Differential effects of central and peripheral desipramine on sympathoadrenal function and heart rate in conscious rabbits.

The effects of the tricyclic antidepressant, desipramine, on the baroreflex regulation of renal sympathetic nerve activity (SNA) and heart rate (HR), the nasopharyngeal reflex, plasma epinephrine and blood pressure (BP) were studied in conscious rabbits. Renal SNA and HR were recorded during slow ramp changes in mean arterial pressure (MAP) and during inhalation of cigarette smoke. Intracisternal (i.c.) and intravenous (i.v.) drug administration were compared, using doses which produced similar total central nervous system (CNS) concentrations. After a brief sympathoexcitation, i.c. desipramine inhibited renal SNA and MAP and increased plasma adrenaline and HR. The renal sympathetic baroreflex was substantially attenuated, with reflex range and gain reduced by 46 and 31%, respectively, but the cardiac baroreflex and nasopharyngeal reflex were affected minimally. Sixty-four percent of the desipramine remaining in the brain was concentrated in the medulla oblongata and spinalis; levels in cortex, thalamus, midbrain, lower spinal cord, and peripheral tissues were minimal. Treatment with i.v. desipramine decreased renal SNA and increased HR without altering MAP or epinephrine release. There was a slight attenuation of the nasopharyngeal reflex, a slight baroreceptor-independent reduction in renal SNA at most MAP levels, and an augmentation of the cardiac baroreflex. The drug was uniformly distributed throughout the CNS; only 20% of the centrally accumulated dose was in the medulla. Thus, i.c. desipramine produces a differentiated pattern of sympathoadrenal effects, probably by increasing norepinephrine (NE) concentrations at several sites within the medulla. The effects of i.v. desipramine were different, owing to poorer access to the medulla and the consequences of peripheral neuronal uptake blockade, which may include a modest inhibition at the sympathetic ganglia and an excitation at cardiac and vasoconstrictor neuroeffector junctions.     

REFLEXES MEDIATED BY CARDIAC SYMPATHETIC AFFERENTS DURING MYOCARDIAL ISCHAEMIA: ROLE OF ADENOSINE

1. Myocardial ischaemia and infarction activate vagal and sympathetic sensory endings in the ischaemic myocardium, resulting in powerful reflex effects. The vagal afferents are either mechano- or chemosensitive, whereas sympathetic afferents may be mechano-, chemosensitive or both. 2. Activation of vagal afferents results in sympathoinhibitory, cardioinhibitory, vasodepressor responses. Cardiac sympathetic afferents activated during myocardial ischaemia mediate sympathoexcitatory, vasoconstrictor cardioaccelerator responses. 3. The focus of the present review is on the activation of sympathetic afferents by myocardial ischaemia and on the resulting reflex responses that they mediate. 4. These endings are more likely to be activated as the degree of ischaemia progresses from subendocardial towards transmural. They are evenly distributed between the anterior and inferoposterior wall. Although it has been suggested that these endings are activated by bradykinin, recent evidence indicates that they are activated by adenosine released from the ischaemic myocardium. Results from our laboratory indicate that this effect is due to the activation of adenosine A₁, but not adenosine A₂ receptors. 5. Activation of ventricular vagal and sympathetic afferent fibres during myocardial ischaemia in humans is responsible for the autonomic changes observed and, in the case of the sympathetic afferents, for the sensation of angina pectoris.     

Effects of sinoaortic denervation on the reflex actions of digoxin and a polar aminocardenolide.

To determine the role of carotid sinus and aortic arch baroreceptors in the reflex cardiac sympathetic nerve activity (SNA) responses to administration of ASI-222, a polar aminocardenolide, and to digoxin, a neutral cardenolide, we used anesthetized dogs from which these reflex receptor areas had been removed. The SNA was measured in postganglionic fibers from the stellate ganglion. After we made baseline measurements, we infused either ASI-222 or digoxin intravenously (i.v.) at dose rates that produce cardiac arrhythmias in approximately 100 min (0.7 and 1.2 micrograms/kg/min), respectively. Our data indicate that with sinoaortic baroreceptors removed, progressive infusion of digoxin increases cardiac SNA. In contrast, cardiac SNA decreases progressively during continuous infusion of ASI-222. In saline-treated dogs, SNA was not significantly altered. In another series of experiments, we examined the effects of these drugs and saline on cardiac vagal afferent nerve activity (VANA). ASI-222 (50 micrograms/kg i.v. in 10 min) caused a progressive increase in cardiac VANA in a 60-min observation period. Neither digoxin, at less than or equal to 120 micrograms/kg i.v. in 100 min, nor saline altered VANA. Digoxin appears to reduce SNA by interacting with the carotid sinus and aortic arch baroreceptors, which are myelinated. It does not affect VANA acutely. In contrast, ASI-222 appears to decrease cardiac SNA by interacting with other reflex receptor areas--the unmyelinated cardiopulmonary afferent nerve endings, particularly cardiac mechanoreceptors.     

The effect of atenolol on the spontaneous and reflex activity of the sympathetic nerves in the cat: influence of cardiopulmonary receptors

1 Atenolol reduces sympathetic efferent discharge and attenuates the responses of the sympathetic nerves to changes in blood pressure. The present experiments were carried out to determine whether these changes were mediated by cardiopulmonary receptors whose afferents lie in the vagal nerves.

2 Cats were anaesthetized with α-chloralose and artificially ventilated. In one group of cats recordings were made of sympathetic efferent discharge from few-fibre preparations from the lumbar trunk, splanchnic or renal nerves over a range of blood pressures. In a second group of cats changes in heart rate and blood pressure in response to bilateral occlusion of the common carotid arteries were investigated. In all cats the influence of vagal afferent fibres was removed by cooling both vagal nerves in the neck, both before and after administration of atenolol (3 mg kg^-1 i.v.).

3 Cooling both vagal nerves produced significant increases in blood pressure, heart rate and spontaneous sympathetic efferent discharge but did not affect the relationship between sympathetic efferent discharge and mean blood pressure or the responses to carotid occlusion. Atenolol significantly reduced blood pressure, heart rate and sympathetic efferent discharge but the change in sympathetic efferent discharge on vagal cooling was less than before giving the drug. Atenolol also attenuated the reflex responses of the sympathetic nerves to changes in blood pressure and reduced responses to carotid occlusion. This attenuation was not removed by vagal cooling.

4 Thus, neither the reduction in spontaneous sympathetic efferent discharge nor the attenuation of the baroreceptor reflex seen after atenolol, are due to an increased input to the brain from vagal afferent fibres. Other possible mechanisms whereby atenolol might exert its effects on the sympathetic nerves are discussed.

     

CARDIAC VAGAL AFFERENT STIMULATION BY FREE RADICALS DURING ISCHAEMIA AND REPERFUSION

1. Myocardial ischaemia and reperfusion can evoke excitation of cardiac vagal afferent nerve endings and activation of a cardiogenic depressor reflex (Bezold-Jarisch effect). We postulate that oxygen free radicals, which are well known to be produced during ischaemia and reperfusion, contribute to this excitation. 2. Activity from vagal afferent fibres in rats, whose endings were located in the walls of all four chambers of the heart, was recorded in response to topical application of pro-oxidant chemicals to the surface of the heart. Activity was also recorded from vagal afferent fibres, whose endings were located in the left ventricle, in response to occlusion of the left anterior coronary artery (LAC) for 30 min and subsequent reperfusion. A majority of the recorded fibres were classified as chemosensitive C-fibre endings due to their irregular discharge under resting conditions, their activation in response to the topical application of capsaicin (1-10μg) to the surface of the heart encompassing the receptive field and their conduction velocities. 3. Topical application of either H₂O₂ or xanthine/xanthine oxidase to the heart activated 50% of the chemosensitive endings and did not directly affect cardiac mechanoreceptors. This effect was reproducible, dose-dependent and was not due to [H⁺]. 4. Administration of the superoxide radical scavenging enzyme, superoxide dismutase (20 000 U/kg, i.v.), decreased the response of fibres to xanthine/xanthine oxidase but had no effect on the activation caused by H₂O₂. The antioxidants deferoxamine (20 mg/kg, i.v.) or dimethylthiourea (10 mg/kg, i.v.), which scavenge the hydroxyl radical, abolished the responses to xanthine/xanthine oxidase and H₂O₂. Administration of indomethacin (5 mg/kg, i.v.) had no effect on the afferent response to H₂O₂. 5. In response to ligation of the left anterior coronary (LAC), the activity of chemosensitive endings within the ischaemic zone increased within the first 2 min of occlusion. Endings outside the ischaemic zone were not affected at the beginning of ischaemia. Reperfusion activated only chemosensitive endings responsive to topical H₂O₂. These reperfusion-sensitive endings were located both within and outside the ischaemic zone of the left ventricle. 6. Indomethacin (5 mg/kg, i.v.) prevented activation of chemosensitive endings at the beginning of LAC occlusion regardless of their sensitivity to H₂O₂ but had no effect on the response to reperfusion. Conversely, deferoxamine (20 mg/kg, i.v.) had no effect on the activation of chemosensitive fibres at the onset of ischaemia, whereas it completely prevented activation at reperfusion. 7. We propose that there are two different mechanisms that activate chemosensitive afferent vagal fibres in the rat heart during ischaemia and reperfusion. The first causes excitation of these endings at the onset of ischaemia and is mediated by prostaglandin synthesis within the ischaemic zone. The second mechanism leads to a more widespread activation of chemosensitive afferents in the left ventricle during prolonged ischaemia and at the moment of reperfusion and is mediated by oxygen free radical formation.     

Longitudinal assessment of the effects of oestrogen on blood pressure and cardiovascular autonomic activity in female rats

• 1 Published data concerning the effects of ovarian hormones on haemodynamic variability are contradictory. For the first time, the present study used radiotelemetric haemodynamic monitoring to investigate the long‐term effects of chronic oestrogen depletion and repletion on cardiovascular autonomic control and arterial baroreflex sensitivity (BRS) in female rats.
• 2 Blood pressure (BP), heart rate (HR) and +dP/dt_max of arterial pressure (an estimate of myocardial contractility) were monitored in sham‐operated (SO), ovariectomized (OVX) and oestrogen‐replaced OVX rats (OVXE2) for 16 weeks. Cardiovascular autonomic control and baroreflexes were assessed by frequency domain analysis of interbeat intervals (IBI) and systolic BP (SBP).
• 3 Compared with SO rats, OVX rats exhibited no changes in BP, short‐lived decreases in HR and sustained reductions in +dP/dt_max of arterial pressure. The high‐ (HF; 0.75–3 Hz) and low‐frequency (LF; 0.25–0.75 Hz) components of spectral power of IBI were significantly decreased and increased, respectively, by ovariectomy. An increase in the IBI_LF/HF ratio in OVX rats suggests a shift in the cardiac sympathovagal balance towards sympathetic dominance. Index α, the spectral index of spontaneous BRS, was reduced by OVX.
• 4 Oestrogen replacement caused significant reductions in BP and HR and reversed OVX‐induced changes in +dP/dt_max of arterial pressure and cardiac autonomic activity. The LF oscillations of SBP were reduced in OVXE2 rats, suggesting a reduction in vascular sympathetic tone by oestrogen.
• 5 These findings highlight the importance of long‐term oestrogen therapy in rectifying the detrimental effects of depletion of ovarian hormones on the cardiovascular system and baroreflex.

     

Prazosin depression of baroreflex function in hypertensive man

Summary Prazosin is a post synaptic alpha adrenergic blocker effective in hypertension, whose hypotensive effect is unaccompanied by reflex tachycardia or hyperreninemia, nor by other evidence of increased sympathetic activity. We studied the baroreceptor reflex arc as a potential mediator of these effects. Twenty-two essential hypertensive men were treated with prazosin alone versus placebo, and experienced a blood pressure fall (from 114.8±3.6 down to 101.1±2.5 mm Hg,p<0.005) unaccompanied by any change in heart rate, plasma renin activity, or several other indices of sympathetic nervous system activity (plasma dopamine-β-hydroxylase activity; urinary excretion of free catecholamines and vanillyl mandelic acid; allp>0.1). Concomitant with the blood pressure fall, there was a significant depression of baroreflex arc sensitivity, from 11.4±2.0 ms/mmHg down to 6.6±1.9 ms/mmHg (p<0.05), without an associated change in cardiac vagal inhibition (291.2±46.2 versus 300.3±19.2 ms,p>0.1). Baroreflex arc sensitivity depression may in part explain the lack of reflex sympathetic outflow noted during prazosin treatment of hypertension.     

MODIFICATION BY DILTIAZEM, A CALCIUM ANTAGONIST, OF THE PULMONARY VAGAL AND CARDIAC SYMPATHETIC CHEMOREFLEXES IN THE DOG

1. Experiments were performed on anaesthetized, open-chest dogs to determine the effects of diltiazem on: the pulmonary vagal chemoreflex evoked by intravenous (i.v.) injection of capsaicin; cardiac sympathetic chemoreflexes activated by epicardial application of bradykinin or capsaicin; and baroreflex-mediated changes in heart rate resulting from both pressor and depressor effects produced by i.v. injections of noradrenaline and bradykinin, respectively. 2. Diltiazem infused i.v. at a rate of 10-30 micrograms/kg per min (mean cumulative dose 0.53 +/- 0.05 mg/kg, n = 9), did not affect basal heart rate, despite significant (P less than 0.001) reduction of resting blood pressure. 3. Diltiazem treatment did not affect the pressor responses to i.v. noradrenaline (0.3 micrograms/kg) or the hypotensive effects of i.v. bradykinin (0.3 micrograms/kg), but reduced significantly both the baroreflex-mediated bradycardia (P less than 0.01) and tachycardia (P less than 0.05) occurring with noradrenaline and bradykinin, respectively. 4. In contrast, diltiazem greatly enhanced reflex bradycardia (P less than 0.001) and systemic hypotension (P less than 0.01) resulting from activation of the afferent vagal pulmonary receptors by i.v. capsaicin (3-5 micrograms/kg). 5. Reflex pressor responses evoked by activation of the afferent cardiac sympathetic neurons by epicardial application of bradykinin (1 microgram) or capsaicin (10-20 micrograms) were not affected by diltiazem, but the corresponding reflex increases in heart rate evoked by both substances were significantly (P less than 0.01) reduced. 6. The results indicate that diltiazem, while reducing the influence of sinoaortic baroreceptors on heart rate, facilitates the reflex vagal control of the cardiac pacemaker by the afferent cardiopulmonary vagal receptors. These nervous reflex mechanisms, which include attenuation of positive chronotrophic effects that may result from ischaemia-induced activation of the afferent cardiac sympathetic neurons, may play an important role in the protective action of diltiazem in ischaemic heart disease.     

INFLUENCE OF CARDIAC AFFERENTS ON TIME-DEPENDENT CHANGES IN THE RENAL SYMPATHETIC BAROREFLEX OF CONSCIOUS RABBITS

1. The stability of the renal sympathetic baroreflex and nasopharyngeal reflex, and the role of cardiac sensory receptors, was studied in conscious rabbits over a 5 h experimental period. 2. Renal sympathetic nerve activity (SNA) was recorded during (i) slow ramp changes in mean arterial pressure (MAP) of 1-2 mmHg/s induced by inflating perivascular balloon cuffs, and (ii) the inhalation of cigarette smoke. Experiments were repeated in other rabbits after blocking cardiac afferents with 5% intrapericardial procaine. 3. Baroreflex responses to the first two caval cuff inflations of the day were significantly greater than subsequent responses. After this, triplicate sets of reflex curves were relatively stable during a 2 h period in the morning. When the experiment was repeated in the afternoon, there was a significant attenuation of baroreflex range and a small fall in resting renal SNA which were abolished by pericardial procaine. 4. Changes in baroreflex properties were minimal when the reflex was assessed only twice, at the beginning and end of a 5 h period. No change was seen in the nasopharyngeal reflex whether the rabbits had been subjected to few or to many cuff inflations. 5. We conclude that time dependent changes can occur in the renal sympathetic baroreflex of conscious rabbits which must be allowed for by appropriate protocol design. These include increasing inhibitory influences from cardiac sensory receptors in experimental situations requiring multiple reflex estimations.     

Reflex bradycardia induced by hydralazine in sino-aortic deafferented conscious rats

1. It is generally recognized that the vasodilator hydralazine produces hypotension accompanied by baroreflex-mediated tachycardia. In some experimental conditions, however, the accompanying heart rate change is bradycardia, a paradoxical response which has not been satisfactorily explained. The present study examined the possibility of hydralazine-induced bradycardia being mediated by vagal or sympathetic afferents activated by changes in left ventricular pressure. 2. Systolic blood pressure and heart rate responses to hydralazine were recorded in conscious normotensive intact rats by a tail cuff method and compared with responses in animals subjected to previous sino-aortic deafferentation (SAD) to remove the influence of the arterial baroreflex. Responses were also obtained after blockade of myocardial afferent vagal C-fibres with urethane, of efferent vagal impulses to the heart with methylatropine, of positive inotropic effects of hydralazine with atenolol, and of prostanoid sensitization of myocardial nerve fibres with indomethacin. 3. Hydralazine produced hypotension and tachycardia in intact rats, and hypotension and bradycardia in SAD animals. In intact rats, this pattern was not affected by any of the pretreatments, while in SAD rats, all pretreatments reversed the bradycardia to hydralazine. 4. The present results indicate that suppression of the arterial baroreflex by SAD propitiates the appearance of a bradycardiac response to hydralazine. This reaction probably results from activation of a vagal cardiodepressant reflex originating in the heart, as suggested by its blockade by drugs acting at various sites along the reflex arch.     

RENAL SYMPATHETIC BAROREFLEX EFFECTS OF ANGIOTENSIN II INFUSIONS INTO THE ROSTRAL VENTROLATERAL MEDULLA OF THE RABBIT

1. The effects of local infusion of angiotensin II (AII) into the rostral ventrolateral medulla (RVLM) pressor area on the renal sympathetic baroreflex were compared with the excitatory amino acid glutamate in urethane anaesthetized rabbits with chronically implanted renal nerve electrodes. Baroreflex blood pressure-renal nerve activity curves were obtained by intravenous infusion of phenylephrine and nitroprusside before and after treatments. 2. Infusion of 4 pmol/min of All into the RVLM increased blood pressure by 12 ± 2 mmHg and transiently increased resting sympathetic nerve activity. The renal sympathetic baroreflex curves were shifted to the right. The upper plateau of the sympathetic reflex increased by 29 ± 8% (n= 6, P < 0.025). 3. Infusions of glutamate into the RVLM, at a dose which was equipressor to that of AII, also increased resting renal sympathetic nerve activity. In contrast to AII, this increase was maintained throughout the infusion. Glutamate shifted the reflex curve to the right and increased the upper plateau of the sympathetic reflex by 44 ± 5% without affecting the lower plateau. 4. These results support the suggestion that AII can act at the level of the RVLM pressor area to facilitate baroreflex control of renal sympathetic activity in a similar fashion to that produced by fourth ventricular administration. 5. Thus the RVLM is a likely candidate site for modulation of the renal sympathetic baroreflex. The similarity of the actions of AII to those of glutamate suggest that it may directly excite sympathetic vasomotor cells in this region.     

Antinociceptive properties of esculetin in non‐inflammatory and inflammatory models of pain in rats

Some studies suggest that 5‐lipoxygenase (5‐LOX) inhibition or leukotriene receptor antagonism may effectively attenuate different kinds of pain. In the present study, we investigated whether esculetin (which, among other actions, potently inhibits 5‐LOX) possesses analgesic activity in acute non‐inflammatory pain and acute inflammatory pain models in rats. We also examined the effects of zileuton, a selective 5‐LOX inhibitor, on esculetin activity. Plasma concentrations of leukotriene B₄ (LTB₄) after administration of esculetin were also determined. Esculetin (1.25–20 mg/kg, i.p.) dose‐dependently alleviated hyperalgesia and exhibited antinociceptive effects in both experimental models. The greatest effect of esculetin was observed with a dose of 20 mg/kg. In carrageenan‐induced inflammatory pain in rats, 20 mg/kg esculetin reversed or mitigated hyperalgesia, increasing the threshold to mechanical stimuli from a control value of ?23.8 ± 1.8% to 15.2 ± 2.2% (P < 0.01) and that to thermal stimuli from ?52.5 ± 6.1% to ?9.5 ± 3.9% (P < 0.01). In non‐inflammatory pain, after esculetin (20 mg/kg) administration the threshold values to mechanical and thermal stimuli increased to 75.9 ± 4.2% and 59.2 ± 4.3%, respectively (P < 0.01 for both). Zileuton (30 mg/kg, p.o.) alone slightly but significantly increased the pain threshold in the non‐inflammatory and inflammatory acute pain models. Pretreatment with 30 mg/kg, p.o., zileuton significantly enhanced the analgesic activity of 5 mg/kg, i.p., esculetin in both pain models. Moreover, esculetin (10 mg/kg, i.p.) decreased LTB₄ concentrations in the blood from 244 ± 29 pg/mL in the control group to 185 ± 11 pg/mL (P < 0.005). The results of the present study suggest the involvement of the 5‐LOX pathway in esculetin analgesia.     

The effect of ketanserin on cardiovascular reflexes in conscious normotensive and spontaneously hypertensive rats

The effect of ketanserin (3 mg/kg i.v.) on the baroreceptor heart rate reflex and the Bezold-Jarisch reflex was examined in conscious Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In the control situation (before ketanserin treatment), reflex bradycardia in response to phenylephrine (baroreflex) and phenyldiguanide (Bezold-Jarisch reflex) were impaired in SHR as compared with WKY, while reflex tachycardia in response to nitroprusside was similar in the two groups. However, after ketanserin administration in SHR, there was a reversal of the baroreflex-mediated tachycardia in response to nitroprusside into a bradycardic response. The nitroprusside-induced bradycardia was not caused by the release of 5-HT stimulating chemosensitive vagal afferents since the 5-HT3 receptor antagonist MDL 72222 did not block this response. In the same SHR, the Bezold-Jarisch reflex evoked by phenyldiguanide and the phenylephrine-induced bradycardia were potentiated by ketanserin. All the above effects of ketanserin were less evident in the WKY. Ketanserin did not alter vagal efferent function in anaesthetized SHR since it did not affect bradycardia induced by electrical stimulation of the vagus nerve. Therefore, it is suggested that ketanserin has sensitised cardiac vagal afferent mechanisms in SHR, which led to a normalization of reflex bradycardic function to a level normally observed in conscious normotensive WKY (i.e. prior to ketanserin treatment).     

Angiotensin peptides as neurotransmitters/neuromodulators in the dorsomedial medulla

1. The present review provides an update on evidence of the neurotransmitter pathways and location of receptors within the nucleus tractus solitarii (NTS) mediating the baroreflex and other haemodynamic actions of angiotensin (Ang) II. 2. A series of studies suggests a significant role for substance P in the acute cardiovascular and carotid sinus chemoreceptor facilitatory actions of AngII in the NTS. The use of antisense oligonucleotides to AT1 receptors indicates both pre- and post-synaptic AngII receptors are likely to be involved in these actions. 3. With respect to baroreceptor reflex actions, it is clear that endogenous AngII impairs the gain for operation of the baroreceptor reflex, because AT1 receptor antagonists facilitate reflex function. This effect is either independent of substance P or involves inhibition of release. Moreover, initial data obtained using antisense oligonucleotides to AT1 receptors suggest that, in the NTS, the effect of endogenous AngII on the baroreceptor reflex is mainly due to presynaptic actions on vagal or carotid sinus afferent fibres. In contrast, the level of endogenous AngII within the NTS appears to have variable effects on activation of cardiopulmonary vagal afferent fibres by phenylbiguanide. These results indicate a divergence of effects of AngII on reflexes evoked by these two different types of sensory input. 4. Use of transgenic rats with alterations in brain angiotensin peptides allowed us to assess the effect of long-term alterations in brain Ang peptides on reflex function. We studied (mRen2)27 transgenic rats (TGR(mRen2)) with high brain medulla AngII levels and transgenic rats with angiotensinogen (Aogen) antisense linked to glial fibrillary acidic protein promoter (TGR(ASrAogen)) with greatly reduced brain Aogen. The reflex evoked by activation of cardiac vagal chemosensitive afferent fibres was enhanced in TGR(ASrAogen), whereas the baroreceptor reflex control of heart rate was attenuated in TGR(mRen2), further confirming a divergence of effects of AngII on these two sensory modalities. 5. The overall results are consistent with a sustained inhibitory effect of AngII on the baroreceptor reflexes, with dose-dependent or activation-dependent effects on cardiac vagal afferent fibre activation. Moreover, alterations in substance P pathways may contribute to the actions of AngII on reflex function.     

Dose-dependent effects of propofol on renal sympathetic nerve activity, blood pressure and heart rate in urethane-anesthetized rabbits

To evaluate the role of the autonomic nervous system in hemodynamic changes after propofol bolus injection, we used direct recordings of renal sympathetic nerve activity to examine the dose-dependent effects of propofol (2.5, 5, 10, and 20 mg/kg) on heart rate, mean blood pressure and renal sympathetic nerve activity in urethane-anesthetized rabbits. The animals were divided into four groups: animals with an intact neuraxis (intact group), cervical vagal nerve-sectioned animals (vagotomy group), carotid sinus and aortic-nerve sectioned animals (SAD group), and animals with SAD plus vagotomy (SADV group). Heart rate did not change significantly even after administration of 2.5 and 5 mg/kg but decreased markedly on 20 mg/kg injection in all groups. The intact and vagotomy groups had augmented renal sympathetic nerve activity with insignificant changes in mean blood pressure after 5 mg/kg injection of the agent. Insignificant changes of renal sympathetic nerve activity but a remarkable decrease of mean blood pressure appeared after 10 mg/kg propofol. Sustained hypotension in parallel with a profound depression of renal sympathetic nerve activity developed at the dose of 20 mg/kg. In SAD and SADV groups, however, dose-dependent depressions of renal sympathetic nerve activity were accompanied by decreases of mean blood pressure. These results suggest the following: (1) propofol-induced hypotensive effects are probably produced by the central-mediated sympathetic depression. (2) The baroreceptor reflex may be preserved at the lower dose of the agent. (3) Heart rate does not change significantly unless a large dose of propofol is used. The difference in effects on heart rate and on mean blood pressure may denote a greater inhibition of sympathetic vascular outflow than of the cardiac sympathetic outflow regulating cardiac rate and contractility. This hypothesis needs further clarification.     

EFFECT OF EXERCISE ON GLUTAMINE SYNTHESIS AND TRANSPORT IN SKELETAL MUSCLE FROM RATS

• 1 Reductions in plasma glutamine are observed after prolonged exercise. Three hypotheses can explain such a decrease: (i) high demand by the liver and kidney; (ii) impaired release from muscles; and (iii) decreased synthesis in skeletal muscle. The present study investigated the effects of exercise on glutamine synthesis and transport in rat skeletal muscle.
• 2 Rats were divided into three groups: (i) sedentary (SED; n = 12); (ii) rats killed 1 h after the last exercise bout (EX‐1; n = 15); and (iii) rats killed 24 h after the last exercise bout (EX‐24; n = 15). Rats in the trained groups swam 1 h/day, 5 days/week for 6 weeks with a load equivalent to 5.5% of their bodyweight.
• 3 Plasma glutamine and insulin were lower and corticosterone was higher in EX‐1 compared with SED rats (P < 0.05 and P < 0.01, respectively). Twenty‐four hours after exercise (EX‐24), plasma glutamine was restored to levels seen in SED rats, whereas insulin levels were higher (P < 0.001) and costicosterone levels were lower (P < 0.01) than in EX‐1. In the soleus, ammonia levels were lower in EX‐1 than in SED rats (P < 0.001). After 24 h, glutamine, glutamate and ammonia levels were lower in EX‐24 than in SED and EX‐1 rats (P < 0.001). Soleus glutamine synthetase (GS) activity was increased in EX‐1 and was decreased in EX‐24 compared with SED rats (both P < 0.001).
• 4 The decrease in plasma glutamine concentration in EX‐1 is not mediated by GS or glutamine transport in skeletal muscle. However, 24 h after exercise, lower GS may contribute to the decrease in glutamine concentration in muscle.

     

Beneficial effect of adenosine on myocardial perfusion in patients treated with primary percutaneous coronary intervention for acute myocardial infarction

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Furosemide Elicits Immediate Sympathoexcitation via a Renal Mechanism Independent of Angiotensin II

Abstract: This investigation aimed at examing the hypothesis that furosemide elicits renal sympathoexcitation through stimulation of renal renin release, which in turn produces increased plasma angiotensin II levels, causing centrally mediated sympathoexcitation. In addition, direct central nervous actions of furosemide on central control of mean arterial pressure, heart rate, and efferent renal sympathetic nerve activity were examined. Furosemide (300 mg/kg intravenously) was administered to four groups of rats: (1) control; (2) nephrectomized; (3) with intravenous losartan blockade (10 μmol/kg); and (4) with intracerebroventricular losartan blockade (10 nmol). In a fifth group of rats, furosemide was administered intracerebroventricularly (0, 2.5, 25 or 250 μg). To eliminate reflex control of mean arterial pressure, heart rate and efferent renal sympathetic nerve activity, all experiments were performed in rats with sinoaortic denervation and bilateral vagotomy. Experiments were performed during Saffan anaesthesia (0.9% alphaxalone/0.3% alphadolone), and rats were paralyzed with pancuronium and artifically ventilated. Furosemide produced an immediate 40% increase in efferent renal sympathetic nerve activity while the furosemide vehicle, 2 vol.% ethanolamine, did not affect efferent renal sympathetic nerve activity. The furosemide-induced increase in efferent renal sympathetic nerve activity was abolished in rats with bilateral nephrectomy but it was not affected by intravenous or intracerebroventricular losartan blockade. Intracerebroventricular angiotensin II produced an increase in mean arterial pressure and efferent renal sympathetic nerve activity whereas intravenous angiotensin II produced a pressor response in absence of increased efferent renal sympathetic nerve activity. Losartan effectively blocked responses to intravenous or intracerebroventricular angiotensin II. Intracerebroventricular administration of furosemide produced no changes in mean arterial pressure, heart rate or efferent renal sympathetic nerve activity. It is concluded that intravenous administration of furosemide elicits an immediate increase in efferent renal sympathetic nerve activity via a renal mechanism independent of angiotensin II. Intracerebroventricular furosemide has no effect on central nervous control of mean arterial pressure, heart rate or efferent renal sympathetic nerve activity.     

Cholinergic stimulation with pyridostigmine improves autonomic function in infarcted rats

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