Reduction In Sympathetic Outflow Research Articles

Review of clinical pharmacokinetics and pharmacodynamics of clonidine as an adjunct to opioids in palliative care.

Clonidine is an α-adrenoceptor agonist acting on receptors in the brain and peripheral tissues, leading to a reduction in sympathetic outflow and release of certain neurotransmitters. Clonidine has multiple uses across various medical conditions. One of its uses is as adjuvant to anaesthetic and analgesic agents specially opioids, mostly administered through intravenous and epidural routes. The opioids, effective in cancer pain management, are associated with various side effects such as sedation, pruritus, constipation, nausea, respiratory depression, tolerance and dependence. Combination of clonidine with opioids seems to help to achieve better pain management and less need of opioids. Use of clonidine in palliative care has been less common, but it is gradually gaining recognition for its potential benefits in managing symptoms like cancer pain and agitation. This combination approach has been explored in palliative care settings, including cancer pain and agitation, where patients experience complex and refractory symptoms. It seems to be well tolerated and gives better symptom relief. The available literature on clonidine's use in cancer pain and agitation management, especially in subcutaneous form, is limited and outdated. Therefore, the optimal dosing, safety profile and overall effectiveness of subcutaneous clonidine requires further exploration through prospective research studies.

Transcutaneous auricular Vagus Nerve Stimulation and Median Nerve Stimulation reduce acute stress in young healthy adults: a single-blind sham-controlled crossover study.

Stress is a major determinant of health and wellbeing. Conventional stress management approaches do not account for the daily-living acute changes in stress that affect quality of life. The combination of physiological monitoring and non-invasive Peripheral Nerve Stimulation (PNS) represents a promising technological approach to quantify stress-induced physiological manifestations and reduce stress during everyday life. This study aimed to evaluate the effectiveness of three well-established transcutaneous PNS modalities in reducing physiological manifestations of stress compared to a sham: auricular and cervical Vagus Nerve Stimulation (taVNS and tcVNS), and Median Nerve Stimulation (tMNS). Using a single-blind sham-controlled crossover study with four visits, we compared the stress mitigation effectiveness of taVNS, tcVNS, and tMNS, quantified through physiological markers derived from five physiological signals peripherally measured on 19 young healthy volunteers. Participants underwent three acute mental and physiological stressors while receiving stimulation. Blinding effectiveness was assessed via subjective survey. taVNS and tMNS relative to sham resulted in significant changes that suggest a reduction in sympathetic outflow following the acute stressors: Left Ventricular Ejection Time Index (LVETI) shortening (tMNS: p = 0.007, taVNS: p = 0.015) and Pre-Ejection Period (PEP)-to-LVET ratio (PEP/LVET) increase (tMNS: p = 0.044, taVNS: p = 0.029). tMNS relative to sham also reduced Pulse Pressure (PP; p = 0.032) and tonic EDA activity (tonicMean; p = 0.025). The nonsignificant blinding survey results suggest these effects were not influenced by placebo. taVNS and tMNS effectively reduced stress-induced sympathetic arousal in wearable-compatible physiological signals, motivating their future use in novel personalized stress therapies to improve quality of life.

Vasopressin Use in the Support of Organ Donors: Physiological Rationale and Review of the Literature.

Detailed search strategies in PubMed, OVID Medline, and EMBASE were undertaken using Medical Subject Headings and Key Words. Physiological articles regarding brain death, and preclinical animal and human studies about the use of vasopressin or analogs, as an intervention in organ support for donation, were considered. Two authors independently screened titles, abstracts, and full text of articles to determine eligibility. Data encompassing models, population, methodology, outcomes, and relevant concepts were extracted. Following brain death, profound reduction in sympathetic outflow is associated with reduced cardiac output, vascular tone, and hemodynamic instability in donors. In addition to reducing catecholamine needs and reversing diabetes insipidus, vasopressin has been shown to limit pulmonary injury and decrease systemic inflammatory response in animals. Several observational studies show the benefit of vasopressin on hemodynamic parameters and catecholamine sparing in donors. Small trials suggest that vasopressin increase organ procurement and have some survival benefit for recipients. However, the risk of bias is overall concerning, and therefore the quality of the evidence is deemed low. Despite potential impact on graft outcome and a protective effect through catecholamine support sparing, the benefit of vasopressin use in organ donors is based on low evidence. Well-designed observational and randomized controlled trials are warranted.

Brain-Derived Acetylcholine Maintains Peak Bone Mass in Adult Female Mice.

Preclinical and clinical data support a role of the sympathetic nervous system in the regulation of bone remodeling, but the contribution of parasympathetic arm of the autonomic nervous system to bone homeostasis remains less studied. In this study, we sought to determine whether acetylcholine (ACh) contributes to the regulation of bone remodeling after peak bone mass acquisition. We show that reduced central ACh synthesis in mice heterozygous for the choline transporter (ChT) leads to a decrease in bone mass in young female mice, thus independently confirming the previously reported beneficial effect of ACh signaling on bone mass accrual. Increasing brain ACh levels through the use of the blood brain barrier (BBB)-permeable acetylcholinesterase inhibitor (AChEI) galantamine increased trabecular bone mass in adult female mice, whereas a peripheral increase in ACh levels induced by the BBB-impermeable AChEI pyridostigmine caused trabecular bone loss. AChEIs did not alter skeletal norepinephrine level, and induced an overall increase in osteoblast and osteoclast densities, two findings that do not support a reduction in sympathetic outflow as the mechanism involved in the pro-anabolic effect of galantamine on the skeleton. In addition, we did not detect changes in the commitment of skeletal progenitor cells to the osteoblast lineage in vivo in AChEI-treated mice, nor a direct impact of these drugs in vitro on the survival and differentiation of osteoblast and osteoclast progenitors. Last, ChT heterozygosity and galantamine treatment triggered bone changes in female mice only, thus revealing the existence of a gender-specific skeletal response to brain ACh level. In conclusion, this study supports the stimulatory effect of central ACh on bone mass accrual, shows that it also promotes peak bone mass maintenance in adult mice, and suggests that central ACh regulates bone mass via different mechanisms in growing versus sexually mature mice. © 2020 American Society for Bone and Mineral Research.

Abstract P214: Serum Glucocorticoid Kinase 1 and Sympathetic Nerve Activity in Salt-Sensitive Hypertension.

Salt-sensitive hypertension affects nearly 50% of the population and reducing salt intake decreases blood pressure and cardiovascular events in the general population. The precise mechanism of how dietary salt contributes to blood pressure (BP) elevation, renal injury, and cardiovascular disease remains unclear. Substantial evidence supports a role of increased sympathetic output in salt-dependent hypertension and this promotes renal inflammation and dysfunction. It has been shown that salt accumulates in the interstitium of hypertensive humans and animals and drives immune cells toward a proinflammatory phenotype through the salt sensing kinase serum/glucocorticoid kinase 1 (SGK1). We have also shown an important role of monocytes and monocyte-derived dendritic cells in hypertension. In this study, we tested the hypothesis that SGK1 in myeloid CD11c + cells promote salt-sensitive hypertension by increasing sympathetic outflow. To test this hypothesis, we created mice lacking SGK1 in CD11c + cells (SGK1 CreCD11c mice) and used SGK1 fl/fl mice as controls. To induce salt-sensitivity, mice received 0.5 mg/ml of N-Nitro-L-arginine methyl ester hydrochloride (L-NAME) in the drinking water for 2 weeks. This was followed by a 2-week washout period and then a 4% high salt diet for 3 weeks. BP was monitored using telemetry. We found that BP elevation during high salt feeding was significantly attenuated in SGK1 CreCD11c mice compared to SGK1 fl/fl mice (125 ± 1 vs. 141 ± 1 mmHg; p < 0.01). SGK1 CreCD11c mice had a significant reduction in CD45 + , CD3 + , CD4 + CD8 + and CD19 + cells in the kidney compared to SGK1 fl/fl mice as assessed by flow cytometry (p < 0.05). Interestingly, on high salt, SGK1 CreCD11c mice had a significant reduction in heart rate (HR) compared to SGK1 fl/fl mice (528 ± 2 vs. 592 ± 7 bpm; p = 0.006). Microglial cells of the brain express CD11c, and we found that the reduction in HR was associated with a marked reduction in HR variability in SGK1 CreCD11c mice compared to SGK1 fl/fl mice (1.65 ± 0.38 vs. 3.00 ± 0.57; p = 0.0018), indicating a reduction in sympathetic outflow. Our data indicate that SGK1 in CD11c + myeloid cells and likely those of the central nervous system, modulate BP and sympathetic outflow promoting the pathogenesis of salt-sensitive hypertension.

The role of the paravertebral ganglia in human sympathetic neural discharge patterns.

The mechanisms affecting recruitment patterns of postganglionic sympathetic nerves remain unclear. The divergent and convergent preganglionic innervation patterns of postganglionic neurons and the presence of differently sized postganglionic nerves suggest that the ganglia may participate in modifying the discharge patterns of single sympathetic postganglionic neurons innervating the skeletal muscle circulation. Whether the ganglia affect the ordered behaviour of varying sized postganglionic sympathetic neurons in humans has not been studied. Trimethaphan infusion produced an ordered pattern of action potential (AP) de-recruitment whereby the firing of larger, low probability APs present at baseline was abolished first, followed by progressive decreased probability of smaller APs. Although integrated sympathetic bursts were no longer detected after several minutes of trimethaphan, firing of the smallest APs was detected. These data suggest the ganglia affect the distribution of firing probabilities exhibited by differently sized sympathetic neurons. The ganglia may contribute to sympathetic neural emission patterns involved in homeostatic regulation. Do the ganglia contribute to the ordered behaviour of postganglionic neuronal discharge within the sympathetic nervous system? To further understand the functional organization of the sympathetic nervous system we employed the microneurographic approach to record muscle sympathetic nerve activity (MSNA) and a continuous wavelet transform to study postganglionic action potential (AP) behaviour during nicotinic blockade at the ganglia (trimethaphan camsylate, 1-7mgmin-1 ) in seven females (37± 5 years). Trimethaphan elicited a progressive reduction in sympathetic outflow characterized by fewer integrated bursts with decaying amplitude. Underlying trimethaphan-mediated attenuations in integrated MSNA were reductions in AP incidence (186± 101 to 29± 31 AP(100 beats)-1 ) and AP content per integrated burst (7± 2 to 3± 1 APsburst-1 ) (both P< 0.01) in the final minute of detectable bursting activity in the trimethaphan condition, compared to baseline. We observed an ordered de-recruitment of larger to smaller AP clusters active at baseline (14± 3 to 8± 2 active AP clusters, P< 0.01). Following cessation of integrated bursts in the trimethaphan condition, the smallest 6± 2 sympathetic AP clusters persisted to fire in an asynchronous pattern (49± 41AP (100 beats)-1 ) in all participants. Valsalva's manoeuvre did not increase the incidence of these persistent APs (60± 42 AP(100 beats)-1 , P= 0.52), or recruit any larger APs in six of seven participants (6± 1 total AP clusters, P= 0.30). These data suggest that the ganglia participate in the ordered recruitment of differently sized postganglionic sympathetic nerves.

Influence of Inspiratory Muscle Training on Sympatho‐excitation in Healthy Young Adults

Inspiratory muscle training (IMT) lowers blood pressure in healthy young adults and adults with obstructive sleep apnea (Vranish &amp; Bailey, 2015; 2016). Importantly, in healthy young adults, 6 weeks IMT also is associated with significant declines in systemic vascular resistance (Delucia et al. 2017). In light of these outcomes, in the current study we test the hypothesis that 6 weeks IMT reduces sympathetic outflow. Accordingly, we recruited healthy college‐aged students and randomly allocated them to either IMT or to Sham training groups. At intake (Week 1) and study completion (Week 6) we recorded MSNA as subjects performed sympatho‐excitatory challenges as follows: Valsalva maneuver, Mueller maneuver, submaximal grip test, cold pressor test, and mental stress tests (Stroop and mental arithmetic). Additionally, we performed weekly (blinded) assessments of systolic and diastolic blood pressures (SBP and DBP), and assessed maximal inspiratory pressure and respiratory function. Our preliminary results indicate subjects in the IMT group have lowered systolic (114.3 ± 3.4 mmHg vs. 106.7 ± 1.8 mmHg, p=0.0115) and diastolic (68.39 ± 1.58 mmHg vs. 63.5 ± 0.97 mmHg, p=0.0413) blood pressures relative to Sham trained subjects (SBP 114.7 ± 2.94 mmHg vs. 108.9 ± 1.34 mmHg and DBP 72.47 ± 3.29 mmHg vs. 69.99 ± 1.75 mmHg). Consistent with our hypothesis, preliminary analyses highlight lowered sympathetic burst frequency in the IMT group during Valsalva maneuvers (Week 1:15 ± 2.2 bursts per 15 seconds vs. Week 6: 11 ± 1.5 bursts per 15 seconds) as compared to Sham trained subjects (Week 1:12.13 ± 1.48 bursts per 15 seconds vs. Week 6:11.63 ± 0.83 bursts per 15 seconds). Data collection is ongoing however, our early findings show a reduction in sympathetic outflow during respiratory challenges which may underpin declines in peripheral resistance and blood pressure seen in healthy young adults following IMT.Support or Funding InformationThis work was supported by start up monies awarded to EFB.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sevoflurane sparing effect of dexmedetomidine in patients undergoing laparoscopic cholecystectomy: A randomized controlled trial.

Background and Aims:Sevoflurane is an excellent but expensive anesthetic agent for laparoscopic cholecystectomy. To decrease sevoflurane consumption during surgery adjuvants like dexmedetomidine may be used. Dexmedetomidine is a recently introduced drug which alleviates the stress response of surgery, produces sedation and analgesia. We aimed to evaluate sevoflurane sparing effect of dexmedetomidine in patients undergoing laparoscopic cholecystectomy under entropy-guided general anesthesia (GA).Material and Methods:In this prospective randomized control study, 100 American Society of Anesthesiologists physical status I–II adult surgical patients scheduled to undergo laparoscopic cholecystectomy were enrolled. Patients were randomly divided into two groups (n = 50). In dexmedetomidine group, patients received intravenous (IV) dexmedetomidine 0.5 μg/kg over 10 min before induction followed by 0.5 μg/kg/h infusion while in control group, patients received the same volume of normal saline.Results:Sevoflurane consumption was 41% lower in dexmedetomidine group as compared to control group (7.1 [1.6] vs. 12.1 [1.9] ml, P <0.001). A 40% reduction was observed in induction dose of propofol (83.0 [19.1] vs. 127.6 [24.8] mg, P <0.001). Mean Riker sedation-agitation score, visual analog score for pain and Aldrete's score were significantly lower in dexmedetomidine group as compared to control group. None of the patients experienced any significant side effects.Conclusion:A 41% reduction in sevoflurane consumption was observed in patients receiving IV dexmedetomidine as an adjuvant in patients undergoing laparoscopic cholecystectomy under GA.

Effect of simvastatin in the autonomic system is dependent on the increased gain/sensitivity of the baroreceptors

A number of mechanisms have been proposed to explain the pleiotropic effect of statin therapy to reduce sympathetic outflow in cardiovascular disease. We tested the hypothesis that statin treatment could improve baroreflex gain-sensitivity triggered by morphological adaptations in the mechanoreceptor site, thus reducing sympathetic activity, regardless of arterial pressure (AP) level reduction. Male spontaneously hypertensive rats (SHR) were divided into control (SHR, n = 8) and SHR-simvastatin (5 mg/kg/day, for 7 days) (SHR-S, n = 8). After treatment, AP, baroreflex sensitivity (BRS) in response to AP-induced changes, aortic depressor nerve activity, and spectral analyses of pulse interval (PI) and AP variabilities were performed. Internal and external carotids were prepared for morphoquantitative evaluation. Although AP was similar between groups, sympathetic modulation, represented by the low frequency band of PI (SHR: 6.84 ± 3.19 vs. SHR-S: 2.41 ± 0.96 msec2) and from systolic AP variability (SHR: 3.95 ± 0.36 vs. SHR-S: 2.86 ± 0.18 mmHg2), were reduced in treated animals. In parallel, simvastatin induced an increase of 26% and 21% in the number of elastic lamellae as well as a decrease of 9% and 25% in the carotid thickness in both, external and internal carotid, respectively. Moreover, improved baroreceptor function (SHR: 0.78 ± 0.03 vs. SHR-S: 1.06 ± 0.04% mv/mmHg) was observed in addition to a 115% increase in aortic depressor nerve activity in SHR-S rats. Therefore, our data suggest that the reduction of sympathetic outflow in hypertension by simvastatin treatment may be triggered by structural changes in the carotid arteries and increased BRS in response to an improvement of the baroreceptors discharge and consequently of the afferent pathway of the baroreflex arch.

Angiotensin-converting enzyme 2 overexpression improves central nitric oxide-mediated sympathetic outflow in chronic heart failure

Angiotensin (ANG)-converting enzyme (ACE)2 in brain regions such as the paraventricular nucleus (PVN) controlling cardiovascular function may be involved in the regulation of sympathetic outflow in chronic heart failure (CHF). The purpose of this study was to determine if ACE2 plays a role in the central regulation of sympathetic outflow by regulating neuronal nitric oxide (NO) synthase (nNOS) in the PVN. We investigated ACE2 and nNOS expression within the PVN of rats with CHF. We then determined the effects of ACE2 gene transfer in the PVN on the contribution of NO-mediated sympathoinhibition in rats with CHF. The results showed that there were decreased expressions for ACE2, the ANG-(1-7) receptor, and nNOS within the PVN of rats with CHF. After the application of adenovirus vectors encoding ACE2 (AdACE2) into the PVN, the increased expression of ACE2 in the PVN was confirmed by Western blot analysis. AdACE2 transfection significantly increased nNOS protein levels (change of 50 ± 5%) in the PVN of CHF rats. In anesthetized rats, AdACE2 treatment attenuated the responses of renal sympathetic nerve activity (RSNA), mean arterial pressure, and heart rate to the NOS inhibitor N-monomethyl-L-arginine in rats with CHF (RSNA: 28 ± 3% vs. 16 ± 3%, P < 0.05) compared with CHF + AdEGFP group. Furthermore, neuronal NG-108 cells incubated with increasing doses of AdACE2 showed a dose-dependent increase in nNOS protein expression (60% at the highest dose). Taken together, our data highlight the importance of increased expression and subsequent interaction of ACE2 and nNOS within the PVN, leading to a reduction in sympathetic outflow in the CHF condition.

Effects of moxonidine on sympathetic nerve activity in patients with end-stage renal disease

End-stage renal disease (ESRD) is characterized by markedly increased sympathetic outflow that contributes to increased cardiovascular mortality in these patients. The central sympatholytic drug moxonidine (MOX) has been shown to reduce muscle sympathetic nerve activity (MSNA) in initial stages of chronic kidney disease; however, the effects in ESRD are not known. The aim of this study was to test the hypothesis that low-dose MOX causes sustained decreases in sympathetic outflow in ESRD patients. Twenty-three ESRD patients (mean age 46.4 +/- 16 years, 14 men, seven women, no diabetic patients) were randomized to a daily treatment of 0.3 mg MOX or placebo (PLA) in addition to pre-existing antihypertensive therapy. At baseline and after 1 and 6 months of treatment, heart rate (HR, ECG), blood pressure (mean arterial pressure, automatic sphygmanometer), calf blood flow (CBF, venous occlusion plethysmography), muscle sympathetic nerve activity (MSNA) (microneurography at the peroneal nerve) were measured. Data are mean +/- SEM. MOX acutely decreased MSNA within 2 h after oral intake (from 45 +/- 3.7 to 35 +/- 3.9 bursts/min, P < 0.05). This decrease was sustained over 6 months (MSNA 45 +/- 3.7, 35 +/- 4.6, 33 +/- 4.5 bursts/min at 0, 1 and 6 months, P < 0.05). PLA had no effect. Neither MOX nor PLA resulted in any significant acute or long-term changes in HR, MAP or CBF. In ESRD patients, low-dose MOX produced sustained and substantial reductions in sympathetic outflow without hemodynamically compromising them. We suggest that the inhibition of central sympathetic outflow may improve cardiovascular prognosis in ESRD.

Role of SNA in the pathophysiology of cardiovascular collapse during syncope: muscle vs. brain

Role of SNA in the pathophysiology of cardiovascular collapse during syncope: muscle <i>vs.</i> brain

Orthostatic stress, haemorrhage and a bankrupt cardiovascular system

Orthostatic stress, haemorrhage and a bankrupt cardiovascular system

Exercise training and sympathetic regulation in experimental heart failure.

In this review, we put forth the hypothesis that reduction in sympathetic outflow after exercise training of animals with heart failure is mediated by reductions in angiotensin II and in angiotensin type 1 receptors. Furthermore, we provide evidence that exercise training provides for an upregulation of the neuronal isoform of nitric oxide synthase in the central nervous system that is sympathoinhibitory.

The role of diastolic ventricular interaction in abnormal cardiac baroreflex function in chronic heart failure.

Baroreflex abnormalities have been well documented in both patients with chronic heart failure and experimental animal models of heart failure. These abnormalities are associated with increased mortality and probably contribute to neurohumoral activation. While it is likely that several mechanisms contribute to reduced baroreflex sensitivity, it has been difficult to explain why baroreflex control mechanisms during acute volume unloading in patients with severe chronic heart failure should be directionally opposite to those in normal subjects. Volume unloading normally causes a reduction in baroreceptor activity, and hence an increase in sympathetic outflow; however, patients with chronic heart failure develop attenuated increases or paradoxical reductions in forearm vascular resistance, muscle sympathetic nerve activity, and noradrenaline spillover. It has been suggested that this probably represents paradoxical activation of left ventricular (LV) mechanoreceptors, but why LV receptors should behave in such a fashion has not been determined. In the setting of diastolic ventricular interaction, the filling of the left ventricle is constrained by the surrounding pericardium and right ventricle. In these patients, the reduction in right ventricular (RV) volume that normally occurs during acute volume unloading allows for an increase in LV end-diastolic volume (as opposed to the reduction in LV volume that normally occurs). We have demonstrated this to be important in some patients with chronic heart failure, and observed that baroreflex control of forearm vascular resistance was markedly impaired in these patients. We propose that the increase in LV volume that occurred during volume unloading would increase LV mechanoreceptor activity, and could therefore explain the paradoxical reductions in sympathetic outflow. As discussed, this has important therapeutic implications.

Neural and hypotensive effects of angiotensin II receptor blockade.

Angiotensin II participates in the neural regulation of the heart and circulation at both central and peripheral sites. To explore the role of endogenous angiotensin II in blood pressure regulation, we conducted a randomized double-blind crossover trial in nine young healthy men (aged 33+/-3 [mean+/-SE] years) studied in the absence of salt restriction, comparing the effect of 1 week treatment with the angiotensin II receptor antagonist losartan (100 mg daily) against placebo with respect to the following variables, recorded during supine rest: intra-arterial blood pressure (BP), heart rate (HR), forearm vascular resistance and norepinephrine appearance rate, total body norepinephrine spillover, variability of BP and HR (spectral analysis), and baroreflex sensitivity for HR (gain of the transfer function from systolic BP to HR). Blood pressure was 119+/-7/66+/-4 mm Hg (systolic BP/diastolic BP) after 1 week of placebo and 112+/-6/61+/-3 mm Hg after 1 week of losartan (P<.05). Forearm vascular resistance tended to fall, from 42.3+/-6.9 U on placebo to 32.8+/-5.0 U with losartan treatment (P=.07). Losartan had no effect on HR (60+/-3 on placebo versus 59+/-2 beats per minute with losartan), total body norepinephrine spillover (3.0+/-0.8 versus 3.3+/-1.2 nmol/min), forearm norepinephrine appearance rate (3.8+/-1.1 versus 5.3+/-1.1 pmol/100 mL forearm tissue per minute), power in the high- or low-frequency components of the HR variability and BP variability spectra or on baroreflex sensitivity for HR. Endogenous angiotensin II contributes to the maintenance of supine BP in normal subjects, studied in the absence of sodium restriction. The fall in BP caused by losartan is accompanied by a resetting of the baroreflex regulation of HR and sympathetic outflow, but baroreflex sensitivity for heart rate is not altered. Therefore, the reduction in BP observed after short-term angiotensin type 1 receptor antagonism may be achieved through a direct effect on vascular tone rather than through a primary reduction in sympathetic outflow.

Pharmacological analysis of the haemodynamic effects of 5-HT1B/D receptor agonists in the normotensive rat.

1 The receptors involved in mediating the haemodynamic effects of three 5-HT1B/D receptor agonists were investigated in pentobarbitone anaesthetized rats (n = 6-17 per group). 2 Cumulative intravenous (i.v.) infusions of rizatriptan and sumatriptan (from 0.63 to 2500 microg kg(-1); each dose over 5 min) induced dose-dependent and marked hypotension (-42+/-6 and -34+/-4 mmHg at the highest dose, respectively; both P<0.05 vs vehicle: +5+/-3 mmHg) and bradycardia (-85+/-16 and -44+/-12 beats min(-1) at the highest dose, respectively; both P<0.05 vs vehicle: +16+/-6 beats min(-1)). Zolmitriptan evoked only moderate hypotension at the highest dose (-19+/-9 mmHg; P<0.05 vs vehicle). 3 A high dose of the 5-HT1B/D receptor antagonist, GR 127935 (0.63 mg kg(-1), i.v.), failed to antagonize the hypotension and bradycardia evoked by sumatriptan (-35+/-6 mmHg and -52+/-19 beats min(-1), respectively; both not significant vs sumatriptan in untreated rats), but moderately reduced the hypotension and bradycardia evoked by rizatriptan (-20+/-5 mmHg and -30+/-17 beats min(-1), respectively; both P<0.05 vs vehicle and vs rizatriptan in untreated rats). 4 The selective 5-HT1A receptor antagonist, WAY 100635 (0.16 and 0.63 mg kg(-1), i.v.), dose-dependently attenuated the haemodynamic responses evoked by rizatriptan and sumatriptan, which were almost abolished by the higher dose of WAY 100635 (-4+/-3 mmHg and -15+/-8 beats min(-1); both not significant vs vehicle and P<0.05 vs rizatriptan in untreated rats). A slight but statistically significant reduction in mean arterial pressure (MAP) persisted at the highest dose of sumatriptan (-13+/-4 mmHg following the higher dose of WAY 100635; P<0.05 vs vehicle). 5 In pithed rats with MAP normalized by angiotensin II, rizatriptan failed to induce hypotension or bradycardia (+5+/-4 mmHg and -6+/-16 beats min(-1), respectively; both NS vs vehicle and P<0.05 vs rizatriptan in untreated rats). Similarly, sumatriptan failed to induce bradycardia in pithed rats (+5+/-6 beats min(-1); not significant vs vehicle and P<0.05 vs sumatriptan in untreated rats), whereas a slight but statistically significant reduction in MAP, compared to controls, occurred at the highest dose (-9+/-9 mmHg; P<0.05 vs both vehicle and sumatriptan in untreated rats). 6 In bilaterally vagotomized and atropine-treated (1 mg kg(-1), i.v.) rats, the reductions in MAP and heart rate evoked by rizatriptan (-31+/-4 mmHg and -64+/-9 beats min(-1), respectively; both P<0.05 vs vehicle and not significant vs rizatriptan in controls) and sumatriptan (-47+/-8 mmHg and -56+/-10 beats min(-1), respectively; both P<0.05 vs vehicle and not significant vs sumatriptan in controls) were not statistically significantly different from those observed in controls. 7 In conclusion, the 5-HT1B/D receptor agonists, rizatriptan and sumatriptan, elicit hypotension and bradycardia in the normotensive anaesthetized rat predominantly via activation of central 5-HT1A receptors, and a consequent reduction in sympathetic outflow.

Clonidine, but not morphine, delays the development of thermal hyperesthesia induced by sciatic nerve constriction injury in the rat.

It has been shown that the spinal facilitation induced by the injury discharge evoked by a nerve constriction injury is crucial in the development of thermal hyperesthesia. Both opioids and alpha 2 agonists have been reported to prevent the development of spinal facilitation evoked by the small afferent input to the spinal cord. Moreover, it has been reported that the thermal hyperesthesia induced by a nerve constriction injury is sympathetically maintained and that spinally administered alpha 2 agonists can modulate the sympathetic outflow from the spinal cord. The current study investigated the effect of spinally administered morphine and clonidine, an alpha 2 agonist, on the development of thermal hyperesthesia induced by nerve constriction injury in the rat. A model of thermal hyperesthesia induced by a constriction injury created by making four loose ligatures around the rat sciatic nerve was used to examine the development of thermal hyperesthesia. Morphine, clonidine, and idazoxan were administered intrathecally or intraperitoneally 20 min before (pretreatment study) or 20 min after (posttreatment study) the nerve injury. Pretreatment, but not posttreatment, with intrathecal clonidine significantly delayed the development of thermal hyperesthesia in a dose-dependent manner, and this delay in onset produced by clonidine was 3 days after the nerve injury. This effect of clonidine's was completely antagonized by the coadministration of idazoxan with clonidine. Intrathecal morphine had no effect on the development of thermal hyperesthesia in this study. Spinal alpha 2 receptors, but not opioid receptors, may play an important role in the development of thermal hyperesthesia induced by a nerve constriction injury. This suggested that the activation of spinal alpha 2 receptor may reduce the sympathetic outflow and this reduction of sympathetic outflow may be the key mechanism that delays the development of thermal hyperesthesia.

Drug withdrawal and rebound hypertension: differential action of the central antihypertensive drugs moxonidine and clonidine.

To examine the antihypertensive action of the centrally acting antiadrenergic drugs moxonidine and clonidine, systolic and diastolic blood pressure as well as heart rate were monitored by radio telemetry in spontaneously hypertensive rats (SHR) with established high blood pressure. Increasing doses were administered with regular rat chow for 6-8 day periods. Moxonidine reduced (p < 0.05) diastolic blood pressure at a dose of 8 mg/kg/day and systolic blood pressure at 13 mg/kg/day. Heart rate was reduced during high activity of rats corresponding to an antitachycardiac action. After withdrawal of 18 mg/kg administered for only 1 day, blood pressure returned to pretreatment values within 8 days. Clonidine reduced systolic and diastolic blood pressure at 0.3 mg/kg/day. At 0.8 and 1.3 mg/kg/day, systolic blood pressure reduction was less pronounced, although heart rate was reduced further, reaching values that were below those of untreated sleeping rats. When 1.3 mg/kg/day clonidine was discontinued, systolic as well as diastolic blood pressure increased above pretreatment values within 1 day. A rebound was also observed in heart rate, which increased by 150 beats/ min. A comparable rebound in blood pressure was observed after withdrawal of 0.3 mg/kg/day. Since a blood pressure rebound occurred also after withdrawal of 0.3 mg/kg/day clonidine in normotensive rats, the rebound phenomenon was independent of the presence of high blood pressure. No blood pressure rebound was observed when moxonidine (8 mg/kg/ day) was administered (chow or gavage) in normotensive rats. These findings in unanesthetized undisturbed rats demonstrate distinct differences in the mode of action of moxonidine and clonidine, which can be accounted for by specific interactions of moxonidine with imidazoline I1-receptors, whereas clonidine would interact not only with I1-receptors but also with alpha2-adrenoceptors, and most probably also with the vagal activity. In view of our previous studies demonstrating a rise in blood pressure and heart rate after a hypercaloric dietary intake, the selective I1-receptor agonist moxonidine appears particularly appropriate for treating overweight hypertension associated with an enhanced sympathetic outflow of the brain. Of importance in this respect is that a moxonidine-induced reduction in sympathetic outflow was not associated with a gain in body weight but resulted in reduced caloric intake.

Enalaprilat augments arterial and cardiopulmonary baroreflex control of sympathetic nerve activity in patients with heart failure

Objectives. This study sought to determine the effects of enalaprilat on reflex control of sympathetic nerve activity.Background. Angiotensin-converting enzyme inhibitors decrease mortality in patients with congestive heart failure. Their efficacy appears to be related importantly to antiadrenergic effects, the mechanism for which has not been determined. Because baroreflexes tonically inhibit sympathetic outflow, and baroreflexes are blunted in heart failure, we hypothesized that these agents reduce sympathetic activity by augmenting baroreflexes.Methods. We assessed baroreflex control sympathetic nerve activity and heart rate in patients with congestive heart failure and in control subjects before and after enalaprilat (0.02 mg/kg body weight intravenously). Arterial baroreflexes were perturbed by bolus administration of sodium nitroprusside and phenylephrine. Cardiopulmonary baroreflexes were perturbed by lower body negative pressure and head-down tilt. Muscle sympathetic nerve activity was recorded by microneurography.Results. Enalaprilat decreased systolic blood pressure in patients with heart failure and control subjects. Sympathetic nerve activity increased in control subjects but decreased in patients with heart failure after enalaprilat despite reductions in central venous pressure in this group. Baroreflex control of sympathetic nerve activity was unchanged by enalaprilat in control subjects. In patients with heart failure, both arterial and cardiopulmonary baroreflex control of sympathetic nerve activity was enhanced by enalaprilat. Baroreflex control of heart rate was unchanged by enalaprilat in either group.Conclusions. Enalaprilat augments both arterial and cardiopulmonary baroreflex control of sympathetic activity in heart failure. These augmented inhibitory influences are associated with a reduction in sympathetic outflow and may contribute to the beneficial effects of angiotensin-converting enzyme inhibitors in heart failure.