Sinoaortic Denervation Group Research Articles

Oxytocin Blocks Tachycardic Responses in the Restraint Stress Model Acting on the Oxytocin Receptor Coupled to Gq Protein

IntroductionStress is common in modern life and demands physiological, endocrine and behavioral responses to cope. In acute restraint stress model (ARS), increased OXY is found in plasma whereas no changes are seen in novelty stress (NS). OXT acts on G‐protein receptor (OXTR) recruiting coupled to Gq, Gi and Gs. Atosiban (ATO) was initially categorized as an OXTR antagonist, but was reclassified as an OXTR biased agonist favoring Gi/o over Gq.AimThis study aimed to evaluate the selective functional effects of oxytocin on ARS after treatment with Atosiban.MethodsAll experimental procedures were approved by the University of São Paulo Ethical Committee (number 079/2017). Male Wistar rats, 250g, were used. Pulsatile arterial pressure (PAP) was recorded. Some animals were subjected to hypophysectomy (HYP) or sinoaortic denervation (SAD). Animals were divided into: vehicle, Atosiban (0.3, 1 and 3 μg/kg), dTyr AVP (V1a antagonist receptor, 30 μg/kg), homatropine (M2 antagonist receptor, 200 μg/kg) and exposed to ARS. One vehicle and one Atosiban (1μg/kg) group were exposed to NS. From PAP were calculated: mean arterial pressure (MAP) and heart rate (HR) for time curve analysis, and systolic arterial pressure (SAP) and cardiac interval (CI) for heart rate variability (HRV) and spontaneously baroreflex sensitivity (SBS).ResultsARS increased MAP and HR, due to increased autonomic activity. ATO inhibited ARS‐evoked tachycardia (F3,19=4.074; P<0.05), without effecting MAP increase (F3,19=0.1664, P>0.05). Pretreatment with dTYR AVP did not affect the ATO blockade of tachycardia. HRV analysis of PAS and CI showed a tendency for Atosiban to reduce the low frequency band (P=0.08) and increase the high frequency band (P=0.053) under ARS. The tendency to increase parasympathetic activity was evidenced by parasympathetic blockade with HOM, that reversed ATO effect (HR ‐ ATO vs. HOM+ATO; P<0.05) to that of vehicle group (HR ‐ Vehicle vs. HOM+ATO; P>0.05). SBS analysis of baroreflex effectiveness index (BEI) showed a significant difference in time and treatment for the BEI UP (BEI UP – Time: F8, 32 = 2,702; P<0.05; Treatment: F1, 8 = 6,277; P<0.05). BEI UP tended to increase after ATO on the first hour of restraint (P=0.08). Gain mean analysis showed results similar to BEI; GAIN UP was significantly different after ATO (P<0.05). No differences were observed after ATO in the SAD vs vehicle group. To test if ATO effect depends on oxytocin, HYP animals either ATO or vehicle were subjected to ARS. No differences were observed between ATO and vehicle. Animals were treated with ATO or vehicle were also subjected to NS, an oxytocin secretion‐free stress model, and no differences were observed.ConclusionOur results suggest that OXY secreted to periphery attenuates tachycardic responses evoked by ARS, possibly by a parasympathetic activity facilitation. Atosiban acts on OXTR coupled to Gi/o and OXY secreted is dislocated to OXTR coupled to Gq to promote effects on cardiac frequency during ARS.Support or Funding InformationCAPES, CNPq, FAEPA‐HCFMRP and FAPESP [2016/25502‐7]. Oxytocin mechanism in restraint stress after Atosiban treatmentimageOxytocin mechanism in restraint stress after Atosiban treatmentThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of losartan on vasomotor function and canonical transient receptor potential channels in the aortas of sinoaortic denervation rats

ABSTRACTIncreased short-term blood pressure variability (BPV) is strongly correlated with target organ damage. However, the molecular mechanisms underlying abnormal BPV-induced organ damage and effective therapeutic targets are poorly understood. The purpose of this study was to investigate the effects of losartan on vasomotor function and canonical transient receptor potential (TRPC) channels in the aortas of rats with arterial pressure lability induced by sinoaortic denervation (SAD). SAD was performed in male Sprague-Dawley rats at the age of 10 weeks. The experiment included sham-operated (Sham), SAD, and losartan-treated SAD (SAD+Los) groups. After 8 weeks of treatment, hemodynamic parameters were measured via catheterization, thoracic aortic vasomotor functions were evaluated using a physiological vascular ring tension recording system, and TRPC1 and 6 mRNA and protein expression levels in the endothelial cells (ECs) and smooth muscle cells (SMCs) of the thoracic aorta were determined via reverse transcription polymerase chain reaction (RT-PCR) and Western-blotting, respectively. Compared with Sham rats, SAD rats exhibited significantly increased BPV, enhanced norepinephrine-induced aortic contraction, and attenuated acetylcholine-induced aortic relaxation. Both the mRNA and the protein expression levels of TRPC1 and 6 were significantly downregulated in the ECs and upregulated in the SMCs of the thoracic aortas of SAD rats. Losartan treatment prevented these SAD-induced changes. In conclusion, losartan efficiently prevented vasomotor function impairment in SAD rats by reducing BPV and regulating TRPC1 and 6 expression levels.

Role of respiratory changes in the modulation of arterial pressure in rats submitted to sino-aortic denervation.

What is the central question of this study? The arterial baroreflex regulates arterial pressure within a narrow range of variation. After sino-aortic denervation (SAD), rats show a large increase in arterial pressure variability, but mean arterial pressure levels remain similar to those of control rats. Considering that breathing influences the control of arterial pressure, the question is: to what extent does SAD cause changes in breathing? What is the main finding and its importance? Removal of arterial baroreceptors produced changes in breathing in rats, marked by a reduction in respiratory frequency, but not hypertension. These findings are indicative of a possible interaction of respiratory and autonomic neural mechanisms in the regulation of arterial pressure after SAD. Sino-aortic denervated (SAD) rats exhibit a mean arterial pressure (MAP) similar to that of control rats. Given that respiration modulates MAP, we hypothesized that conscious SAD rats show respiratory changes associated with the normal MAP. In this study, we evaluated the cardiovascular and respiratory activities and arterial blood gases in control and SAD rats. Male juvenile Wistar rats (postnatal day19-21) were submitted to SAD, sham surgery or selective removal of the carotid bodies (CBX), and the three groups were evaluated 10 days after the surgery (SAD, n=21; Sham, n=18; and CBX, n=13). The MAP in Sham, SAD and CBX groups was similar (P>0.05), but the variability of MAP was significantly higher in SAD than in Sham and CBX rats (P<0.0001). The duration of expiration and inspiration increased in SAD rats compared with Sham and CBX rats, which resulted in a reduced respiratory frequency and minute ventilation (P<0.05). The arterial partial pressure of O2 and the haemoglobin saturation were reduced in SAD and CBX compared with Sham rats, whereas the arterial partial pressure of CO2 was increased in SAD compared with Sham rats. The short- and long-term respiratory variability were significantly higher in SAD than in Sham and CBX rats (P<0.05). In addition, the reductions in MAP during deep breaths were greater in SAD than in Sham and CBX rats (P<0.0001). The data show that SAD rats exhibit respiratory changes, which may be one of the compensatory mechanisms associated with the maintenance of normal levels of MAP in the absence of arterial baroreceptors.

Increased Blood Pressure Variability Prior to Chronic Kidney Disease Exacerbates Renal Dysfunction in Rats

Increased blood pressure variability (BPV), which can be experimentally induced by sinoaortic denervation (SAD), has emerged as a new marker of the prognosis of cardiovascular and renal outcomes. Considering that increased BPV can lead to organ-damage, the goal of the present study was to evaluate the effects of SAD on renal function in an experimental model of chronic kidney disease (CKD). SAD was performed in male Wistar rats 2 weeks before 5/6 nephrectomy and the animals were evaluated 4 weeks after the induction of CKD. Our data demonstrated that BPV was increased in SAD and CKD animals and that the combination of both conditions (SAD+CKD) exacerbated BPV. The baroreflex sensitivity index was diminished in the SAD and CKD groups; this reduction was more pronounced when SAD and CKD were performed together. 5/6 nephrectomy led to hypertension, which was higher in SAD+CKD animals. Regarding renal function, the combination of SAD and CKD resulted in reduced renal plasma and blood flow, increased renal vascular resistance and augmented uraemia when compared to CKD animals. Glomerular filtration rate and BPV were negatively correlated in SAD, CKD, and SAD+CKD animals. Moreover, SAD+CKD animals presented a higher level of glomerulosclerosis when compared to all other groups. Cardiac and renal hypertrophy, as well as oxidative stress, was also further increased when SAD and CKD were combined. These results show that SAD prior to 5/6 nephrectomy exacerbates renal dysfunction, suggesting that previous augmented BPV should be considered as an important factor to the progression of renal diseases.

Multiscale entropy analysis of heart rate variability in heart failure, hypertensive, and sinoaortic-denervated rats: classical and refined approaches.

The analysis of heart rate variability (HRV) by nonlinear methods has been gaining increasing interest due to their ability to quantify the complexity of cardiovascular regulation. In this study, multiscale entropy (MSE) and refined MSE (RMSE) were applied to track the complexity of HRV as a function of time scale in three pathological conscious animal models: rats with heart failure (HF), spontaneously hypertensive rats (SHR), and rats with sinoaortic denervation (SAD). Results showed that HF did not change HRV complexity, although there was a tendency to decrease the entropy in HF animals. On the other hand, SHR group was characterized by reduced complexity at long time scales, whereas SAD animals exhibited a smaller short- and long-term irregularity. We propose that short time scales (1 to 4), accounting for fast oscillations, are more related to vagal and respiratory control, whereas long time scales (5 to 20), accounting for slow oscillations, are more related to sympathetic control. The increased sympathetic modulation is probably the main reason for the lower entropy observed at high scales for both SHR and SAD groups, acting as a negative factor for the cardiovascular complexity. This study highlights the contribution of the multiscale complexity analysis of HRV for understanding the physiological mechanisms involved in cardiovascular regulation.

Analysis of the Baroreceptor and Vestibular Receptor Inputs in the Rostral Ventrolateral Medulla following Hypotension in Conscious Rats.

Input signals originating from baroreceptors and vestibular receptors are integrated in the rostral ventrolateral medulla (RVLM) to maintain blood pressure during postural movement. The contribution of baroreceptors and vestibular receptors in the maintenance of blood pressure following hypotension were quantitatively analyzed by measuring phosphorylated extracellular regulated protein kinase (pERK) expression and glutamate release in the RVLM. The expression of pERK and glutamate release in the RVLM were measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or sinoaortic denervation (SAD) following hypotension induced by a sodium nitroprusside (SNP) infusion. The expression of pERK was significantly increased in the RVLM in the control group following SNP infusion, and expression peaked 10 min after SNP infusion. The number of pERK positive neurons increased following SNP infusion in BL, SAD, and BL+SAD groups, although the increase was smaller than seen in the control group. The SAD group showed a relatively higher reduction in pERK expression when compared with the BL group. The level of glutamate release was significantly increased in the RVLM in control, BL, SAD groups following SNP infusion, and this peaked 10 min after SNP infusion. The SAD group showed a relatively higher reduction in glutamate release when compared with the BL group. These results suggest that the baroreceptors are more powerful in pERK expression and glutamate release in the RVLM following hypotension than the vestibular receptors, but the vestibular receptors still have an important role in the RVLM.

Angiotensin converting enzyme is involved in the cardiac hypertrophy induced by sinoaortic denervation in rats.

The present study was designed to test the hypothesis that local angiotensin converting enzyme (ACE) was involved in the cardiac hypertrophy induced by sinoaortic denervation (SAD) in rats. Experiment 1: Six weeks after SAD of rats, components of renin-angiotensin system (RAS) in left ventricles were assayed by quantitative real-time PCR and Western blotting analysis. Experiment 2: Rats were divided into five groups treated as follows: (1) sham-operated group; (2) SAD group; (3) SAD group treated with angiotensin II type 1 receptor (AT1R) antagonist losartan (10 mg·kg(-1)·day(-1), orally); (4) SAD group treated by ACE inhibitor ramipril (1 mg·kg(-1)·day(-1), orally); (5) SAD group treated by ramipril and the B2-kinin receptor selective antagonist HOE-140 (0.25 mg·kg(-1)·day(-1), subcutaneously). SAD led to augmentation of the mRNA levels and protein expression of left ventricular ACE and AT1R. Both losartan and ramipril ameliorated SAD-induced left ventricular hypertrophy. Both losartan and ramipril abated oxidative stress, suppressed inflammation, and reduced expression TGFβ-R in left ventricles. In addition, the protective effect of ramipril could be abolished by HOE-140. Local ACE is involved in the left ventricular hypertrophy induced by sinoaortic denervation in rats, via both angiotensin II/AT1R and bradykinin/B2R pathways.

Arterial baroreflex dysfunction impairs ischemia-induced angiogenesis.

BackgroundEndothelium‐derived acetylcholine (eACh) plays an important role in the regulation of vascular actions in response to hypoxia, whereas arterial baroreflex (ABR) dysfunction impairs the eACh system. We investigated the effects of ABR dysfunction on ischemia‐induced angiogenesis in animal models of hindlimb ischemia with a special focus on eACh/nicotinic ACh receptor (nAChR) signaling activation.Methods and ResultsMale Sprague‐Dawley rats were randomly assigned to 1 of 3 groups that received (1) sham operation (control group), (2) sinoaortic denervation (SAD)‐induced ABR dysfunction (SAD group), or (3) SAD rats on diet with an acetylcholinesterase inhibitor pyridostigmine (30 mg/kg per day, SAD+Pyr group). After 4 weeks of the SAD intervention, unilateral limb ischemia was surgically induced in all animals. At postoperative day 14, SAD rats exhibited impaired angiogenic action (skin temperature and capillary density) and decreased angiogenic factor expressions (vascular endothelial growth factor [VEGF] and hypoxic inducible factor [HIF]‐1α) in ischemic muscles. These changes were restored by acetylcholinesterase inhibition. Rats with ABR dysfunction had lower eACh levels than did control rats, and this effect was recovered in SAD+Pyr rats. In α7‐nAChR knockout mice, pyridostigmine improved ischemia‐induced angiogenic responses and increased the levels of VEGF and HIF‐1α. Moreover, nicotinic receptor blocker inhibited VEGF expression and VEGF receptor 2 phosphorylation (p‐VEGFR2) induced by ACh analog.ConclusionsThus, ABR dysfunction appears to impair ischemia‐induced angiogenesis through the reduction of eACh/α7‐nAChR‐dependent and ‐independent HIF‐1α/VEGF‐VEGFR2 signaling activation.

Comparative analysis of vestibular receptor and baroreceptor inputs to the nucleus tractus solitarius following acute hypotension in conscious rats

Blood pressure is maintained by the interaction between the arterial baroreflexes and the vestibulo-cardiovascular reflexes during postural changes. In this study, the influence of the vestibular receptors on the maintenance of blood pressure following acute hypotension was quantitatively compared with the role of baroreceptors in terms of c-Fos protein expression in the nucleus tractus solitarius (NTS). Expression of c-Fos protein in the NTS was measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or sinoaortic denervation (SAD). Expression of c-Fos protein increased significantly in the NTS in the sham group after sodium nitroprusside (SNP) administration. However, the BL, SAD, and SAD+BL groups showed significant decreases in c-Fos protein expression compared to that of the sham group. The SAD group showed relatively more reduction in c-Fos protein expression than the BL group, and the SAD+BL group showed the least expression among the three experimental groups. The c-Fos protein expression in the NTS following acute hypotension was localized to the caudal portions of the nuclei in the BL and SAD groups. These results suggest that the role of vestibular receptors in maintaining blood pressure following acute hypotension is less potent than that of the baroreceptors but more potent than other afferent inputs in conscious rats. In addition, afferent signals for maintaining blood pressure originating from the vestibular receptors and the baroreceptors may converge in the caudal portion of the NTS.

Effect of Vestibulosympathetic Reflex and Baroreflex on Expression of pERK in the Nucleus Tractus Solitarius following Acute Hypotension in Conscious Rats.

Control of blood pressure is maintained by the interaction between the arterial baroreflex and vestibulosympathetic reflex during postural changes. In this study, the contributions of vestibular receptors and baroreceptors to the maintenance of blood pressure following acute hypotension were compared in terms of phosphorylated extracellular regulated protein kinase (pERK) expression in the nucleus tractus solitaries (NTS). Expression of pERK in the NTS was measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or sinoaortic denervation (SAD) 5, 10, 20, and 40 min following acute hypotension induced by sodium nitroprusside (SNP) infusion. Expression of pERK increased significantly in the NTS in the control group following SNP infusion, and the expression peaked at 10 min after SNP infusion. The number of pERK positive neurons increased following SNP infusion in BL, SAD, and BL+SAD groups, although the increase was smaller than in control group. The BL group showed a relatively higher reduction in pERK expression than the SAD group, and the pERK expression in the NTS was localized to the caudal portion of the nuclei in the BL and SAD groups. These results suggest that the vestibular receptors may play a key role in maintaining blood pressure following acute hypotension; thus, the vestibular system may contribute to compensate for orthostatic hypotension.

Abstract 9454: Arterial Baroreflex Dysfunction Impairs Angiogenesis in Response to Hindlimb Ischemia

Objective: We examined whether ischemia-induced angiogenesis was reduced by the arterial baroreflex (ABR) dysfunction, and if so, we further examined whether the reduced angiogenesis was associated with a reduction of endothelium-derived acetylcholine (Ed-ACh) release using a rat model of hindlimb ischemia (HLI). We also determined whether this effect would be restored by the administration of pyridostigmine (Pyr), a cholinesterase inhibitor. Methods and Results: Male Sprague-Dawley rats were randomly assigned to 3 groups that received 1) sham operation (control), 2) sinoaortic denervation (SAD)-induced ABR dysfunction, 3) SAD rat diet with Pyr. 4 weeks after the SAD intervention, HLI was surgically induced in all groups. Infrared spectrum analyses showed that the recovery of the ischemic/normal limb temperature ratio in the SAD rats remained impaired throughout the follow-up period. At postoperative day 14, immunohistochemical analyses in the ischemic limb revealed significantly lower capillary densities in the SAD group than in the control, which were associated with decreased tissue expression of choline acetyltransferase (ChAT) and acetylcholine transporter (AChT). Pyr significantly improved the temperature ratio and capillary densities, accompanied by elevation of ChAT and AChT protein in the ischemic muscles. Interestingly, Pyr not only elevated the levels of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) proteins of ischemic muscles but also improved functional recovery following hindlimb ischemia in α7-nicotinic ACh receptor (α7-nAChR) knockout mice. Furthermore, in vitro, acetylcholine analogue (carbachol) stimulated the expression of VEGF and phosphorylation of VEGF receoptor-2 (VEGFR2) in umbilicus vein endothelial cells, and these changes were diminished by methyllycaconitine, a nicotinic receptor blocker. Conclusions: These findings suggest that the ABR dysfunction likely triggers and impairs angiogenesis in response to ischemia and that the Pyr-mediated augmentation of tissue Ed-ACh activity stimulates VEGF expression and VEGFR2 phosphorylation by the α7-nAChR-dependent/-independent activation of the Pyr, thereby improving vascular angiogenic action.

Additive Role of the Vestibular End Organ and Baroreceptors on the Regulation of Blood Pressure in Rats

Contribution of the vestibular end organ to regulation of arterial pressure was quantitatively compared with the role of baroreceptors in terms of baroreflex sensitivity and c-Fos protein expression in the rostral ventrolateral medulla (RVLM). Baroreflex sensitivity and c-Fos protein expression in the RVLM were measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or baroreceptor unloading. BL attenuated baroreflex sensitivity during intravenous infusion of sodium nitroprusside (SNP), but did not significantly affect the sensitivity following infusion of phenylephrine (PE). Baroreflex sensitivity became positive following sinoaortic denervation (SAD) during infusion of PE and attenuated sensitivity during infusion of SNP. Baroreflex sensitivity also became positive following double ablation (BL+SAD) during infusion of PE, and attenuated sensitivity during infusion of SNP. c-Fos protein expression increased significantly in the RVLM in the sham group after SNP administration. However, the BL, SAD, and SAD+BL groups showed significant decreases in c-Fos protein expression compared with that in the sham group. The SAD group showed more reduced c-Fos protein expression than that in the BL group, and the SAD+BL group showed less expression than that in the SAD group. These results suggest that the vestibular system cooperates with baroreceptors to maintain arterial pressure during hypotension but that baroreceptors regulate arterial pressure during both hypotension and hypertension. Additionally, afferent signals for maintaining blood pressure from the vestibular end organs and the baroreceptors may be integrated in the RVLM.

Abstract 335: Isolated Baroreflex Dysfunction May Impair Renal Function

Autonomic and renal dysfunctions are common chronic conditions that frequently coexist in the same individual, and both are associated with significant morbidity and mortality. Aim: To evaluate if total arterial baroreflex abolishment leads to alterations in renal function. Methods: Wistar rats divided into: control (n=9) and SAD (n=9). Sinoaortic denervation (SAD) was performed using the method previously described by Krieger (1964). Metabolic cage was used to evaluate in vivo renal function. BP and HR signals were recorded using a data acquisition system (Codas, 2 kHz). Autonomic function was evaluated by spectral analysis. Colored microspheres (CM) were infused into the left ventricle to determine renal blood flow and resistance changes quantified by spectrophotometry. Ex vivo renal perfusion was used to measure renal function. Results: Neither BP (C: 106 ± 2 vs. SAD: 108 ± 2 mmHg) nor HR (C: 355 ± 7 vs. SAD: 357 ± 15 bpm) were modified by SAD. HRV was decreased in SAD (43 ± 5 vs. C: 103 ± 12 ms2). However, BPV and LF component of BPV, respectly, were increased in SAD (46 ± 10; 6 ± 0.5 mmHg2) compared to C (35 ± 6; 2.6 ± 2 mmHg2). Although BP was similar between groups, it was observed a reduction in cardiac output in denervated animals (85 ± 6 vs. C: 111 ± 7 mL/min, p=0.02) and an increase in total peripheral resistance (1.25 ± 0.03 vs. C: 0.97 ± 0.02 mmHg/mL/min). These alterations resulted in a decreased plasmatic renal flow in SAD group (1.49 ± 0.18 vs. 3.47 ± 0.21 mL/min/g). Water intake and urine volume were higher in SAD (34 ± 1 mL/24h; 26 ± 6 mL) compared to C (25 ± 2 mL/24h; 8 ± 1 mL) and SAD showed proteinuria (0.03 ± 0.01 vs. C: 0.015 ± 0.0005 g/24h). Ex vivo evaluations demonstred a decreased urinary flow (0.07 ± 0.01 vs . C: 0.15 ± 0.01 mL.g-1.min-1) and glomerular filtration rate in SAD group ( 0.5 ± 0.1 vs. C: 0.3 ± 0.01 mL.g-1.min-1). Our data suggest that total baroreflex impairment leads to a renal and peripheral autonomic dysfunction, since SAD induced proteinuria and increased BPV, both markers of functional organ damage. Moreover, even without neurohumoral influence the kidneys from SAD group was not able to work properly. In conclusion, the results obtained in this study provide evidence that the homeostatic role of the baroreflex is essential in the course of changes of renal function.

Abstract 202: Temporal Evaluation of Baroreflex Dysfunction: Role in Target Organ Damage

Introduction: Baroreceptors regulate moment-to-moment blood pressure (BP) variations, but their long-term effect on the cardiovascular system and target organ damage remains unclear. Purpose: to investigate the temporal mechanisms enrolled in the relationship between baroreceptor reflex dysfunction and end-organ damage in different pathophysiological conditions as hypertension, heart failure and myocardial infarction. Method: Male Wistar rats were divided into 5 groups: control (n = 9),SAD1(n=8,24h), SAD2(n=8,28 days), SAD3 (n=8, 90 days) and SAD4 (n=7, 6 months). Sinoaortic denervation (SAD) was used as a model of arterial baroreflex deficit. BP, HR were analysed using a data acquisition system (Codas, 2kHz). Cardiac output and tissues blood flow were evaluated using colored microspheres. Result: BP and the HR was incresed in SAD after 24h (C:106 ± 0.6 vs . SAD1: 142 ± 2 mmHg; C: 355 ± 7 vs . SAD1: 453 ± 10 bpm), but it were normalizaed in chronic SAD. Moreover, it was observed a gradual reduction over time in cardiac output (C: 111 ± 7, SAD1:81±5, SAD2:85 ± 6, SAD3:69±5 SAD4:35±2 mL/min) accompanied by an increase in total peripheral resistance (C:0.97±0.07, SAD1:1.74±0.05, SAD2:1.23±0.07, SAD3:1.60±0.09, SAD4:3.00±0.05 mL/min/mmHg) in SAD groups. Those alterations resulted in a decreased renal blood flow (C:3.47±0.21, SAD1:1.37±0.19, SAD2:1.49±0.18, SAD3:1.12±0.13, SAD4:0.42±0.16 mL/min/g) , cardiac blood flow (C:2.91±0.71, SAD1:2.07±0.19, SAD2:1.58±0.28, SAD3:0.92±0.13, SAD4:0.34±0.16 mL/min/g) and muscle blood flow (C:0.24±0.02, SAD1:0.08±0.005, SAD2:0.10±0.02, SAD3:0.05±0.01, SAD4:0.05±0.007 mL/min/g) in SAD groups. Conclusion: The acute total baroreflex dysfuntion incresed BP and HR and reduced blood flow and cardiac output, these changes are associated with the body’s attempt to maintain homeostasis. Howerer, the temporal evaluation showed a progressive reduction in CO and regional blood flow associated with an increase in RPT to maintain blood pressure levels. These adjustements may play an important role in target organ-damage in different pathological conditions, independently of BP levels.

Sinoaortic denervation prevents enhanced heat loss induced by central cholinergic stimulation during physical exercise

The present study investigated whether the effects of central cholinergic stimulation on thermoregulation during exercise are modulated by arterial baroreceptors. Wistar rats were submitted to sinoaortic denervation (SAD) or sham denervation (SHAM) and then fitted with a chronic guide cannula into the lateral cerebral ventricle. After 2 weeks, a catheter was implanted into the ascending aorta, and a temperature sensor was implanted into the peritoneal cavity. Two days later, the rats were submitted to exercise on a treadmill at 18 m/min until fatigued. Thermoregulatory and cardiovascular responses were measured after injection of 2 μL of 10 mM physostigmine (Phy) or 0.15 M NaCl solution (Sal) into the cerebral ventricle. In SHAM rats, Phy injection induced a greater exercise-induced increase in blood pressure and lower increase in heart rate than Sal treatment. In the SAD group, the attenuation of heart rate in response to Phy was blocked despite an exaggerated increase in blood pressure. SHAM rats treated with Phy had a higher increase in tail skin temperature compared to Sal injection (31.9 ± 0.4 °C Phy-SHAM vs. 30.1 ± 0.6 °C Sal-SHAM, 5 min after injection; p < 0.05), resulting in a lower exercise-induced increase in core temperature. In contrast, SAD blocked the Phy injection effects in thermoregulatory responses during exercise (tail temperature: 30.1 ± 1.2 °C Phy-SAD vs. 29.5 ± 1.2 °C Sal-SAD, 5 min, p = 0.65). Therefore, we conclude that the enhancement of cutaneous heat loss induced by central cholinergic stimulation during exercise is mediated primarily by arterial baroreceptors.

Arterial baroreflex function is an important determinant of acute cerebral ischemia in rats with middle cerebral artery occlusion

Aims To clarify whether arterial baroreflex function is an important determinant of acute cerebral ischemia in rats. Main methods Three animal models were used in this study. In the first, saponin conjugated with substance P (SP-SAP) was injected into the nucleus tractus solitarii (NTS) of Sprague–Dawley (SD) rats to block the central baroreflex arc. In the second model, sinoaortic denervation (SAD) was performed to destroy the peripheral baroreflex arc in SD rats. In the third model, SD rats were divided into two groups according to their naturally occurring BRS values. After determining hemodynamic indexes and baroreflex sensitivity (BRS), we subjected the animals to middle cerebral artery (MCA) occlusion. Levels of interleukin (IL)-1β and IL-6 were detected both in SAD/sham operation groups and low/high BRS groups. Key findings In all three animal models, baroreflex dysfunction significantly increased the infarct volume and weight. The levels of inflammatory factors were markedly elevated in SAD and low BRS groups. Significance These results demonstrate that the function of arterial baroreflex is an important determinant of acute cerebral ischemia in rats with MCA occlusion. Inflammation might be an important mechanism for the arterial baroreflex dysfunction-induced increase in brain damage in rats with MCA occlusion.

Fosinopril Prevents the Pulmonary Arterial Remodeling in Sinoaortic-denervated Rats by Regulating Phosphodiesterase

To study the effects of fosinopril on sinoaortic denervation (SAD)-induced pulmonary vascular remodeling and on phosphodiesterases (PDE) 1 in rats. SAD was performed in male Sprague-Dawley rats at the age of 10 weeks. The experiment included sham-operated (Sham), SAD, and fosinopril-treated SAD groups. Fosinopril (15 mg/kg/d) was given in rat chow. After 16 weeks of treatment, the pulmonary arteries were taken for investigations, including pharmacological study, measurement of cGMP, light microscopy, immunohistochemistry, Western blotting, and quantitative real-time RT-PCR. Compared with Sham rats, blood pressure variability (BPV) was significantly increased in the SAD group. However, the mean pulmonary artery pressure (mPAP) was not significant change among 3 groups. After SAD, maximal contraction of pulmonary artery rings to phenylephrine was markedly decreased; the most prominent morphological change in the lung included thickening vascular walls, increasing number of smooth muscle cells, and greater wall-to-lumen ratio; the tissue concentrations of cGMP was reduced significantly; PDE1A or PDE1C expression was upregulated significantly, and endothelial nitric oxide synthase (eNOS) expression was downregulated significantly. Fosinopril treatment prevented these changes induced by SAD. Pulmonary artery remodeling (structural and functional abnormalities) was induced by SAD. Fosinopril, an angiotensin-converting enzyme inhibitor, mainly via potentiating eNOS pathway and inhibiting AngII formation, effectively prevented increased blood pressure variability and vascular remodeling of the pulmonary artery after SAD by regulating the activity levels or expression of eNOS, cGMP, and PDE1s.

The Survival Time Post-Cecal Ligation and Puncture in Sinoaortic Denervated Rats

Arterial baroreflex (ABR) function is an important determinant factor in prognosis of many cardiovascular diseases. The present work was designed to study the relationship between ABR function and the survival time of septic shock in a cecal ligation and puncture (CLP) rat model. The dysfunction of ABR was introduced by sinoaortic denervation (SAD). It was found that the survival time after CLP was significantly reduced in SAD rats compared with sham-operated rats (12.7 +/- 2.92 hours versus 15.0 +/- 4.01 hours; P < 0.05). Furthermore, significant differences were also seen when the results were expressed by Kaplan-Meier survival curves. Compared with the baseline values, both noradrenaline and adrenaline significantly increased in both SAD and Sham groups after CLP, but we found the baseline of noradrenaline was significantly elevated in SAD rats. In addition, the TNF-alpha, noradrenaline, and adrenaline levels of the SAD group were significantly higher than those of the Sham group at 5 hours post-CLP. In conclusion, the present work demonstrates that ABR function was related to the survival time in CLP-induced lethal shock model. The loss of inhibition in the sympathetic activity and in the release of some inflammatory cytokines during CLP-induced septic shock related to baroreflex and/or chemoreflex dysfunction may be the mechanisms involved in the poorer prognosis in septic shock.

EARLY STRUCTURAL CHANGES OF AORTIC WALL IN SINOAORTIC‐DENERVATED RATS

1. The present work was designed to observe the early structural changes in the aortic wall in Sprague-Dawley rats 1, 2 and 4 weeks after sinoaortic denervation (SAD). 2. Rats were examined 1, 2 and 4 weeks after SAD. Blood pressure (BP) was recorded in the conscious state. The thoracic aortas were taken for investigations, including: light microscopy, electron microscopy, immunohistochemistry and terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labelling (TUNEL). 3. Blood pressure variability (BPV) was significantly increased in the SAD groups 1, 2 and 4 after the operation when compared with the sham-operated ones. 4. Two weeks after SAD the percentage proportion of smooth muscle cell density (SMC%) was obviously increased. 5. Four weeks after SAD: the SMC%, percentage proportion of collagen density (CD%) and aortic wall thickness (WT) were obviously increased with vascular smooth muscle cells blebbing concomitantly. Endothelial cells showed degenerative changes and swelling with blebbing of the cell membrane and increased condensation of peripheral nuclear chromatin and cytoplasmic vacuolization. It was also found that the number of apoptotic endothelial cells was increased and expression of eNOS was reduced. 6. This is the first study that shows the time-course of aortic wall and endothelial cell changes induced by SAD. Increased BPV might be the priming factor in the development of organ damage induced by SAD.

Roles of baroreflex and vestibulosympathetic reflex in controlling arterial blood pressure during gravitational stress in conscious rats.

Gravity acts on the circulatory system to decrease arterial blood pressure (AP) by causing blood redistribution and reduced venous return. To evaluate roles of the baroreflex and vestibulosympathetic reflex (VSR) in maintaining AP during gravitational stress, we measured AP, heart rate (HR), and renal sympathetic nerve activity (RSNA) in four groups of conscious rats, which were either intact or had vestibular lesions (VL), sinoaortic denervation (SAD), or VL plus SAD (VL + SAD). The rats were exposed to 3 G in dorsoventral axis by centrifugation for 3 min. In rats in which neither reflex was functional (VL + SAD group), RSNA did not change, but the AP showed a significant decrease (-8 +/- 1 mmHg vs. baseline). In rats with a functional baroreflex, but no VSR (VL group), the AP did not change and there was a slight increase in RSNA (25 +/- 10% vs. baseline). In rats with a functional VSR, but no baroreflex (SAD group), marked increases in both AP and RSNA were observed (AP 31 +/- 6 mmHg and RSNA 87 +/- 10% vs. baseline), showing that the VSR causes an increase in AP in response to gravitational stress; these marked increases were significantly attenuated by the baroreflex in the intact group (AP 9 +/- 2 mmHg and RSNA 38 +/- 7% vs. baseline). In conclusion, AP is controlled by the combination of the baroreflex and VSR. The VSR elicits a huge pressor response during gravitational stress, preventing hypotension due to blood redistribution. In intact rats, this AP increase is compensated by the baroreflex, resulting in only a slight increase in AP.