent. Finally, in rats, AVP does not appear to interact with the baroreceptor reflexes in a manner unique from other vasoconstrictor agents to buffer MAP.

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.

Cardiovascular and neuroendocrine responses to behavioral stress after central or peripheral barodenervation in rats

The cardiovascular and neuroendocrine responses to acute behavioral stress were evaluated in rats after disruption of the baro reflexes by electrolytic lesions of the nucleus tractus solitarii (NTS) or sinoaortic denervation (SAD). Rats with NTS lesions or SAD showed significantly greater increases in mean arterial pressure (MAP) and plasma norepinephrine (NE) concentrations than control rats during a single 30-min escape-avoidance test. In addition, the increases in MAP and plasma NE concentration of NTS lesion rats were significantly greater than those of SAD rats. However, NTS lesion raats showed no increase in plasma renin activity (PRA), as observed in the other groups. Thus, disruption of the baroreflexes by NTS lesions oraugments the arterial pressure and plasma NE responses to stress. Additionally, NTS lesions appeared to eliminate the neurons or fibers of passage participating in the sympathetically mediated increase in PRA.

Increased Plasma Vasopressin in Sinoaortic Denervated Rats

The main purpose of this study was to evaluate changes in plasma arginine vasopressin (AVP) associated with arterial baroreceptor deafferentation. Food and water intake of sham-operated (SO) rats was matched to that of sinoaortic denervated (SAD) rats, and blood samples were collected from groups of SAD and SO rats 15 min, 1-4 h, 24 h and 4-7 days after operation. Plasma AVP was 2-4 times higher in SAD than SO rats at each of the times studied during the 1st week (p less than 0.001); at those times no significant differences in hematocrit, plasma sodium or osmolality were found. Three weeks after surgery, plasma AVP was similar in both groups of rats. Mean arterial pressure, measured in additional groups of rats, was approximately 35 mm Hg higher in SAD than SO rats for the first 4 postsurgical hours, remaining about 20 mm Hg higher at the later times. Administration of an AVP pressor antagonist to SAD rats caused a small (8-11%), statistically significant reduction in the elevated pressure of SAD rats during the first 4 postsurgical days. Thus, AVP contributes modestly to the elevation of arterial pressure caused mainly by neurogenic mechanisms in SAD rats during the early postoperative period. Ingestive behavior was monitored in additional SO and SAD rats. SAD rats had significantly reduced food and water intake for 5 days after surgery, however, by day 6 intake was comparable to that of SO rats. Preoperative body weight was not regained until 2 weeks after surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of baroreflex activation in the regional hemodynamic effects of the beta-blockers tertatolol and propranolol in conscious spontaneously hypertensive rats.

The effects of the beta-adrenoceptor-blocking drugs tertatolol and propranolol on regional hemodynamics were compared in intact and sinoaortic denervated (SAD) conscious spontaneously hypertensive rats (SHR). Miniaturized Doppler flow probes were used for the continuous determination of changes in flows and resistances in the renal, mesenteric, and hindquarter vascular beds. In intact animals 5 mg/kg propranolol i.v. caused an initial increase and a later gradual fall in mean arterial blood pressure (MAP) and an early rise in all three resistances. In SAD rats the reduction in MAP occurred more readily and no increases in RR and MR were observed. RR even decreased significantly. 0.5 mg/kg tertatolol i.v. caused a similar change in MAP as did propranolol. In contrast, tertatolol increased resistance only in the hindquarter vascular bed, both in intact and SAD animals. These data show an important role of sinoaortic baroreflex activation in the early peripheral vasoconstriction caused by propranolol in conscious SHR. Moreover, the data suggest that tertatolol inhibits the sympathetic nervous system-mediated reflex vasoconstriction.

Contractile performance of papillary muscles of sinoaortic denervated rats

The effects of sinoaortic baroreceptor denervation (SAD) was studied in left ventricle papillary muscles from rats with 15 days of hypertension, compared to sham operated normotensive controls (SO). SAD muscles develop less force (F) with slower force development (dF/dt) than SO ones, characterizing a depressed contractile performance. To verify if the mechanical response produced by cardiac beta-adrenoceptors stimulation displays a desensitization similar to what is observed for rate changes, percentual changes of F and dF/dt resulting from isoproterenol (IPA) actions were compared in SO and SAD muscles, being similar in both groups. Rest potentiation was analyzed to test if this behavior only occurs during beta-adrenoceptors stimulation or if it is an interference with the contractile machinery. Absolute and percentual changes of F and dF/dt, in SO and SAD rats were again similar, as observed before. The results suggest that in this model. of experimental hypertension it is not possible to demonstrate beta-adrenoceptors desensitization in ventricular myocardium. The behavior of SAD muscles must result from changes occurring in a common place for both inotropic interventions probably at the contractile machinery level.

The cardiovascular effects of oxytocin in conscious male rats

In conscious, chronically instrumented normotensive male Wistar rats intravenous (i.v.) administration of oxytocin (OXT) (⩾ 100 ng) induced a dose-related biphasic change in mean arterial pressure (MAP). This consisted of an initial pressor effect accompanied by bradycardia and a decrease in cardiac output (CO), followed by a more prolonged fall in MAP which reached a maximum 30 min after injection and was accompanied by an increase in CO. The more specific (Thr4, Gly7]OXT analogue (0.01–10 μg i.v.) caused a dose-related fall in MAP and a rise in CO which reached a maximum after 15–30 min. Similarly in spontaneously hypertensive rats of the stroke prone strain (SHRSP) an initial pressor effect and delayed fall in MAP were apparent after OXT (0.1 and 10 μg i.v.) only the decrease in MAP being evident with the [Thr4, Gly7]OXT analogue. These responses were significantly larger than those observed in Wistar Kyoto controls. The pressor effects are therefore interpreted to be due to vasopressin receptor activation while the depressor effects appear to be oxytocin specific. In sinoaortic denervated rats, OXT (0.1 and 10 μg i.v.) induced an enhanced initial pressor effect with a much reduced reflex bradycardia and fall in CO. A larger and more prolonged delayed fall in MAP was apparent with both OXT and [Thr4, Gly7]OXT accompanied by a decrease in CO when compared to sham-operated controls. Intracisternally (i.c.) administered OXT (0.05–10 ng) had no effect on MAP or heart rate. However OXT and [Thr4, Gly7]OXT (10 ng i.c.) caused a decrease in baroreflex sensitivity in response to both a rise and a fall in MAP induced by phenylephrine (1 μg) and sodium nitroprusside (13 μg) respectively. It is concluded that OXT is involved in cardiovascular regulation, inducing a decrease in baroreflex sensitivity upon central administration and a fall in MAP when injected i.v.

Effects of intraventricular neurotensin on blood pressure and heat balance in rats.

The effects of intraventricular neurotensin (NT) at doses of 0.1, 1.0, and 10.0 micrograms on blood pressure (BP), heart rate (HR), heat production (M), heat loss (H), and colonic temperature (T co1) were investigated in conscious rats in a direct calorimeter at 18 and 28 degrees C. At 18 degrees C, a 10.0 micrograms of NT significantly increased BP for several minutes after injection with prolonged bradycardia. The larger two doses (1.0 and 10.0 micrograms) significantly reduced M and T co1. In sinoaortic denervated rats, a 1.0 microgram of NT elevated BP and decreased HR. The decrease in HR was significantly smaller than that in nerve intact rats, which indicates the occurrence of baroreflex with intraventricular NT. The changes in M and T co1 in the denervated rats were, however, not statistically different from the intact rats. The baroreflexive suppression of metabolism seems to play a minimum role in the NT-induced hypothermia. H slightly increased for several minutes after central NT (1.0 and 10.0 micrograms) and significantly decreased thereafter. Thermal conductance significantly increased for a longer period of time after NT injection. At 28 degrees C, 1.0 microgram of NT increased H and M. It is concluded that central NT produced hypothermia by reducing M and enhancing H in the cool environment, but not at 28 degrees C.

Participation of cholinergic pathways in sinoaortic denervated rats

1. 1. Seven days after sinoaortic denervation (SAD), mean blood pressure (MBP) and heart rate measured in conscious rats were not significantly different from sham-operated animals. 2. 2. A high dose of atropine, 8 mg kg −1, reduced MBP only in SAD rats. Atropine, 0.08–0.8 mg kg −1, or methylatropine, 0.8 mg kg −1, induced tachycardia in sham rats. This effect was reduced after sinoaortic denervation and it involves peripheral muscarinic receptors. 3. 3. The hypertension and tachycardia provoked by physostigmine were more marked in SAD than in sham rats. The cardiovascular responses induced by physostigmine were abolished by atropine and were not affected by methylatropine. The hypertension caused by physostigmine in SAD animals was more sensitive to the antagonism of atropine than in sham rats. 4. 4. Our results show that baroreceptor deafferentation affects peripheral parasympathetic tone to the heart and changes the cholinergic pathways involved in the modulation of cardiovascular response.