Sinoaortic-denervated Rats Research Articles

Pharmacokinetic profile of methyldopa in the brain of sinaortic-denervated rats

Pharmacokinetics of methyldopa (MD) and the effect on the dopaminergic metabolism was studied in anesthetized sham-operated (SO) and sinoaortic-denervated (SAD) rats by using the microdialysis technique. A concentric microdialysis probe was placed in the striatum or in the posterior hypothalamus. Levels of MD, homovanillic acid (HVA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were measured by high pressure liquid chromatography coupled to electrochemical detection (HPLC-EC). Following the i.p. administration of MD (50 mg kg −1, i.p.), striatal dialysates showed that this drug rapidly reaches the brain. However, in SAD rats the MD levels of dialysates were lower and decreased more rapidly compared to SO rats. On the other hand, dialysates of posterior hypothalamus showed that in SAD animals the accumulation of MD was significantly greater than in SO rats. MD does not significantly reduce the striatal production of dopaminergic metabolite DOPAC in both groups of rats. The drug also induces a decrease of DOPAC levels in hypothalamic dialysates of SO and SAD animals. On the other hand, a no significative decay of HVA levels was seen in the striatal dialysate of both groups of experimental animals. In conclusion, this study by using a microdialysis technique shows that MD has different kinetic profiles in dialysates from posterior hypothalamus and striatum of SO and SAD rats at a dose that alters dopaminergic metabolism.

Central interleukin-1beta antibody increases renal and splenic sympathetic nerve discharge.

We tested the hypothesis that intracerebroventricular (lateral ventricle) administration of interleukin-1beta (IL-1beta) antibody increases the level of sympathetic nerve discharge (SND) in alpha-chloralose-anesthetized rats. Mean arterial pressure (MAP), heart rate (HR), and SND (splenic and renal) were recorded before (Preinfusion), during (25 min), and for 45 min after infusion of IL-1beta antibody (15 microg, 50 microl icv) in baroreceptor-intact (intact) and sinoaortic-denervated (SAD) rats. The following observations were made. First, intracerebroventricular infusion of IL-1beta antibody (but not saline and IgG) significantly increased MAP and the pressor response was higher in SAD compared with intact rats. Second, renal and splenic SND were significantly increased during and after intracerebroventricular IL-1beta antibody infusion and sympathoexcitatory responses were higher in SAD compared with intact rats. Third, intracerebroventricular administration of a single dose of IL-1beta antibody (15 microg, 5 microl for 2 min) significantly increased splenic and renal SND in intact rats. These results suggest that under the conditions of the present experiments central neural IL-1beta plays a role in the tonic regulation of SND and arterial blood pressure.

Reduced endothelial vasomotor function and enhanced neointimal formation after vascular injury in a rat model of blood pressure lability.

Increased short-term blood pressure variability is known to be associated with hypertensive target organ damage. Sinoaortic denervation (SAD) induces a marked increase in blood pressure lability without affecting the average blood pressure level. The aim of this study was to investigate the effects of blood pressure lability on endothelial vasomotor function and neointimal formation after balloon injury in SAD rats. Direct longterm measurement of mean arterial pressure showed no significant difference in the average of mean arterial pressure between the SAD group and sham-operated control group. In contrast, the standard deviation of mean arterial pressure, as an index of blood pressure lability, was 3-fold greater in SAD rats. To study endothelial function, isometric tension of aortic rings was measured 4 weeks after SAD or sham operation. Endothelium-dependent vasorelaxation induced by acetylcholine was significantly reduced in the SAD group (20% reduction at maximum relaxation). Endothelium-independent vasorelaxation induced by sodium nitroprusside was similar in each group. Acetylcholine-induced NO release from aortic rings was significantly reduced in the SAD group. Next, we examined neointimal formation in carotid arteries in SAD and sham-operated rats at 2 weeks after balloon injury. The neointimal-to-medial area ratio in the SAD group was 50% higher than that in the sham-operated group. The percentage of proliferating cell nuclear antigen-positive cells in the intima was significantly higher in the SAD group. These findings suggest that increased blood pressure lability, independently of average blood pressure level, impairs endothelial function by inhibiting NO production, enhances neointimal formation after balloon injury, and may thereby contribute to atherogenesis.

The Role of the Vestibular System in Modulating Blood Pressure of Sinoaortic Denervated Rats

Background and Objectives:The vestibuloautonomic reflex controls respiration and blood pressure during locomotion. The purpose of this study was to investigate the role of the peripheral vestibular receptor in the control of blood pressure in sinoaortic denervated (SAD) rats. Materials and Methods:The baroreceptor reflex was removed by SAD in labyrinthectomized rats. The expression of c-Fos protein in the vestibular nuclear complex, and other nuclei related to control of blood pressure, was measured following the induction of acute hypotension using sodium nitroprusside (SNP). Results:The SNP induced acute hypotension, in intact labyrinthine rats, increased the expression of c-Fos protein in the supraoptic nucleus, paraventricular nucleus, rostral ventrolateral medulla, solitary nucleus, and vestibular nuclear complex. The expression of c-Fos protein, following the SNP induced acute hypotension in the SAD rats, increased the expression of c-Fos protein in the paraventricular nucleus, rostral ventrolateral medulla, and medial and inferior vestibular nuclei. The acute hypotension induced by SNP in a unilateral labyrinthectomy, with SAD, increased the expression of c-Fos protein in the contralesional vestibular nuclear complex, but decreased its expression in the ipsilesional vestibular nuclear complex. The acute hypotension induced by SNP in a bilateral labyrinthectomy, with SAD, showed only slight expression of c-Fos protein in the bilateral vestibular nuclear complex. Conclusion:These results suggest that the acute hypotension induced by SNP activates the vestibular nuclear neurons by decreasing the blood flow in the peripheral vestibular receptors, and that these in turn modulate blood pressure through activation of the catecholaminergic nervous system and neuroendocrine reflex. (Korean Circulation J 2003;33 (6):513-522)

The importance of blood pressure variability in rat aortic and left ventricular hypertrophy produced by sinoaortic denervation.

The main objective was to examine the role of hemodynamics in rat aortic and left ventricular hypertrophy produced by sinoaortic denervation (SAD). Rats were examined at different times after SAD or sham operation (Sham). Hemodynamics were recorded continuously in conscious unrestrained rats. The time course of hemodynamic changes and cardiovascular hypertrophy was observed and linear regression analysis was performed to study the role of hemodynamics in SAD-induced aortic and left ventricular hypertrophy. Long-term mortality, water and food intake, and body weight were also determined after operation. High mortality (40%), dramatic reduction of water and food intake, and weight loss occurred within 1 week after SAD. Chronic SAD rats exhibited a marked increase in blood pressure variability (BPV), with no change in the average level of blood pressure (BP), as compared with the Sham control rats. Increased BPV was higher at 2 weeks (about threefold) than 16 weeks (about twofold) after SAD. Aortic hypertrophy existed in all three kinds of examined rats: 2-, 10- and 16-week SAD rats. Left ventricular hypertrophy was found only in 10- and 16-week SAD rats. Both aortic hypertrophy and left ventricular hypertrophy were significantly and positively correlated with BPV, but not with BP level. Persistent high BPV following SAD can lead to aortic and left ventricular hypertrophy. The aorta is more sensitive to increased BPV than the heart.

Acute sympathoexcitatory action of angiotensin II in conscious baroreceptor-denervated rats.

Angiotensin II (ANG II) has complex actions on the cardiovascular system. ANG II may act to increase sympathetic vasomotor outflow, but acutely the sympathoexcitatory actions of exogenous ANG II may be opposed by ANG II-induced increases in arterial pressure (AP), evoking baroreceptor-mediated decreases in sympathetic nerve activity (SNA). To examine this hypothesis, the effect of ANG II infusion on lumbar SNA was measured in unanesthetized chronic sinoaortic-denervated rats. Chronic sinoaortic-denervated rats had no reflex heart rate (HR) responses to pharmacologically evoked increases or decreases in AP. Similarly, in these denervated rats, nitroprusside-induced hypotension had no effect on lumbar SNA; however, phenylephrine-induced increases in AP were still associated with transient decreases in SNA. In control rats, infusion of ANG II (100 ng x kg(-1) x min(-1) iv) increased AP and decreased HR and SNA. In contrast, ANG II infusion increased lumbar SNA and HR in sinoaortic-denervated rats. In rats that underwent sinoaortic denervation surgery but still had residual baroreceptor reflex-evoked changes in HR, the effect of ANG II on HR and SNA was variable and correlated to the extent of baroreceptor reflex impairment. The present data suggest that pressor concentrations of ANG II in rats act rapidly to increase lumbar SNA and HR, although baroreceptor reflexes normally mask these effects of ANG II. Furthermore, these studies highlight the importance of fully characterizing sinoaortic-denervated rats used in experiments examining the role of baroreceptor reflexes.

Arterial baroreceptors mediate the inhibitory effect of acute increases in arterial blood pressure on thirst.

The present study sought to determine whether arterial baroreceptor afferents mediate the inhibitory effect of an acute increase in arterial blood pressure (AP) on thirst stimulated by systemically administered ANG II or by hyperosmolality. Approximately 2 wk after sinoaortic denervation, one of four doses of ANG II (10, 40, 100, or 250 ng. kg(-1) x min(-1)) was infused intravenously in control and complete sinoaortic-denervated (SAD) rats. Complete SAD rats ingested more water than control rats when infused with 40, 100, or 250 ng x kg(-1) x min(-1) ANG II. Furthermore, complete SAD rats displayed significantly shorter latencies to drink compared with control rats. In a separate group of rats, drinking behavior was stimulated by increases in plasma osmolality, and mean AP was raised by an infusion of phenylephrine (PE). The infusion of PE significantly reduced water intake and lengthened the latencies to drink in control rats but not in complete SAD rats. In all experiments, drinking behavior of rats that were subjected to sinoaortic denervation surgery but had residual baroreceptor reflex function (partial SAD rats) was similar to that of control rats. Thus it appears that arterial baroreceptor afferents mediate the inhibitory effect of an acute increase in AP on thirst stimulated by ANG II or hyperosmolality.

ANP potentiates nonarterial baroreflex bradycardia: evidence from sinoaortic denervation in rats

Previous findings indicate that atrial natriuretic peptide (ANP) enhances the reflex bradycardia arising from stimulation of cardiac mechanoreceptors and chemoreceptors, but not that from arterial baroreceptors. The present study tests this proposal by examining the effect of ANP on these reflexes in six chronically sinoaortic-denervated (SAD), and eight sham-operated (sham), conscious rats. Arterial baroreceptor-heart rate (HR) reflex function was examined by constructing full-range steady-state blood pressure (BP)-HR curves using alternating doses of pressor (methoxamine, 2–100 μg/kg) and depressor (nitroprusside, 1–50 μg/kg) agents. Nonarterial baroreceptor reflex function was assessed by the ‘ramp’ bradycardic response to the rapid BP rise after i.v. methoxamine (100 μg/kg bolus dose). The cardiopulmonary chemoreflex was evoked by i.v. injections of serotonin (1–20 μg/kg). These three tests were performed on each rat during infusions, in random order, of rat ANP (150 ng/kg/min i.v.) and saline vehicle. The ability of ANP to significantly enhance ramp reflex bradycardia was not diminished in SAD compared with sham rats (+54±12% vs. +42±15%, respectively). ANP also significantly enhanced cardiopulmonary chemoreflex bradycardia in both groups (+60±15% in SAD, +40±8% in sham). Neither the normal steady-state BP-HR response in sham rats nor the small residual response in SAD rats was enhanced by ANP (−1±7% in sham, −11±8% in SAD). We conclude that ANP enhances reflex bradycardias of nonarterial, probably cardiac mechanoreceptor, origin.

Fos immunoreactivity in the diagonal band and the perinuclear zone of the supraoptic nucleus after hypertension and hypervolaemia in unanaesthetized rats.

We used Fos immunocytochemistry to study the effects of hypertension and hypervolaemia on neurones in the diagonal band of Broca and the perinuclear zone of the supraoptic nucleus, two nuclei that are both involved in the baroreceptor regulation of vasopressin neurones in the supraoptic nucleus. In addition, we used sino-aortic denervation to examine the role of arterial baroreceptors in the response to these haemodynamic changes. Sham-operated and sino-aortic denervated rats were infused with phenylephrine sufficient to increase blood pressure for 2 h. Control rats were infused with the same volume of isontonic saline. Only Sham sino-aortic denervated rats showed reflex bradycardia in response to the increased blood pressure. Volume expansion was produced by infusing the rats with isotonic saline equal to 10% of their body weight for 10 min, which significantly increased central venous pressure. In the diagonal band of Broca and the perinuclear zone, the number of Fos-positive neurones was significantly increased after phenylephrine infusion. Sino-aortic denervation blocked the significant increase in both regions. After volume expansion, a significant increase in Fos staining was observed only in the perinuclear zone of the supraoptic nucleus. This increase was not blocked by sino-aortic denervation. Our results indicate that both the diagonal band of Broca and the perinuclear zone of the supraoptic nucleus are activated by stimulating arterial baroreceptors; however, the perinuclear zone of the supraoptic nucleus is stimulated during volume expansion. Furthermore, the activation of perinuclear zone of the supraoptic nucleus after volume expansion is not dependent on intact arterial baroreceptors.

Blood pressure variability and organ damage.

1. Blood pressure variability (BPV) is expressed as the standard deviation of the average blood pressure (BP). Blood pressure variability is increased in hypertensive patients and animals. However, BPV is not necessarily related to the BP level. 2. For nearly any level of 24 h mean BP, hypertensive patients in whom the BPV is low have a lower prevalence and severity of organ damage than patients in whom the 24 h BPV is high. This observation has been confirmed further in spontaneously hypertensive rats with direct pathological analysis for organ damage. 3. In sinoaortic-denervated (SAD) rats, 24 h average BP is normal and BPV is markedly increased. Myocardial damage, renal lesions and vascular remodelling are seen in these animals 4 weeks after SAD. 4. Haemodynamic effects and activation of the renin- angiotensin system are hypothesized to contribute to organ damage induced by increased BPV. 5. Blood pressure variability is of potential importance in antihypertensive therapy.

Arterial baroreflex deficit induced organ damage in sinoaortic denervated rats.

To verify the independent role of the arterial baroreceptor dysfunction involved in target-organ damage in hypertension, sinoaortic denervated (SAD) rats were used as a model of arterial baroreflex (ABR) deficit. SAD, isolated aortic-denervated (AD), and isolated sinus-denervated (SD) rats were instrumented to record blood pressure (BP), heart rate (HR), BP variability (BPV), HR variability (HRV), ABR function control of heart period (ABR-HP), and BP (ABR-BP). Vascular maximum contractile/relaxant function was determined and organ damage was estimated by observation of morphologic changes. Short-term (postoperative 1 week) SAD caused hypertension and tachycardia in rats. Eighteen weeks after operation, BP and HR values in SAD and SD rats were not different from those in sham-operated rats, but AD rats were hypertensive compared with control group. Although 24-h mean BP values of long-term SAD rats were not different from those of sham-operated rats, 24-h BPV of SAD rats was significantly higher than that of sham-operated rats. Arterial baroreflex function in short-term SAD rats was significantly less than in sham-operated rats, whereas in long-term SAD rats, ABR-HP and ABR-BP were higher than those in short-term SAD rats, but were still significantly lower than those in control groups. At postoperative 18 weeks, baroreflex function in SAD and AD rats was significantly less than function in SD and control groups. SBPmax after phenylephrine and DBPmin after nitroprusside were significantly higher in SAD, AD, and SD rats than in control rats. Baroreflex function was negatively correlated to DBPmin and SBPmax in all denervated rats (n = 44). Some morphologic changes were found 18 weeks after denervation in heart, kidney, and small artery in SAD, AD, and SD rats. Baroreflex function in all denervated rats was negatively related to 24-h BPV values. In contrast, 24-h BPV values in SAD, AD, and SD rats were positively related to organ-damage score. A negative correlation between ABR function and end-organ damage score was found. Arterial baroreflex deficit played an independent and important role in organ-damage in SAD rats with significantly elevated 24-h BPV.

PVN lesions prevent the endothelin 1-induced increase in arterial pressure and vasopressin.

Endothelin (ET) acts within the central nervous system to increase arterial pressure and arginine vasopressin (AVP) secretion. This study assessed the role of the paraventricular nuclei (PVN) in these actions. Intracerebroventricular ET-1 (10 pmol) or the ET(A) antagonist BQ-123 (40 nmol) was administered in conscious intact or sinoaortic-denervated (SAD) Long-Evans rats with sham or bilateral electrolytic lesions of the magnocellular region of the PVN. Baseline values did not differ among groups, and artificial cerebrospinal fluid (CSF) induced no significant changes. In sham-lesioned rats, ET-1 increased mean arterial pressure (MAP) 15.9 +/- 1.3 mmHg in intact and 22.3 +/- 2.7 mmHg in SAD (P < 0.001 ET-1 vs. CSF) rats. PVN lesions abolished the rise in MAP: -0.1 +/- 2.8 mmHg in intact and 0.0 +/- 2.9 mmHg in SAD. AVP increased in only in the sham-lesioned SAD group 8.6 +/- 3.5 pg/ml (P < 0.001 ET-1 vs. CSF). BQ-123 blocked the responses. Thus the integrity of the PVN is required for intracerebroventricularly administered ET-1 to exert pressor and AVP secretory effects.

SINO-AORTIC DENERVATION ALTERS THE HEMODYNAMIC RESPONSE TO EXERCISE IN HYPERTENSIVE RATS

The effect of sino-aortic denervation (SAD) on the heart rate (HR), arterial pressure (AP) and regional blood flow responses during dynamic exercise was examined in spontaneously hypertensive rats (SHR). Intact (n = 14) and SAD (n = 17) rats were instrumented with arterial catheters and mesenteric and iliac Doppler ultrasonic flow probes. After recovery, all rats underwent a graded exercise test. Heart rate increased significantly during exercise in intact and SAD rats. There was no significant difference in the steady state heart rate response to exercise in the intact and SAD rats. Arterial pressure increased during exercise in the intact rats. In sharp contrast, arterial pressure decreased during exercise in the SAD rats. Iliac vascular conductance increased during exercise in the intact and SAD rats. The increase in iliac vascular conductance during exercise was significantly greater in the SAD rats. Mesenteric vascular conductance decreased during exercise in the intact and SAD rats. The decrease in mesenteric vascular conductance during exercise was significantly attenuated in the SAD rats. Results suggest that functioning arterial baroreceptors are required for the typical hemodynamic responses during dynamic treadmill running in hypertensive rats.

Arterial remodeling in chronic sinoaortic-denervated rats.

The spontaneous variation of blood pressure is defined as "blood pressure variability" (BPV). The chronic sinoaortic-denervated (SAD) rat is a model of high BPV without sustained hypertension. Little is known about vascular remodeling in this model. In the present study, we examined blood pressure, vascular remodeling, and aortic angiotensin II concentration in chronic SAD rats in separate experiments. In experiment 1, intra-arterial blood pressure was continuously recorded in conscious unrestrained rats. The 16-week SAD rats had a significant increase in BPV and no change in the mean level of blood pressure over a 24-h period. In experiment 2, we measured structural changes of seven kinds of arteries by histologic method and computer image analysis and functional changes of thoracic aortas by isolated artery preparation. Structural remodeling after 16-week sinoaortic denervation was characterized by increase in wall thickness, wall area, and ratio of wall thickness to internal diameter, with different changes in internal diameter and external diameter in different arteries, indicating that arterial structural remodeling expresses itself mainly as vascular growth. This vascular growth might be caused by medial smooth muscle cell growth and collagen accumulation. Aortic contraction induced by norepinephrine was potentiated, whereas aortic relaxation induced by acetylcholine was attenuated after sinoaortic denervation. In experiment 3, plasma and aortic angiotensin II concentrations were determined by radioimmunoassay. The former remained unchanged, whereas the latter was significantly increased in 10-week SAD rats. It is concluded that in rats chronic sinoaortic denervation can produce vascular remodeling that might be related to increased BPV and an activated tissue renin-angiotensin system.

The effect of adenosine on blood pressure variability in sinoaortic denervated rats is mediated by adenosine A2a-Receptor.

It is known that adenosine decreases blood pressure (BP) level as well as blood pressure variability (BPV). However, there is little information about the effect of adenosine on BPV. With a computerized analytic system for BP and heart rate (HR) that could sample the data continuously in conscious, freely moving rats, we studied the effects of different agonists and antagonists of adenosine receptors on BPV in sinoaortic denervated (SAD) rats. It was found that both adenosine and 5'-N-cyclopropyl-carboxamidoadenosine (CPCA, a selective adenosine A,-receptor agonist) decreased BPV. whereas N6-cyclopentyladenosine (CPA, a selective adenosine A1-receptor agonist) had no significant effect on BPV. When the rats were pretreated with theophylline (the nonselective adenosine-receptor antagonist), the inhibitory effects of adenosine as well as CPCA on BPV were abolished. Furthermore, it was found that 8-(3-chlorostyryl)caffeine (CSC, a selective adenosine A2a-receptor antagonist), also could prevent such an effect on BPV of CPCA. By itself, however, neither theophylline nor CSC had any influence on BPV. These results suggest that the effect of adenosine on BPV is mediated by adenosine A2a-receptor.

Inhibition of baroreflex vagal bradycardia by activation of the rostral ventrolateral medulla in rats.

In stressful conditions, baroreflex vagal bradycardia (BVB) is often suppressed while blood pressure is increased. To address the role of the rostral ventrolateral medulla (RVL), a principal source of sympathetic tone, in inhibition of BVB, we microinjected DL-homocysteic acid (DLH, 6 nmol) into the RVL of chloralose-urethan-anesthetized, sinoaortic-denervated rats to examine the effect on BVB. The BVB was provoked by electrical stimulation of the aortic depressor nerve ipsilateral to the injection sites. DLH microinjection was found to suppress BVB while increasing blood pressure. The inhibition of BVB was observed even during the early phase in which DLH transiently suppressed central inspiratory activity. The inhibition was not affected either by upper spinal cord transection or suprapontine decerebration. Similar results were obtained by microinjection of bicuculline methiodide (160 pmol), a GABA antagonist, into the RVL of carotid sinus nerve-preserved rats due to withdrawal of a tonic GABA-mediated, inhibitory influence including the input from arterial baroreceptors. In conclusion, activation of the RVL inhibits BVB at brain stem level independently of central inspiratory drive.

Hypoxic depression of circadian oscillations in sino-aortic denervated rats.

We hypothesized that hypoxia depresses the circadian oscillations of body temperature (T(b)) and oxygen consumption (V(O(2))) even in the absence of inputs from the peripheral chemoreceptors. Adult rats were sino-aortic denervated bilaterally (SAX, N=17) or sham-operated (Sham, N=17). Ten rats of each group were instrumented for measurements of T(b) and activity by telemetry. Animals were exposed to normoxia (21% O(2)), hypoxia (10.5% O(2)), and again normoxia, each for a 5-day duration, in constant light ('free-running') conditions. Hypoxia almost eliminated the T(b) circadian oscillations, mostly by abolishing the daily rise in T(b). Upon return to normoxia T(b) rapidly increased and the normal oscillation was reestablished at the expected phase of the cycle. The hypoxic effects did not differ between Sham and SAX. During hypoxia the amplitude of the circadian oscillation of activity was reduced by approximately 25%, and that of V(O(2)), measured by an open flow method in the remaining Sham and SAX rats (N=7 each), was reduced by almost 50%. In all cases there was no difference between the two groups. We conclude that activation of the peripheral chemoreceptors is not required for the manifestation of the hypoxic depression of the metabolic and temperature circadian oscillations. The results are compatible with the view that hypoxia depresses thermogenesis acting on the thermoregulatory centers of the hypothalamus.

STUDY OF THE EVOLUTION OF BLOOD AND STRIATAL LEVELS OF METHYLDOPA: A MICRODIALYSIS STUDY IN SINAORTIC DENERVATED RATS

Pharmacokinetic of methyldopa (50 mg kg−1i.p.) was studied in anesthetized sham operated and sinoaortic denervated (SAD) rats by using the microdialysis technique. Vascular shunt probe was inserted into the carotid artery and concentric probe was placed in the striatum. Levels of methyldopa were measured by HPLC-EC. The number of animals in each group was six and normal distribution of the variables of the study was assumed. Peak concentrations in arterial blood of methyldopa were similar in both groups of rats but the elimination rate constant was 0.31±0.09 h−1for sham rats (n =6) and 1.28±0.31 h−1for SAD rats (n =6,P <0.05). Low levels of methyldopa and a more pronounced decrease were seen in striatum of sinoaortic denervated rats. In conclusion, by using a microdialysis technique, different kinetic profiles of methyldopa were observed in sham operated and sinoaortic denervated rats.

Nociceptin modulates renal sympathetic nerve activity through a central action in conscious rats.

Nociceptin, an endogenous agonist of the opioid receptor-like(1) receptor, is expressed in the hypothalamus, where it is implicated in autonomic nervous system control. However, the central actions of nociceptin on sympathetic nerve activity have not been studied. We investigated the effect of intracerebroventricularly administered nociceptin (2-10 nmol) on blood pressure, heart rate (HR), and renal sympathetic nerve activity (RSNA) in conscious rats and sinoaortic-denervated (SAD) rats. Intracerebroventricularly administered nociceptin resulted in a dose-dependent decrease in mean arterial pressure (MAP) and HR in intact rats. RSNA decreased 31.5 +/- 2.1 and 19.9 +/- 5.0% at a dose of 2 and 5 nmol, respectively. In SAD rats, MAP, HR, and RSNA decreased in a dose-dependent manner, and the maximum responses were larger than those in intact rats. The decrease in HR induced by nociceptin was blocked by propranolol but not by atropine, which indicates that nociceptin is acting by inhibiting cardiac sympathetic outflow. These nociceptin-induced depressor and bradycardic responses were not antagonized by pretreatment with naloxone and nocistatin. These findings suggest that central nociceptin may have a functional role in regulating cardiovascular and sympathetic nervous systems.

Importance of imidazoline receptors in the cardiovascular responses of clonidine in sinoaortic denervated rats.

Importance of imidazoline receptors in the cardiovascular responses of clonidine in sinoaortic denervated rats.