Pulmonary Artery Denervation: Update on Clinical Studies.

PURPOSE OF REVIEW: Sympathetic overactivity plays an important role in the progression of pulmonary arterial hypertension (PAH). The purpose of this review is to illustrate localization of pulmonary arterial sympathetic nerves, the key steps of pulmonary artery denervation (PADN) procedure, and to highlight clinical outcomes. RECENT FINDINGS: Sympathetic nerves mostly occurred in the posterior region of the bifurcation and pulmonary trunk. Emerging preclinical data provided the potential of PADN for PAH. PADN, produced at bifurcation area, improved a profound reduction of pulmonary arterial pressure and ameliorated clinical outcomes with an exclusive ablation catheter. The application of PADN in the patients of PAH or combined pre-capillary and post-capillary PH (CpcPH) improved the hemodynamic parameters and increased 6MWD. Sympathetic overactivity aggravates PAH. PADN is a promising interventional treatment for PAH and CpcPH. Additional clinical trials are warranted to confirm the efficacy of PADN.

Pulmonary artery denervation to treat pulmonary arterial hypertension: the single-center, prospective, first-in-man PADN-1 study (first-in-man pulmonary artery denervation for treatment of pulmonary artery hypertension).

OBJECTIVES: This study was designed to test the safety and efficacy of pulmonary artery (PA) denervation (PADN) for patients with idiopathic PA hypertension (IPAH) not responding optimally to medical therapy. BACKGROUND: Baroreceptors and sympathetic nerve fibers are localized in or near the bifurcation area of the main PA. We previously demonstrated that PADN completely abolished the experimentally elevated PA pressure responses to occlusion of the left interlobar PA. METHODS: Of a total of 21 patients with IPAH, 13 patients received the PADN procedure, and the other 8 patients who refused the PADN procedure were assigned to the control group. PADN was performed at the bifurcation of the main PA, and at the ostial right and left PA. Serial echocardiography, right heart catheterization, and a 6-min walk test (6MWT) were performed. The primary endpoints were the change of PA pressure (PAP), tricuspid excursion (Tei) index, and 6MWT at 3 months follow-up. RESULTS: Compared with the control group, at 3 months follow-up, the patients who underwent the PADN procedure showed significant reduction of mean PAP (from 55 ± 5 mm Hg to 36 ± 5 mm Hg, p < 0.01), and significant improvement of the 6MWT (from 324 ± 21 m to 491 ± 38 m, p < 0.006) and of the Tei index (from 0.7 ± 0.04 to 0.50 ± 0.04, p < 0.001). CONCLUSIONS: We report for the first time the effect of PADN on functional capacity and hemodynamics in patients with IPAH not responding optimally to medical therapy. Further randomized study is required to confirm the efficacy of PADN. (First-in-Man Pulmonary Artery Denervation for Treatment of Pulmonary Artery Hypertension [PADN-1] study; chiCTR-ONC-12002085).

Percutaneous pulmonary artery denervation completely abolishes experimental pulmonary arterial hypertension in vivo.

AIMS: The study sought to assess the effect of percutaneous pulmonary artery denervation (PADN) on balloon-occlusion-induced acute pulmonary arterial hypertension (PAH) in vivo. The PADN is a minimally invasive and endovascular catheter-based interventional therapy using radiofrequency ablation to abolish the pulmonary arterial baroreceptors to pressure response. METHODS AND RESULTS: To examine the efficacy of balloon-occlusion-induced PAH, twenty Mongolian dogs were randomly assigned to one of two groups: group 1 (left distal pulmonary basal trunk occlusion) and group 2 (left pulmonary interlobar artery occlusion). Afterwards, PADN treatment at the main pulmonary artery bifurcation level with left pulmonary interlobar artery occlusion in all 20 dogs was conducted. Haemodynamic parameters were measured at baseline and during balloon occlusion as well as the PADN treatment at different time points: one, two, three, five, and ten minutes. Before the PADN treatment, most haemodynamic parameters of the pulmonary artery remained unchanged in group 1 with distal pulmonary basal trunk occlusion. However, in group 2 with the occlusion of the left pulmonary interlobar artery, mean pulmonary arterial pressure, mean right ventricular pressure, and pulmonary vessel resistance gradually increased, and mean absolute difference reached peak at five minutes (Δ16.6 mmHg, Δ14.1 mmHg and Δ1,144 dye/s/cm5, respectively; each p<0.01). These haemodynamic parameters at five minutes induced by left pulmonary interlobar artery occlusion were completely abolished with the PADN treatment compared to baseline (Δ0.3 mmHg, Δ0.2 mmHg, and Δ34 dye/s/cm5, respectively). CONCLUSIONS: Balloon occlusion of the left pulmonary interlobar artery led to a significant increase of haemodynamic parameters of the pulmonary artery. The pressure responses were completely abolished by the PADN treatment at the main bifurcation area of the left pulmonary artery.

Novel antihypertensive therapies: renal sympathetic nerve ablation and carotid baroreceptor stimulation.

Therapeutic interventions aimed at reducing high blood pressure still encompass a number of difficulties and limitations. This is the case particularly in resistant hypertension, i.e. a condition characterized by a very high cardiovascular risk. Carotid baroreceptor stimulation and renal sympathetic nerves ablation represent new approaches in the treatment of this condition. This paper will provide a comparison of the effects of the two procedures, highlighting their effects on blood pressure, metabolic profile, target organ damage, safety and tolerability profile.

Timing and efficacy of alternative methods of sympathetic blockade.

Despite the presence of seven different antihypertensive drug classes and over 120 different antihypertensive medications, about 48 % of the 75 million people with hypertension are not reaching their target blood pressure goals. One of the reasons for this lack of control is the failure to adequately inhibit the sympathetic nervous system. Consequently, alternative therapies have been attracting interest. Recent technical advances targeting the sympathetic over-activity of the carotid sinuses (baroreflex activation therapy, BAT) and the renal sympathetic nerves (renal denervation therapy, RDT) have renewed interest in invasive therapies for the treatment of drug-resistant hypertension. Encouraging results from the recent Rheos Pivotal and Symplicity HTN-2 trials on the safety and efficacy of BAT and RDT, respectively, indicate that invasive approaches can safely reduce blood pressure in patients with resistant/refractory hypertension. These approaches, while still experimental in the US, are appropriate for those on more than three fully tolerated doses of antihypertensive medications whose blood pressure is not at goal, i.e. <140/90 mmHg. The present review is focused on the clinical implications of these two technics and when they are appropriate.

Hemodynamic profile in rabbits of fospropofol disodium injection relative to propofol emulsion following rapid bolus injection.

The effects of aqueous fospropofol disodium (FP) and propofol emulsion (PE) on hemodynamics and sympathetic nerve activity in rabbits following bolus injection were evaluated. Barodenervated and neuraxis-intact rabbits received PE at 4 mg/kg (PE(4)) or FP equal to 4 or 8 mg/kg propofol equivalents (FP(4) and FP(8), respectively) intravenously as a rapid bolus injection, and mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded for 20 min. The plasma propofol pharmacokinetic behavior from FP and PE was evaluated to support the pharmacodynamic observations. In barodenervated animals, MAP and RSNA decreased significantly in all groups (PE(4) > FP(8) > FP(4)). HR decreased only in the PE(4) group. The time for the maximum reduction of MAP was significantly longer with FP(8) compared with PE(4). MAP decreased, and RSNA and HR increased significantly in the neuraxis-intact animals (PE(4) > FP(8) > FP(4)). The time for maximum reduction of MAP was essentially the same in all neuraxis-intact groups. Plasma propofol levels from FP were lower than those from PE in the first 4 min following administration. The results suggest that the tachycardia observed in humans following injection of FP is not a direct physiological effect of the agent.

Cardiac and pulmonary arterial remodeling after sinoaortic denervation in normotensive rats.

Blood pressure variability (BPV) and baroreflex dysfunction may contribute to end-organ damage process. We investigated the effects of baroreceptor deficit (10 weeks after sinoaortic denervation - SAD) on hemodynamic alterations, cardiac and pulmonary remodeling. Cardiac function and morphology of male Wistar intact rats (C) and SAD rats (SAD) (n=8/group) were assessed by echocardiography and collagen quantification. BP was directly recorded. Ventricular hypertrophy was quantified by the ratio of left ventricular weight (LVW) and right ventricular weight (RVW) to body weight (BW). BPV was quantified in the time and frequency domains. The atrial natriuretic peptide (ANP), alpha-skeletal actin (α-skelectal), collagen type I and type III genes mRNA expression were evaluated by RT-PCR. SAD did not change BP, but increased BPV (11±0.49 vs. 5±0.3 mmHg). As expected, baroreflex was reduced in SAD. Pulmonary artery acceleration time was reduced in SAD. In addition, SAD impaired diastolic function in both LV (6.8±0.26 vs. 5.02±0.21 mmHg) and RV (5.1±0.21 vs. 4.2±0.12 mmHg). SAD increased LVW/BW in 9% and RVW/BW in 20%, and augmented total collagen (3.8-fold in LV, 2.7-fold in RV, and 3.35-fold in pulmonary artery). Also, SAD increased type I (~6-fold) and III (~5-fold) collagen gene expression. Denervation increased ANP expression in LV (75%), in RV (74%) and increased α-skelectal expression in LV (300%) and in RV (546%). Baroreflex function impairment by SAD, despite not changing BP, induced important adjustments in cardiac structure and pulmonary hypertension. These changes may indicate that isolated baroreflex dysfunction can modulate target tissue damage.

Animal models for the study of arterial hypertension.

Hypertension is one of the leading causes of disability or death due to stroke, heart attack and kidney failure. Because the etiology of essential hypertension is not known and may be multifactorial, the use of experimental animal models has provided valuable information regarding many aspects of the disease, which include etiology, pathophysiology, complications and treatment. The models of hypertension are various, and in this review, we provide a brief overview of the most widely used animal models, their features and their importance.

Baroreflex sensitivity impairment is associated with cardiac diastolic dysfunction in rats.

BACKGROUND: Studies have shown that the autonomic dysfunction accompanied by impaired baroreflex sensitivity was associated with higher mortality. However, the influence of decreased baroreflex sensitivity on cardiac function, especially in diastolic function, is not well understood. This study evaluated the morphofunctional changes associated with baroreflex impairment induced by chronic sinoaortic denervation (SAD). METHODS AND RESULTS: Animals were divided into sinoaortic denervation (SAD) and control (C) groups. Baroreflex sensitivity was evaluated by tachycardic and bradycardic responses, induced by vasoactive drugs. Cardiac function was studied by echocardiography and by left ventricle (LV) catheterization. LV collagen content and the expression of regulatory proteins involved in intracellular Ca(2+) homeostasis were quantified. Results showed higher LV mass in SAD versus C animals. Furthermore, an increase in deceleration time of E-wave in the SAD versus the C group (2.14 ± 0.07 ms vs 1.78 ± 0.03 ms) was observed. LV end-diastolic pressure was increased and the minimum dP/dt was decreased in the SAD versus the C group (12 ± 1.5 mm Hg vs 5.3 ± 0.2 mm Hg and 7,422 ± 201 vs 4,999 ± 345 mm Hg/s, respectively). SERCA/NCX ratio was lower in SAD than in control rats. The same was verified in SERCA/PLB ratio. CONCLUSIONS: The results suggest that baroreflex dysfunction is associated with cardiac diastolic dysfunction independently of the presence of other risk factors.

Autonomic impairment after myocardial infarction: role in cardiac remodelling and mortality.

1. Impairmant of baroreflex sensitivity (BRS) has been implicated in the reduction of heart rate variability (HRV) and in the increased risk of death after myocardial infarction (MI). In the present study, we investigated whether the additional impairment in BRS induced by sinoaortic baroreceptor denervation (SAD) in MI rats is associated with changes in the low-frequency (LF) component of HRV and increased mortality rate. 2. Rats were randomly divided into four groups: control, MI, denervated (SAD) and SAD + MI rats. Left ventricular (LV) function was evaluated by echocardiography. Autonomic components were assessed by power spectral analysis and BRS. 3. Myocardial infarction (90 days) reduced ejection fraction (by approximately 42%) in both the MI and SAD + MI groups; however, an increase in LV mass and diastolic dysfunction were observed only in the SAD + MI group. Furthermore, BRS, HRV and the LF power of HRV were reduced after MI, with an exacerbated reduction seen in SAD + MI rats. The LF component of blood pressure variability (BPV) was increased in the MI, SAD and SAD + MI groups compared with the control group. Mortality was higher in the MI groups compared with the non-infarcted groups, with an additional increase in mortality in the SAD + MI group compared with the MI group. Correlations were obtained between BRS and the LF component of HRV and between LV mass and the LF component of BPV. 4. Together, the results indicate that the abolishment of BRS induced by SAD in MI rats further reduces the LF band of HRV, resulting in a worse cardiac remodelling and increased mortality in these rats. These data highlight the importance of this mechanism in the prognosis of patients after an ischaemic event.

Baroreflex deficit blunts exercise training-induced cardiovascular and autonomic adaptations in hypertensive rats.

1. Baroreceptors regulate moment-to-moment blood pressure (BP) variations, but their long-term effect on the cardiovascular system remains unclear. Baroreceptor deficit accompanying hypertension contributes to increased BP variability (BPV) and sympathetic activity, whereas exercise training has been associated with an improvement in these baroreflex-mediated changes. The aim of the present study was to evaluate the autonomic, haemodynamic and cardiac morphofunctional effects of long-term sinoaortic baroreceptor denervation (SAD) in trained and sedentary spontaneously hypertensive rats (SHR). 2. Rats were subjected to SAD or sham surgery and were then further divided into sedentary and trained groups. Exercise training was performed on a treadmill (five times per week, 50-70% maximal running speed). All groups were studied after 10 weeks. 3. Sinoaortic baroreceptor denervation in SHR had no effect on basal heart rate (HR) or BP, but did augment BPV, impairing the cardiac function associated with increased cardiac hypertrophy and collagen deposition. Exercise training reduced BP and HR, re-established baroreflex sensitivity and improved both HR variability and BPV. However, SAD in trained SHR blunted all these improvements. Moreover, the systolic and diastolic hypertensive dysfunction, reduced left ventricular chamber diameter and increased cardiac collagen deposition seen in SHR were improved after the training protocol. These benefits were attenuated in trained SAD SHR. 4. In conclusion, the present study has demonstrated that the arterial baroreflex mediates cardiac disturbances associated with hypertension and is crucial for the beneficial cardiovascular morphofunctional and autonomic adaptations induced by chronic exercise in hypertension.

Myocardial ischemia-mediated excitatory reflexes: a new function for thromboxane A2?

Clinical and experimental evidence has shown that myocardial ischemia activates cardiac spinal afferents that mediate sympathoexcitatory reflex responses. During myocardial ischemia, thromboxane A2 (TxA2) is released in large quantities by activated platelets in the coronary circulation of patients with coronary artery disease. We hypothesized that endogenous TxA2 contributes to sympathoexcitatory reflexes during myocardial ischemia through stimulation of TxA2/prostaglandin endoperoxide (TP) receptors. Regional myocardial ischemia was induced by occlusion of a diagonal branch of left anterior descending coronary artery of anesthetized cats. Hemodynamic parameters and renal sympathetic nerve activity were recorded after sinoaortic denervation and bilateral vagotomy. Regional myocardial ischemia evoked significant increases in mean blood pressure (122+/-10 vs. 139+/-12 mmHg, before vs. ischemia), aortic flow (153+/-18 vs. 167+/-20 ml/min), first derivative of left ventricular pressure at 40-mmHg developed pressure (2,736+/-252 vs. 2,926+/-281 mmHg/s), systemic vascular resistance (0.6+/-0.1 vs. 0.9+/-0.12 peripheral resistance units), and renal sympathetic nerve activity (by 22%). The reflex nature of the excitatory responses was confirmed by observing its disappearance after blockade of cardiac nerve transmission with intrapericardial 2% procaine treatment. Moreover, application of U-46619 (2.5-10 microg), a TxA2 mimetic, on the heart caused graded increases in mean arterial pressure and renal nerve activity, responses that were abolished 3 min after local blockade of cardiac neural transmission with intrapericardial procaine. BM 13,177 (30 mg/kg iv), a selective TP receptor antagonist, eliminated the reflex responses to U-46619 and significantly attenuated the excitatory responses during brief (5 min) regional myocardial ischemia. The sympathoexcitatory reflex responses to U-46619 were unchanged by blockade of histamine H1 receptors with pyrilamine and serotonin 5-HT3 receptors with tropisetron, indicating specificity of this TP receptor agonist. These data indicate that endogenous TxA2 participates in myocardial ischemia-mediated sympathoexcitatory reflex responses through a TP receptor mechanism.

Central nervous system administration of interleukin-6 produces splenic sympathoexcitation.

Interleukin-6 (IL-6) is a multifunctional cytokine that has been shown to play a pivotal role in centrally-mediated physiological responses including activation of the hypothalamic-pituitary-adrenal axis. Cerebral spinal fluid (CSF) concentrations of IL-6 are elevated in multiple pathophysiological conditions including Alzheimer's disease, autoimmune disease, and meningitis. Despite this, the effect of IL-6 on central regulation of sympathetic nerve discharge (SND) remains unknown which limits understanding of sympathetic-immune interactions in health and disease. In the present study we determined the effect of intracerebroventricular (i.c.v, lateral ventricle) administration of IL-6 on splenic SND in urethane-chloralose-anesthetized rats. A second goal was to determine if icv injected IL-6 enters the brain parenchyma and acts as a volume transmission signal to access areas of the brain involved in regulation of sympathetic nerve outflow. i.c.v administration of IL-6 (10 ng, 100 ng, and 400 ng) significantly and progressively increased splenic SND from control levels in baroreceptor-denervated Sprague-Dawley rats. Administration of 100-ng and 400-ng IL-6 resulted in significantly higher SND responses when compared to those elicited with a 10-ng dose. Sixty minutes following icv administration, fluorescently labeled IL-6 was not distributed throughout the parenchyma of the brain but was localized to the periventricular areas of the ventricular system. Brain sections counter-stained for the IL-6 receptor (IL-6R) revealed that IL-6 and the IL-6R were co-localized in periventricular areas adjoining the third ventricle. These results demonstrate that icv IL-6 administration increases splenic SND, an effect likely achieved via signaling mechanisms originating in the periventricular cells.

Brain stem control of arterial pressure in chronic arterial baroreceptor-denervated rats.

Interruption of the baroreceptor reflex by transection of afferent nerves (sinoaortic denervation; SAD) or lesions of nucleus tractus solitarius (NTS) elevates sympathetic nerve activity (SNA) and arterial pressure (AP). However, within 1 wk, mean AP returns to normal despite the absence of baroreflexes. In this study, we examine central mechanisms that control AP in chronic baroreceptor-denervated rats. In urethane-anesthetized rats (1.5 g/kg i.v.) after autonomic ganglionic blockade (5 mg/kg i.v. chlorisondamine), alpha1-adrenergic-mediated pressor responses (1-100 microg/kg i.v. phenylephrine) were not altered by chronic lesions of NTS, indicating vascular reactivity to sympathetic stimulation is normal. Transection of the spinal cord at T1 profoundly decreased AP and was not further reduced by chlorisondamine in control or denervated rats. Inhibition of the rostral ventrolateral medulla (RVLM) by microinjections of muscimol (100 pmol/side) decreased AP to levels not further reduced by chlorisondamine in control rats, rats with SAD, and rats with NTS lesions. Blockade of GABA(A) receptors in the RVLM (50 pmol/side bicuculline) increased AP similarly in control rats and denervated rats. In agreement, inhibition of the caudal ventrolateral medulla (CVLM) by microinjections of muscimol or blockade of glutamatergic inputs (2.7 nmol/side kynurenate) produced comparable increases in AP in control and denervated rats. These data suggest the RVLM continues to drive the SNA that regulates AP in the chronic absence of baroreceptor inputs. In addition, despite the absence of a tonic excitatory input from NTS, in chronic baroreceptor-denervated rats glutamatergic inputs drive the CVLM to tonically inhibit the RVLM. Baroreceptor-independent regulation of the ventrolateral medulla may underlie central mechanisms contributing to the long-term control of AP.

Effect of lignocaine injection in carotid sinus on baroreceptor sensitivity during carotid endarterectomy.

OBJECTIVES: This study was undertaken to test the hypothesis that there is a neural basis for baroreceptor deterioration during carotid endarterectomy (CEA), by investigating intraoperative hemodynamic changes induced by intraluminal carotid stretch stimulation, before and after application of local anesthetic to the adventitial layer of the carotid sinus region. METHODS: This was a prospective study of 20 patients undergoing elective CEA. During CEA, before removal of the atheroma, intraluminal stretch simulation of the carotid baroreceptors (rub test) was performed before and after injection of 1% lignocaine into adventitial tissue of the artery in the region of the carotid sinus. Continuous measurements of mean arterial blood pressure (MAP), electrocardiographic r-r intervals (R-R), heart rate, cardiac vagal tone, and carotid sinus baroreflex were recorded to determine alterations in baroreceptor function. RESULTS: Rub test before injection of lignocaine was associated with a decrease in MAP and heart rate and an increase in R-R, cardiac vagal tone, and carotid baroreflex response, indicating a functioning baroreflex. After lignocaine injection and repetition of the rub test, no significant change was seen in MAP, heart rate, R-R, cardiac vagal tone, or carotid baroreflex response, indicating a nonfunctioning baroreflex. Comparing the peak responses to the rub test stimulus before and after lignocaine injection showed significant differences for all variables (P <.05), with carotid baroreflex response and heart rate being highly significant (P <.0005). CONCLUSIONS: The baroreflex response to intraluminal stretch stimulation of the carotid sinus area is operational in patients undergoing CEA, and this response is abolished by infiltration of local anesthetic into the periadventitial tissue around the carotid sinus.

Steady-state and dynamic responses of renal sympathetic nerve activity to air-jet stress in sinoaortic denervated rats.

This study examined the role of arterial baroreceptors in mediating the relationship between changes in the mean level and the amplitude of slow oscillations of renal sympathetic nerve activity (RSNA) during environmental stress. In 7 sham-operated (control) and 7 chronically (2 weeks before study) sinoaortic baroreceptor denervated (SAD) conscious rats, arterial pressure (AP) and RSNA were simultaneously recorded during two 15-minute periods, before and during the application of a mild environmental stressor (jet of air). Air-jet stress induced a similar degree of sympathoexcitation in both groups of rats. During stress in control rats, AP and RSNA spectral power in the mid-frequency (MF) range (0.27 to 0.74 Hz) increased, mainly as a consequence of an amplification of strongly coherent oscillations of approximately 0.4 Hz frequency. In SAD rats, MF fluctuations of AP and RSNA were reduced but not abolished before stress, tended to increase during stress, and were linearly related under both experimental conditions. However, in the MF range, there was no well-defined oscillation at any specific frequency. At the peak coherence frequency ( approximately 0.4 Hz), the gain of the transfer function from RSNA to AP did not change during stress in control rats and was similar to that measured in SAD rats, indicating that it mainly reflected the properties of the feedforward effect of RSNA on AP (ie, vascular reactivity). In summary, the parallelism between stress-induced changes in the mean level of RSNA and the amplitude of slow RSNA oscillations requires the functional integrity of the baroreceptor reflex, which is consistent with the hypothesis that slow AP and RSNA rhythms are resonant oscillations within the baroreceptor reflex loop.

Chronic blockade of nitric oxide does not produce hypertension in baroreceptor denervated rabbits.

Although the vascular action of endothelium-derived nitric oxide in modulating arterial pressure is well established, nitric oxide can also act as a neurotransmitter in the central nervous system. In addition, there is evidence for an interaction between nitric oxide and baroreceptor afferent processing; thus, nitric oxide may regulate blood pressure through central modulation of arterial baroreflexes. To test this possible interaction of nitric oxide and baroreflexes in the long-term regulation of blood pressure, we measured arterial pressure and heart rate responses to nitric oxide blockade by using L-NAME (50 mg/kg per day in drinking water) over 7 days in baroreceptor intact and sinoaortic denervated conscious rabbits. In the baroreceptor intact animals, blockade of nitric oxide leads to a significant increase in mean arterial pressure (from 75+/-2 to 84+/-3 mm Hg) and decrease in heart rate (from 233+/-8 to 195+/-8 bpm) that was sustained over the 7 days of nitric oxide blockade. In the sinoaortic denervated animals, blockade of nitric oxide initially led to a similar increase in arterial pressure (82+/-3 mm Hg on the second day), but in all sinoaortic denervated animals this increase was not sustained and recovered back to pre-L-NAME levels. This finding indicates that baroreflexes play an important role in the long-term control of blood pressure, and, second, that one mediator of this control is nitric oxide.

Effect of arterial baroreceptor denervation on sodium balance.

During chronic increased dietary sodium intake, arterial baroreceptors buffer against sustained increases in arterial pressure, and renal sympathoinhibition contributes importantly to the maintenance of sodium balance by decreasing renal tubular sodium reabsorption and increasing urinary sodium excretion. The present study examined the effect of arterial baroreceptor denervation on sodium balance in conscious rats during low, normal, and high dietary sodium intake. Compared with measurements made before arterial baroreceptor denervation, arterial baroreceptor-denervated rats had similar sodium balance during normal dietary sodium intake but significantly more negative sodium balance during low dietary sodium intake and significantly more positive sodium balance during high dietary sodium intake. At the end of the high dietary sodium intake period, arterial pressure (under anesthesia) was 159+/-5 mm Hg after arterial baroreceptor denervation and 115+/-1 mm Hg before arterial baroreceptor denervation. Sham arterial baroreceptor denervation in time control rats had no effect on sodium balance or arterial pressure during the different dietary sodium intakes. These studies indicate that (1) arterial baroreceptor denervation impairs the ability to establish sodium balance during both low and high dietary sodium intake, and (2) arterial baroreceptor denervation leads to the development of increased arterial pressure during high dietary sodium intake in association with increased renal sodium retention.

Exaggerated cardiovascular effects of cocaine in conscious dogs with pacing-induced dilated cardiomyopathy.

BACKGROUND: The aim of this study was to explore the characteristics and mechanisms of the cardiovascular effects of cocaine in dilated cardiomyopathy. METHODS AND RESULTS: We studied the cardiovascular responses to acute intravenous cocaine (1 mg/kg) in 8 conscious, chronically instrumented dogs before and after the development of dilated cardiomyopathy induced by rapid ventricular pacing. To help elucidate the role of altered baroreflex function in mediating the cardiovascular effects of cocaine, we also studied responses in 3 conscious, chronically instrumented dogs that had undergone surgical sinoaortic baroreceptor denervation. Cocaine produced greater increases in heart rate (+57 +/- 8% from 112 +/- 5 beats/min versus +28 +/- 3% from 100 +/- 4 beats/min; P <.01), first derivative of left ventricular pressure (+30 +/- 5% from 1,714 +/- 147 mm Hg/sec versus +15 +/- 3% from 3,032 +/- 199 mm Hg/sec; P <.01), coronary vascular resistance (+28 +/- 5% from 2.3 +/- 0.3 mm Hg/mL/min versus +11 +/- 5% from 2.2 +/- 0.3 mm Hg/mL/min; P <.05) and plasma norepinephrine concentration (+130 +/- 31% from 462 +/- 102 pg/mL versus +86 +/- 32% from 286 +/- 77 pg/mL; P <.05) in dogs with dilated cardiomyopathy as compared to controls. In addition, responses were much more rapid in onset following the development of dilated cardiomyopathy. Chronotropic and inotropic responses to cocaine were similarly rapid and exaggerated in dogs after baroreceptor denervation. CONCLUSIONS: Cocaine produces rapid and exaggerated chronotropic, inotropic, and coronary vasoconstrictor responses in conscious dogs with pacing-induced dilated cardiomyopathy. Alterations in arterial baroreflex function may play a role in these observations, which in turn may underlie the clinically observed association between cocaine and heart failure.

Activation of skeletal muscle afferents evokes release of glutamate in the subretrofacial nucleus (SRF) of cats.

The subretrofacial nucleus (SRF) is a region of the rostral ventrolateral medulla known to play a crucial role in sympathoexcitation. SRF neurons send direct projections to the intermediolateral cell columns of the spinal cord where they form synaptic contact with preganglionic sympathetic motor neurons. Activation of this neural pathway increases sympathetic outflow to the heart and blood vessels affecting cardiac function and vasomotor tone. Previous studies utilizing electrophysiological recording techniques and c-Fos expression have established that the activity of SRF neurons is increased during skeletal muscle contraction. However, the excitatory neurotransmitter mediating this increased activity remains in question. In the present study, static contraction of the triceps surae was induced by electrical stimulation of L7 and S1 ventral roots in anesthetized cats (n=12). Endogenous release of glutamate (Glu) from the SRF was recovered by microdialysis and measured by HPLC. Static muscle contraction for 4 min increased mean arterial pressure (MAP) 38+/-4 mmHg from a control level of 102+/-12 mmHg (P< 0.05). During muscle contraction the extracellular concentration of Glu recovered from the SRF increased from 623+/-117 to 1078+/-187 nM (P<0.05). To determine the effect of muscle contraction on Glu release in the absence of synaptic input from other reflexogenic areas, contraction was repeated following acute sinoaortic denervation and vagotomy. Following this denervation, muscle contraction increased MAP 41+/- 4 mmHg (P < 0.05) and Glu concentration from 635+/-246 to 1106+/-389 nM (P < 0.05). Muscle paralysis prevented the increases in MAP and Glu concentration during ventral root stimulation. These results suggest that: (i) Glu is released in the SRF during activation of contraction-sensitive skeletal muscle afferent fibers in the cat; and (ii) synaptic input from other reflexogenic areas appears to be ineffective in modulating the release of Glu in the SRF during static muscle contraction.