Piezo2 channel in nodose ganglia neurons is essential in controlling hypertension in a pathway regulated directly by Nedd4-2.

Baroreflex plays a crucial role in regulation of arterial blood pressure (BP). Recently, Piezo1 and Piezo2, the mechanically-activated (MA) ion channels, have been identified as baroreceptors. However, the underlying molecular mechanism for regulating these baroreceptors in hypertension remains unknown. In this study, we used spontaneously hypertensive rats (SHR) and NG-Nitro-l-Arginine (L-NNA)- and Angiotensin II (Ang II)-induced hypertensive model rats to determine the role and mechanism of Piezo1 and Piezo2 in hypertension. We found that Piezo2 was dominantly expressed in baroreceptor nodose ganglia (NG) neurons and aortic nerve endings in Wistar-Kyoto (WKY) rats. The expression of Piezo2 not Piezo1 was significantly downregulated in these regions in SHR and hypertensive model rats. Electrophysiological results showed that the rapidly adapting mechanically-activated (RA-MA) currents and the responsive neuron numbers were significantly reduced in baroreceptor NG neurons in SHR. In WKY rats, the arterial BP was elevated by knocking down the expression of Piezo2 or inhibiting MA channel activity by GsMTx4 in NG. Knockdown of Piezo2 in NG also attenuated the baroreflex and increased serum norepinephrine (NE) concentration in WKY rats. Co-immunoprecipitation experiment suggested that Piezo2 interacted with Neural precursor cell-expressed developmentally downregulated gene 4 type 2 (Nedd4-2, also known as Nedd4L); Electrophysiological results showed that Nedd4-2 inhibited Piezo2 MA currents in co-expressed HEK293T cells. Additionally, Nedd4-2 was upregulated in NG baroreceptor neurons in SHR. Collectively, our results demonstrate that Piezo2 not Piezo1 may act as baroreceptor to regulate arterial BP in rats. Nedd4-2 induced downregulation of Piezo2 in baroreceptor NG neurons leads to hypertension in rats. Our findings provide a novel insight into the molecular mechanism for the regulation of baroreceptor Piezo2 and its critical role in the pathogenesis of hypertension.

TRPC6 participates in the development of blood pressure variability increase in sino-aortic denervated rats.

Increased blood pressure variability (BPV) has been proved to be associated with cardiovascular morbidity and mortality. It is of great significance to elucidate the mechanism of BPV increase. The cation channel transient receptor potential canonical 6 (TRPC6) is involved in a series of cardiovascular disease. Our experiment aimed to explore the role of TRPC6 in the development of BPV increase. Sino-aortic denervation (SAD) operation was applied to establish the model of BPV increase in rats. The BPV was presented as the standard deviation to the mean of systolic or diastolic blood pressure every 1 h during 12 h of the light period. SAD was performed in male Sprague Dawley (SD) rats at the age of 10 weeks. At 8 weeks after SAD operation, the hemodynamic parameters were determined non-invasively via a Rodent Blood Pressure Analysis System. The TRPC6 expressions in myocardial and thoracic aortic tissue was determined utilizing Western Blot, immunofluorescence and quantitative RT-PCR. The expression of TRPC3 was detected as well. To investigate whether TRPC6 was a causative factor of BPV increase in SAD rats, TRPC6 activator and inhibitor with three progressively increasing doses were intraperitoneally injected to the SAD rats. We found that SAD rats presented significant augmentation of systolic and diastolic BPV with no change of BP level and heart rate. The mRNA and protein expression levels of TRPC6 in myocardial and thoracic aortic tissue in SAD rats were substantially increased, but there was no obvious change in TRPC3 expression. The systolic and diastolic BPV increase were dose-dependently exacerbated after TRPC6 activation with GSK1702934A but were dose-dependently attenuated after TRPC6 inhibition with SAR7334. In Conclusion, the TRPC6 (but not TRPC3) expressions in myocardial and thoracic aortic tissue were substantially increased in SAD rats, and TRPC6 probably played an important role in the development of BPV elevation.

Tentonin 3/TMEM150C senses blood pressure changes in the aortic arch.

The baroreceptor reflex is a powerful neural feedback that regulates arterial pressure (AP). Mechanosensitive channels transduce pulsatile AP to electrical signals in baroreceptors. Here we show that tentonin 3 (TTN3/TMEM150C), a cation channel activated by mechanical strokes, is essential for detecting AP changes in the aortic arch. TTN3 was expressed in nerve terminals in the aortic arch and nodose ganglion (NG) neurons. Genetic ablation of Ttn3 induced ambient hypertension, tachycardia, AP fluctuations, and impaired baroreflex sensitivity. Chemogenetic silencing or activation of Ttn3+ neurons in the NG resulted in an increase in AP and heart rate, or vice versa. More important, overexpression of Ttn3 in the NG of Ttn3-/- mice reversed the cardiovascular changes observed in Ttn3-/- mice. We conclude that TTN3 is a molecular component contributing to the sensing of dynamic AP changes in baroreceptors.

Pseudoaneurysm of thoracic aorta presenting as inappropriate sinus tachycardia: a case report.

BACKGROUND: Pseudoaneurysm of thoracic aorta as a complication of blunt trauma to the chest, can present with a variety of symptoms due to mass compression effect. Here we report the first pseudoaneurysm of thoracic aorta presenting with chronic cough and inappropriate sinus tachycardia. The purpose of this case report is to highlight pseudoaneurysm of thoracic aorta as a rare differential diagnosis for inappropriate sinus tachycardia. CASE PRESENTATION: Here we report a case of 29-year-old white woman, a nurse, with history of a motor vehicle accident. She initially presented to medical attention with inappropriate sinus tachycardia 2 years following the motor vehicle accident during her pregnancy. Six years later she underwent sinoatrial node modification after failing a number of medications. Days prior to the ablation she developed a mild cough which became constant within a week following ablation. A computed tomography scan of her chest performed as part of a workup revealed an outpouching of the inferomedial aspect of the aortic arch, which was compressing her left main bronchus. She underwent arch repair surgery and recovered without complications. Four years later she presented with significant symptomatic sinus bradycardia requiring pacemaker placement. CONCLUSIONS: This is the first reported case of thoracic pseudoaneurysm of aorta presenting with inappropriate sinus tachycardia due to compression of the vagal nerve and cough as a result of the left main bronchus compressive effect; it highlights the importance of considering structural abnormalities in a differential diagnosis of inappropriate sinus tachycardia before any interventions.

Nebivolol prevents vascular oxidative stress and hypertension in rats chronically treated with ethanol.

BACKGROUND AND AIMS: Chronic ethanol consumption is associated with hypertension and atherosclerosis. Vascular oxidative stress is described as an important mechanism whereby ethanol predisposes to atherosclerosis. We hypothesized that nebivolol would prevent ethanol-induced hypertension and vascular oxidative stress. METHODS: Male Wistar rats were treated with ethanol 20% (vol./vol.) or nebivolol (10 mg/kg/day, p. o., gavage), a selective ß1-adrenergic receptor antagonist. RESULTS: Ethanol-induced increase in blood pressure and in the circulating levels of adrenaline and noradrenaline was prevented by nebivolol. Similarly, nebivolol prevented ethanol-induced increase in plasma levels of renin, angiotensin I and II. Chronic ethanol consumption increased the aortic levels of superoxide anion (O2-), thiobarbituric acid reactive species (TBARS) as well as the expression of Nox1 and nitrotyrosine immunostaining in the rat aorta. Treatment with nebivolol prevented these responses. The decrease in aortic levels of nitrate/nitrite (NOx) induced by ethanol was prevented by the treatment with nebivolol. Finally, nebivolol attenuated ethanol-induced increase in phenylephrine- and noradrenaline-induced contraction of endothelium-intact and endothelium-denuded aortic rings. CONCLUSIONS: The novelty of our study is that nebivolol prevented ethanol-induced hypertension and vascular oxidative stress. Additionally, we showed that the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS) are important endogenous mediators of the cardiovascular effects of ethanol.

Spatial relationships of the bronchial arteries to the left recurrent laryngeal nerve in the sub-aortic arch area.

PURPOSE: To safely perform lymphadenectomy in the sub-aortic arch area during esophagectomy for esophageal cancer, we investigated the spatial relationships between the bronchial arteries (BAs) and the left recurrent laryngeal nerve (LRLN). METHODS: For this macro-anatomical study, 72 cadavers were used. RESULTS: Of the 195 dissected BAs, 15 (7.7%) arteries ran dorsally across the LRLN. Such a running pattern of the BA was found in 15 (20.8%) of the 72 cadavers. Fourteen (93.3%) of the 15 arteries ran anteriorly along the left side of the esophagus, and 13 (86.7%) passed further to the lateral side of the left main bronchus to reach the ventral surface of the tracheobronchus; we named this running pattern "Type III". Of the 51 arteries with the Type III pattern, 25.5% ran across the dorsal side of the LRLN. CONCLUSION: Approximately 20% of the cadavers had BAs running dorsally to the LRLN in the sub-aortic arch area. Most of these arteries had the Type III pattern. One-quarter of the BAs with the Type III pattern showed this running pattern. Care must be practiced to safely perform lymphadenectomy for esophageal cancer in patients with Type III BAs.

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

Increased 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 aortic arch vascular mechanics in cardiovagal baroreflex sensitivity.

Cardiovagal baroreflex sensitivity (cvBRS) measures the efficiency of the cardiovagal baroreflex to modulate heart rate in response to increases or decreases in systolic blood pressure (SBP). Given that baroreceptors are located in the walls of the carotid sinuses (CS) and aortic arch (AA), the arterial mechanics of these sites are important contributors to cvBRS. However, the relative contribution of CS and AA mechanics to cvBRS remains unclear. This study employed sex differences as a model to test the hypothesis that differences in cvBRS between groups would be explained by the vascular mechanics of the AA but not the CS. Thirty-six young, healthy, normotensive individuals (18 females; 24 ± 2 yr) were recruited. cvBRS was measured using transfer function analysis of the low-frequency region (0.04-0.15 Hz). Ultrasonography was performed at the CS and AA to obtain arterial diameters for the measurement of distensibility. Local pulse pressure (PP) was taken at the CS using a hand-held tonometer, whereas AA PP was estimated using a transfer function of brachial PP. Both cvBRS (25 ± 11 vs. 19 ± 7 ms/mmHg, P = 0.04) and AA distensibility (16.5 ± 6.0 vs. 10.5 ± 3.8 mmHg(-1) × 10(-3), P = 0.02) were greater in females than males. Sex differences in cvBRS were eliminated after controlling for AA distensibility (P = 0.19). There were no sex differences in CS distensibility (5.32 ± 2.3 vs. 4.63 ± 1.3 mmHg(-1) × 10(-3), P = 0.32). The present data demonstrate that AA mechanics are an important contributor to differences in cvBRS.

Chronic vagus nerve stimulation attenuates vascular endothelial impairments and reduces the inflammatory profile via inhibition of the NF-κB signaling pathway in ovariectomized rats.

Vagus nerve stimulation (VNS), a method for activating cholinergic anti-inflammatory pathways, could suppress endothelial activation and minimize tissue injury during inflammation. The aim of this study was to investigate the effects of chronic VNS on endothelial impairments and the inflammatory profile in ovariectomized (OVX) rats. Sprague-Dawley rats (7-8 months old) were randomly assigned to the following four groups: sham-OVX, OVX, OVX+sham-VNS, and OVX+VNS. Throughout the experimental period, the OVX+VNS group received VNS for 3h (20.0 Hz, 1.0 mA, and 10.00 ms pulse width) at the same time every other day. After 12 weeks of VNS, blood samples and thoracic aortas were collected for further analyses. Light microscopy and electron microscopy analyses showed that chronic VNS prevented endothelial swelling, desquamation and even necrosis in the OVX rats. In addition, it obviously improved endothelial function in the OVX rats by restoring the endothelial nitric oxide synthase (e-NOS) and serum endothelin-1 level. Increased expression of cell adhesion molecules (VCAM-1, ICAM-1 and E-selectin) in the thoracic aortas and increases in the levels of circulating cytokines (TNF-α, IL-6, MCP-1, and CINC/KC) were also observed in the OVX rats. Chronic VNS significantly restored these detrimental changes partly by increasing the ACh concentrations in vascular walls and blocking NF-κB pathway activity. The results of this in vivo study have shown that the administration of chronic VNS during, in the early stage of estrogen deficiency, protects OVX rats from endothelial impairments and the inflammatory profile. These findings indicate that activation of the vagus nerve could be a promising supplemental therapy for reducing the risks of suffering from further CVDs in postmenopausal women.

Comparison Of Cardiovascular Characteristics In Normotensive And Hypertensive Rat Strains.

BACKGROUND: Hypertensive rats serve as valuable tools for studies of dysregulations in cardiovascular functions before and during pathological elevation of blood pressure. They exhibit many defects in structure and function of heart and vessels which are often related to severity of hypertension. OBJECTIVE: The relationship of blood pressure level and manifestation of aberrations in selected cardiovascular and metabolic parameters were determined in 20-week-old normotensive Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) and in their F1 offspring borderline hypertensive rats (BHR), and also in normotensive Wistar rats which are genetically less compatible with the other mentioned rat strains. METHODS: Systolic blood pressure and heart rate were measured in conscious rats by the non-invasive tail-cuff method. At the end of the treatment, rats were sacrificed, relative weight of their left heart ventricle and liver were determined and plasma concentration of glucose and triglycerides were measured. Thoracic aorta and superior mesenteric artery were isolated and prepared for isometric tension recording. Neurogenic contractions were elicited by electrical stimulation of perivascular adrenergic nerves. RESULTS: The level of systolic blood pressure in WKY rats (106.0 ± 0.4 mmHg), BHR (149.5 ± 2.5 mmHg) and SHR (186.4 ± 3.9 mmHg) corresponded with the impairment of acetylcholine-induced relaxation of isolated thoracic aorta and with the increase in sensitivity of contractile responses to exogenous noradrenaline and to electrical stimulation of perivascular adrenergic nerves in mesenteric artery. However, rats of the normotensive strain Wistar (118.1 ± 2.0 mmHg) exhibited arterial contractions similar to those obtained in hypertensive rats. Wistar rats had also the highest relative liver weight and plasma triglyceride concentration. CONCLUSION: These observations indicate that when comparing non-related rat strains the higher magnitude of arterial contractions and abnormal lipid parameters may not correlate with hypertensive state.

Sympathetic hyperactivity and aortic sympathetic nerve sprouting in patients with thoracic aortic dissection.

BACKGROUND: To determine the yet unknown relation between thoracic aortic dissection (TAD) and sympathetic nervous system activity. METHODS: Variables such as electrocardiography, blood pressure, respiratory activity, postganglionic muscle sympathetic nerve activity (MSNA), plasma norepinephrine, tyrosine hydroxylase-positive nerve fiber density, and growth-associated protein 43-positive nerve fiber density were detected and statistically analyzed. RESULTS: TAD Patients showed a significant lower R-R interval variance and higher blood pressure, heart rate, respiratory rate, MSNA, plasma norepinephrine (reflecting elevated sympathetic nervous system [SNS] activity), higher tyrosine hydroxylase, growth-associated protein 43-positive nerve fiber density (reflecting sympathetic sprouting and innervation) than those of the control group. CONCLUSIONS: In TAD patients, both overall and regional aortic SNS activities are elevated.

Network interactions within the canine intrinsic cardiac nervous system: implications for reflex control of regional cardiac function.

The aims of the study were to determine how aggregates of intrinsic cardiac (IC) neurons transduce the cardiovascular milieu versus responding to changes in central neuronal drive and to determine IC network interactions subsequent to induced neural imbalances in the genesis of atrial fibrillation (AF). Activity from multiple IC neurons in the right atrial ganglionated plexus was recorded in eight anaesthetized canines using a 16-channel linear microelectrode array. Induced changes in IC neuronal activity were evaluated in response to: (1) focal cardiac mechanical distortion; (2) electrical activation of cervical vagi or stellate ganglia; (3) occlusion of the inferior vena cava or thoracic aorta; (4) transient ventricular ischaemia, and (5) neurally induced AF. Low level activity (ranging from 0 to 2.7 Hz) generated by 92 neurons was identified in basal states, activities that displayed functional interconnectivity. The majority (56%) of IC neurons so identified received indirect central inputs (vagus alone: 25%; stellate ganglion alone: 27%; both: 48%). Fifty per cent transduced the cardiac milieu responding to multimodal stressors applied to the great vessels or heart. Fifty per cent of IC neurons exhibited cardiac cycle periodicity, with activity occurring primarily in late diastole into isovolumetric contraction. Cardiac-related activity in IC neurons was primarily related to direct cardiac mechano-sensory inputs and indirect autonomic efferent inputs. In response to mediastinal nerve stimulation, most IC neurons became excessively activated; such network behaviour preceded and persisted throughout AF. It was concluded that stochastic interactions occur among IC local circuit neuronal populations in the control of regional cardiac function. Modulation of IC local circuit neuronal recruitment may represent a novel approach for the treatment of cardiac disease, including atrial arrhythmias.

Sites of action of ghrelin receptor ligands in cardiovascular control.

Circulating ghrelin reduces blood pressure, but the mechanism for this action is unknown. This study investigated whether ghrelin has direct vasodilator effects mediated through the growth hormone secretagogue receptor 1a (GHSR1a) and whether ghrelin reduces sympathetic nerve activity. Mice expressing enhanced green fluorescent protein under control of the promoter for growth hormone secretagogue receptor (GHSR) and RT-PCR were used to locate sites of receptor expression. Effects of ghrelin and the nonpeptide GHSR1a agonist capromorelin on rat arteries and on transmission in sympathetic ganglia were measured in vitro. In addition, rat blood pressure and sympathetic nerve activity responses to ghrelin were determined in vivo. In reporter mice, expression of GHSR was revealed at sites where it has been previously demonstrated (hypothalamic neurons, renal tubules, sympathetic preganglionic neurons) but not in any artery studied, including mesenteric, cerebral, and coronary arteries. In rat, RT-PCR detected GHSR1a mRNA expression in spinal cord and kidney but not in the aorta or in mesenteric arteries. Moreover, the aorta and mesenteric arteries from rats were not dilated by ghrelin or capromorelin at concentrations >100 times their EC(50) determined in cells transfected with human or rat GHSR1a. These agonists did not affect transmission from preganglionic sympathetic neurons that express GHSR1a. Intravenous application of ghrelin lowered blood pressure and decreased splanchnic nerve activity. It is concluded that the blood pressure reduction to ghrelin occurs concomitantly with a decrease in sympathetic nerve activity and is not caused by direct actions on blood vessels or by inhibition of transmission in sympathetic ganglia.

Caracterizacion de las ramas del arco aórtico en una muestra de poblacion colombiana: un estudio con material de autopsia / Characterization of aortic arch branches in a colombian population sample. A study with autopsy material

La variabilidad del arco aórtico y sus ramas emergentes presentan implicaciones en los abordajes quirúrgicos de tórax y cuello, y posiblemente en el desarrollo de procesos ateromatosos ubicados a ese nivel y accidentes cerebrovasculares. Se evaluaron 122 arcos aórticos de individuos adultos de ambos sexos obtenidos como material de autopsia. Se identificó la configuración general de la emergencia de las ramas colaterales de los arcos y se determinó la morfometría de sus componentes con medición electrónica. Se observó la presencia de la configuración usual (tipo A) en 87 arcos (71,3 por ciento); un tronco braqui-bicarotideo (tipo B) en 21 piezas anatómicas (17,2 por ciento) y en 10 casos (8,2 por ciento) la arteria vertebral izquierda se originó directamente del arco aórtico (tipo C); en 4 especímenes (3,3 por ciento) se presentó emergencia atípica de las ramas. El calibre de la aorta en el punto previo a la emergencia de sus ramas y justo después de emitir su última colateral fue de 20,1mm (DE 3,19) y 17,2mm (DE 2,57) respectivamente, con una disminución del 14,5 por ciento. El calibre de las arterias sublavias (7,7mm, DE 1,10) fue significativamente mayor (P=0,0001) que el de las arterias carótidas (6,4mm, DE 0,78). El diámetro de las arterias carótidas derecha e izquierda fue de 6,5mm (DE 0,81) y 6,3mm (DE 0,75) respectivamente. La arteria subclavia derecha presentó mayor calibre que la izquierda (7,9mm, DE 1,09; 7,6mm, DE 1,12) sin diferencia estadisticamente significativa (P=0,0801). La distancia entre el origen del tronco braquiocefálico y el de la subclavia izquierda fue de 32,8mm (DE 6,16) y la longitud del tronco braquiocefálico fue 30,2mm+/-5,27. Se destaca la alta frecuencia de arcos con emergencia de dos y cuatro ramas. Los calibres de las ramas son menores a lo reportado en la literatura.

The variability of the aortic arch and its emergent branches have implications in the surgical approaches of the thorax and neck, and possibly in the development of the atheromatous processes located at that level and the cerebrovascular accidents. We evaluated 122 aortic arches from adult individuals of both sexes obtained as autopsy material. We identified the general configuration of the emergence of the collateral branches of the arcs and determined the morphometry of its components with electronic measurement. We observed the usual configuration (type A) in 87 arches (71.3 percent); a brachio-bicarotid trunk (type B) in 21 anatomical specimens (17.2 percent) and in 10 cases (8.2 percent) the left vertebral artery originated directly from the aortic arch (type C); 4 specimens (3.3 percent) presented atypical emergency in the branches. The caliber of the aorta at the point prior to the emergence of its branches and just after casting his last side was 20.1mm (DS 3.19) and 17.2mm (DS 2.57) respectively, with a decrease of 14.5 percent. The caliber of the subclavian arteries (7.7mm, SD 1.1) was significantly higher (P=0.0001) than of the carotid arteries (64mm, SD 0.78). The diameter of the carotid arteries both right and left were 6.5mm (DS 0.81) and 6.3mm (DS 0.75) respectively. The right subclavian artery presented higher caliber than the left (7.9mm, DS 1.09; 7.6mm, DS 1.12) without significant statistical difference (P=0.0801). The difference between the origin of the brachiocephalic trunk and the left subclavian artery was 32.8 (DS 6.16); the brachiocephalic trunk length was 30.2mm +/- 5.27. It highlights the high frequency of arches with emergency of two and four branches. The calibers of the branches are smaller than those reported in the literature.

Surgical thoracic sympathectomy induces structural and biomechanical remodeling of the thoracic aorta in a porcine model.

BACKGROUND: Sympathetic innervation exerts marked effects on vascular smooth muscle cells, including a short-term homeostatic (vasoconstrictor) and a direct trophic action promoting differentiation. However, the role of sympathetic nervous system in long-term structural and functional modulation of the aortic wall is yet undefined. METHODS: Six Landrace pigs underwent bilateral thoracic sympathectomy from the stellate to T8 ganglion, whereas 10 pigs underwent sham operation. Animals were sacrificed 3 mo postoperatively. Histometrical examination was performed on specimens from the thoracic (TA) and abdominal aorta (AA) utilizing an image-processing system. A uniaxial tensile tester was utilized for biomechanical evaluation; parameters of extensibility, strength, and stiffness of aortic tissue were calculated. RESULTS: Structural aortic remodeling of sympathectomized animals was observed, including increased inner aortic diameter in TA (15.3 ± 0.4 versus 10.4 ± 0.2 mm, P < 0.001) and AA (6.7 ± 0.3 versus 5.3 ± 0.2 mm, P = 0.002), and increased wall thickness in TA (2.0 ± 0.1 versus 1.6 ± 0.1 mm, P < 0.001) but not AA. Microscopic image analysis revealed increased elastin (TA: 50.1 ± 1.1 versus 29.7% ± 0.6%, P < 0.001; AA: 20.4 ± 2.1 versus 16.3% ± 0.6%, P = 0.03) and collagen density (only in TA: 22.0 ± 0.9 versus 15.4% ± 0.5%, P < 0.001), and decreased smooth muscle density (TA: 27.6 ± 1.3 versus 54.9% ± 0.7%, P < 0.001; AA: 57.2 ± 1.5 versus 63.4% ± 0.8%, P < 0.001). Sophisticated biomechanical analysis demonstrated that following sympathectomy, TA was equally extensible but manifested augmented strength (1344 ± 73 versus 1071 ± 52 kPa, P = 0.004) and stiffness (6738 ± 478 versus 5026 ± 273 kPa, P = 0.003), in accordance with extracellular matrix protein accumulation in that region. Differences in the AA were non-significant. CONCLUSIONS: Chronic thoracic sympathetic denervation causes significant structural and biomechanical remodeling of the thoracic aorta. Possible clinical implications for patients undergoing thoracic sympathectomy or chronically treated with sympathetic blockers require further investigation.

The relationship between aortic baroreceptor activity and arterial pressure is not monotonic.

Previous reports indicate that when aortic pressure (AP) falls below the threshold (P (th)) for baroreceptor sensitivity, activity in the aortic depressor nerve (ADN) may increase. To quantify and explain this anomalous behaviour, we analysed curves describing the relationship of baroreceptor fibre activity in rabbit left ADN to AP. Data were obtained in anaesthetised New Zealand White rabbits. Occlusion and release of cuffs around the inferior vena cava and descending aorta generated AP ramps (25-140 mmHg). Response curves were obtained for 173 fibres in 26 animals. Thirty percent of curves had a nadir (J-shaped curve), and in 40% activity was always present. In fibres showing activity below P (th), firing was predominantly diastolic, switching to systolic firing at P (th). The unusual behaviour of a substantial fraction of aortic baroreceptors below P (th) accounts for the J-shaped response curve of the whole ADN. We suggest that fibres that fire during diastole at pressures below P (th) may have sensory endings close to the origin of the left subclavian artery. As a consequence of this anatomical location, low pressures can impose strain on these receptors, which is then relieved by the systolic pulse.

Effect of carotid and aortic baroreceptors on cardiopulmonary reflex: the role of autonomic function.

We determined the sympathetic and parasympathetic control of heart rate (HR) and the sensitivity of the cardiopulmonary receptors after selective carotid and aortic denervation. We also investigated the participation of the autonomic nervous system in the Bezold-Jarish reflex after selective removal of aortic and carotid baroreceptors. Male Wistar rats (220-270 g) were divided into three groups: control (CG, N = 8), aortic denervation (AG, N = 5) and carotid denervation (CAG, N = 9). AG animals presented increased arterial pressure (12%) and HR (11%) compared with CG, while CAG animals presented a reduction in arterial pressure (16%) and unchanged HR compared with CG. The sequential blockade of autonomic effects by atropine and propranolol indicated a reduction in vagal function in CAG (a 50 and 62% reduction in vagal effect and tonus, respectively) while AG showed an increase of more than 100% in sympathetic control of HR. The Bezold-Jarish reflex was evaluated using serotonin, which induced increased bradycardia and hypotension in AG and CAG, suggesting that the sensitivity of the cardiopulmonary reflex is augmented after selective denervation. Atropine administration abolished the bradycardic responses induced by serotonin in all groups; however, the hypotensive response was still increased in AG. Although the responses after atropine were lower than the responses before the drug, indicating a reduction in vagal outflow after selective denervation, our data suggest that both denervation procedures are associated with an increase in sympathetic modulation of the vessels, indicating that the sensitivity of the cardiopulmonary receptors was modulated by baroreceptor fibers.

Effect of carotid and aortic baroreceptors on cardiopulmonary reflex: the role of autonomic function

We determined the sympathetic and parasympathetic control of heart rate (HR) and the sensitivity of the cardiopulmonary receptors after selective carotid and aortic denervation. We also investigated the participation of the autonomic nervous system in the Bezold-Jarish reflex after selective removal of aortic and carotid baroreceptors. Male Wistar rats (220-270 g) were divided into three groups: control (CG, N = 8), aortic denervation (AG, N = 5) and carotid denervation (CAG, N = 9). AG animals presented increased arterial pressure (12 percent) and HR (11 percent) compared with CG, while CAG animals presented a reduction in arterial pressure (16 percent) and unchanged HR compared with CG. The sequential blockade of autonomic effects by atropine and propranolol indicated a reduction in vagal function in CAG (a 50 and 62 percent reduction in vagal effect and tonus, respectively) while AG showed an increase of more than 100 percent in sympathetic control of HR. The Bezold-Jarish reflex was evaluated using serotonin, which induced increased bradycardia and hypotension in AG and CAG, suggesting that the sensitivity of the cardiopulmonary reflex is augmented after selective denervation. Atropine administration abolished the bradycardic responses induced by serotonin in all groups; however, the hypotensive response was still increased in AG. Although the responses after atropine were lower than the responses before the drug, indicating a reduction in vagal outflow after selective denervation, our data suggest that both denervation procedures are associated with an increase in sympathetic modulation of the vessels, indicating that the sensitivity of the cardiopulmonary receptors was modulated by baroreceptor fibers.

Functional properties of the superior vena cava (SVC)-aorta ganglionated plexus: evidence suggesting an autonomic basis for rapid SVC firing.

INTRODUCTION: the mechanism underlying spontaneous rapid superior vena cava (SVC) firing that initiates atrial fibrillation (AF) remains poorly understood. We investigated the role of the SVC-aorta-ganglionated plexus (SVC-Ao-GP) in AF initiated by rapid firing from the SVC. METHODS AND RESULTS: in 42 dogs, a circular catheter was positioned above the SVC-atrial junction. Multielectrode catheters were sutured on atria, atrial appendages and pulmonary veins. The effective refractory period (ERP) and window of vulnerability (WOV) for AF were measured at all sites in the baseline state, during cervical vagosympathetic trunk stimulation and during SVC-Ao-GP stimulation, before and after SVC-Ao-GP ablation. AF inducibility was also assessed by delivering high-frequency stimulation (HFS) within myocardial refractory period to the SVC before and after SVC-Ao-GP ablation. HFS applied to the SVC-Ao-GP slowed the sinus rate and/or atrioventricular conduction. HFS of the SVC-Ao-GP induced more significant shortening of ERP and a greater increase in WOV at the SVC than other sites. Ablation of the SVC-Ao-GP significantly increased the baseline ERP and decreased the baseline WOV only at the SVC. AF induced at the SVC by HFS during refractoriness was eliminated by ablation of the SVC-Ao-GP but was not altered by ablation of the 4 major atrial GP. Direct injection of acetylcholine into the SVC-Ao-GP initiated rapid firing from the SVC in every case. CONCLUSIONS: the SVC-Ao-GP preferentially modulates the electrophysiological function of the SVC sleeves and may contribute to rapid firing from the SVC.

Structural remodeling of vagal afferent innervation of aortic arch and nucleus ambiguus (NA) projections to cardiac ganglia in a transgenic mouse model of type 1 diabetes (OVE26).

Diabetes-induced structural changes of vagal aortic afferent and cardiac efferent axons are not well understood. FVB control and OVE26 diabetic mice at different ages received injections of the tracer tetramethylrhodamine dextran (TMR-D) into the nodose ganglion to label vagal aortic afferents (at 3 and 6 months), or DiI injections into the nucleus ambiguus to label vagal cardiac efferents (at 3, 6, and 9 months). The aortic arch and atria were examined by using confocal microscopy. In the aortic arch, TMR-D labeled large and small vagal afferent axons (axons(L) and axons(S)) that formed different types of terminals: axons(L) produced large flower-sprays (flower-sprays(L)) and end-nets (end-nets(L)), whereas axons(S) produced small flower-sprays (flower-sprays(S)) and end-nets (end-nets(S)). In the atria, DiI-labeled vagal efferent axons formed basket endings around ganglion principle neurons (PNs). The vagal afferents, PNs and vagal cardiac efferents in diabetic mice were compared with age-matched control mice. We found (P < 0.05) that: 1) the size of axons(L), flower-sprays(L), flower-sprays(S) and end-nets(S) were reduced at 6 and 9 months; 2) the size of cardiac ganglia and the somatic area of the PNs were decreased, and the PN density in cardiac ganglia was increased at all ages and the PN nuclei/soma area ratio was increased at 9 months; and 3) the percentage of DiI-labeled axons-innervated PNs was decreased at all ages. Furthermore, the number of synaptic-like terminal varicosities around PNs was decreased. Compared with 3 months, more advanced diabetes at 9 months further reduced the number of varicosities/PN. In addition to these changes, swollen axons and terminals, as well as leaky-like DiI-labeled terminals, were observed in long-term diabetic mice (6 and 9 months of age). Taken together, our data show that chronic diabetes induces a significant structural atrophy of vagal aortic afferent and cardiac efferent axons and terminals. Although different morphologies of vagal afferent terminals in the aortic arch may serve as substrates for the future investigation of aortic depressor afferent physiology, structural remodeling of vagal afferents and efferents provides a foundation for further analysis of diabetes-induced impairment of cardiac autonomic regulation.