The involvement of renal afferents in the maintenance of cardiorenal diseases.

Elevated sympathetic vasomotor activity is a common feature of cardiorenal diseases. Therefore, the sympathetic nervous system is an important therapeutic target, particularly the fibers innervating the kidneys. In fact, renal denervation has been applied clinically and shown promising results in patients with hypertension and chronic kidney disease. However, the underlying mechanisms involved in the cardiorenal protection induced by renal denervation have not yet been fully clarified. This mini-review highlights historical and recent aspects related to the role of renal sensory fibers in the control of cardiorenal function under normal conditions and in experimental models of cardiovascular disease. Results have demonstrated that alterations in renal sensory function participate in the maintenance of elevated sympathetic vasomotor activity and cardiorenal changes; as such, renal sensory fibers may be a potential therapeutic target for the treatment of cardiorenal diseases. Although it has not yet been applied in clinical practice, selective afferent renal denervation may be promising, since such an approach maintains efferent activity and can provide more refined control of renal function compared with total renal denervation. However, more studies are needed to understand the mechanisms by which renal afferents partially contribute to such changes, in addition to the need to evaluate the safety and advantages of the approach for application in the clinical practice.

Cognitive effects of subdiaphragmatic vagal deafferentation in rats.

Vagal afferents are a crucial neuronal component of the gut-brain axis and mediate the information flow from the viscera to the central nervous system. Based on the findings provided by experiments involving vagus nerve stimulation, it has been suggested that vagal afferent signaling may influence various cognitive functions such as recognition memory and cognitive flexibility. Here, we examined this hypothesis using a rat model of subdiaphragmatic vagal deafferentation (SDA), the most complete and selective abdominal vagal deafferentation method existing to date. We found that SDA did not affect working memory in a nonspatial alternation task, nor did it influence short-, intermediate-, and long-term object recognition memory. SDA did also not affect the acquisition of positively reinforced left-right discrimination learning, but it facilitated the subsequent reversal left-right discrimination learning. The SDA-induced effects on reversal learning emerged in the absence of concomitant changes in motivation towards the positive reinforcer, indicating selective effects on cognitive flexibility. Taken together, these findings suggest that the relative contribution of vagal afferent signaling to cognitive functions is limited. At the same time, our study demonstrates that cognitive flexibility, at least in the domains of positively reinforced learning, is subjected to visceral modulation through abdominal vagal afferents.

Efficacy of Transurethral Vesical Deafferentation with Mid-Urethral Sling Operation for Female Mixed Urinary Incontinence: Preliminary Results.

OBJECTIVES: In female patients with mixed urinary incontinence (MUI), a mid-urethral sling operation (MUS) is an effective treatment for stress urinary incontinence (SUI), but urgency urinary incontinence (UUI) frequently persists. We developed a novel transurethral vesical deafferentation procedure and assessed its efficacy in these patients. METHODS: From December 2009 to December 2012, 41 female patients with MUI were enrolled prospectively. After baseline evaluation including urodynamic study and symptom questionnaires (Overactive Bladder Symptom Score (OABSS) and International Consultation on Incontinence Questionnaire - Overactive Bladder [ICIQ-OAB]), patients in the study group underwent both the deafferentation procedure and MUS, and those in the control group underwent MUS alone. The outcome was assessed 3 months after the operation by subjective assessment of SUI and OABSS. RESULTS: At 3 months, the treatment response rate of UUI was significantly higher in the study group than in the control group; UUI was improved in 80 and 57.1% of patients, respectively. SUI was cured in most patients. There were no serious complications, such as voiding symptom and urinary retention. CONCLUSIONS: The transurethral vesical deafferentation procedure combined with MUS is effective for the treatment of MUI. The procedure is simple, safe and efficacious in treating urgency and UUI without affecting voiding function.

Differential role of afferent and efferent renal nerves in the maintenance of early- and late-phase Dahl S hypertension.

Clinical data suggest that renal denervation (RDNX) may be an effective treatment for human hypertension; however, it is unclear whether this therapeutic effect is due to ablation of afferent or efferent renal nerves. We have previously shown that RDNX lowers arterial pressure in hypertensive Dahl salt-sensitive (S) rats to a similar degree observed in clinical trials. In addition, we have recently developed a method for selective ablation of afferent renal nerves (renal-CAP). In the present study, we tested the hypothesis that the antihypertensive effect of RDNX in the Dahl S rat is due to ablation of afferent renal nerves by comparing the effect of complete RDNX to renal-CAP during two phases of hypertension in the Dahl S rat. In the early phase, rats underwent treatment after 3 wk of high-NaCl feeding when mean arterial pressure (MAP) was ∼ 140 mmHg. In the late phase, rats underwent treatment after 9 wk of high NaCl feeding, when MAP was ∼ 170 mmHg. RDNX reduced MAP ∼ 10 mmHg compared with sham surgery in both the early and late phase, whereas renal-CAP had no antihypertensive effect. These results suggest that, in the Dahl S rat, the antihypertensive effect of RDNX is not dependent on pretreatment arterial pressure, nor is it due to ablation of afferent renal nerves.

Cardiac sympathetic afferent denervation attenuates cardiac remodeling and improves cardiovascular dysfunction in rats with heart failure.

The enhanced cardiac sympathetic afferent reflex (CSAR) contributes to the exaggerated sympathoexcitation in chronic heart failure (CHF). Increased sympathoexcitation is positively related to mortality in patients with CHF. However, the potential beneficial effects of chronic CSAR deletion on cardiac and autonomic function in CHF have not been previously explored. Here, we determined the effects of chronic CSAR deletion on cardiac remodeling and autonomic dysfunction in CHF. To delete the transient receptor potential vanilloid 1 receptor-expressing CSAR afferents selectively, epicardial application of resiniferatoxin (50 µg/mL), an ultrapotent analog of capsaicin, was performed during myocardium infarction surgery in rats. This procedure largely abolished the enhanced CSAR, prevented the exaggerated renal and cardiac sympathetic nerve activity and improved baroreflex sensitivity in CHF rats. Most importantly, we found that epicardial application of resiniferatoxin largely prevented the elevated left ventricle end-diastolic pressure, lung edema, and cardiac hypertrophy, partially reduced left ventricular dimensions in the failing heart, and increased cardiac contractile reserve in response to ß-adrenergic receptor stimulation with isoproterenol in CHF rats. Molecular evidence showed that resiniferatoxin attenuated cardiac fibrosis and apoptosis and reduced expression of fibrotic markers and transforming growth factor-ß receptor I in CHF rats. Pressure-volume loop analysis showed that resiniferatoxin reduced the end-diastolic pressure volume relationships in CHF rats, indicating improved cardiac compliance. In summary, cardiac sympathetic afferent deletion exhibits protective effects against deleterious cardiac remodeling and autonomic dysfunction in CHF. These data suggest a potential new paradigm and therapeutic potential in the management of CHF.

Pudendal afferents mapping in posterior sacral rhizotomies.

BACKGROUND: The effectiveness of pudendal afferents mapping in posterior sacral rhizotomies needs to be reviewed. OBJECTIVE: To evaluate the effectiveness of pudendal afferents mapping for both the dorsal penile or clitoral nerve and the inferior anal nerve to decrease the risk of postoperative bowel and bladder dysfunction when the sacral nerve roots are candidates for rhizotomies. METHODS: A retrospective review of 101 Asian children who underwent functional posterior rhizotomies with pudendal afferents mapping for spastic paresis was performed. RESULTS: Pudendal mapping was successful in 75 of 81 patients. The highest activity of afferent fibers of the dorsal penile or clitoral nerve was demonstrated at the S1 roots in 13.3%, at the S2 in 79.3%, and at the S3-5 in 7.3%. Considerable activity of the dorsal penile or clitoral nerve was recorded at 40% of the S1 roots, at 99.3% of the S2 roots, and at 52% of the S3-5 roots. The highest activity of afferent fibers of the inferior anal nerve was demonstrated at S2 roots in 42% and at S3-5 roots in 58%. Considerable activity of the inferior anal nerve was recorded at 10.7% of S1 roots, at 89.3% of S2 roots, and at 76.7% of S3-5 roots. The pathological S1 roots were divided into 3 to 4 rootlets, and the rootlets with significant afferent activity were preserved. None of the 75 patients experienced long-term bowel or bladder complications. CONCLUSION: Pudendal afferent mapping identified the sacral rootlets involved with genital and anal sensation. The preservation of such rootlets in sacral rhizotomies is considered to be important for minimizing postoperative bladder and bowel dysfunction.

Rapid and persistent impairments of the forelimb motor representations following cervical deafferentation in rats.

Skilled motor control is regulated by the convergence of somatic sensory and motor signals in brain and spinal motor circuits. Cervical deafferentation is known to diminish forelimb somatic sensory representations rapidly and to impair forelimb movements. Our focus was to determine what effect deafferentation has on the motor representations in motor cortex, knowledge of which could provide new insights into the locus of impairment following somatic sensory loss, such as after spinal cord injury or stroke. We hypothesized that somatic sensory information is important for cortical motor map topography. To investigate this we unilaterally transected the dorsal rootlets in adult rats from C4 to C8 and mapped the forelimb motor representations using intracortical microstimulation, immediately after rhizotomy and following a 2-week recovery period. Immediately after deafferentation we found that the size of the distal representation was reduced. However, despite this loss of input there were no changes in motor threshold. Two weeks after deafferentation, animals showed a further distal representation reduction, an expansion of the elbow representation, and a small elevation in distal movement threshold. These changes were specific to the forelimb map in the hemisphere contralateral to deafferentation; there were no changes in the hindlimb or intact-side forelimb representations. Degradation of the contralateral distal forelimb representation probably contributes to the motor control deficits after deafferentation. We propose that somatic sensory inputs are essential for the maintenance of the forelimb motor map in motor cortex and should be considered when rehabilitating patients with peripheral or spinal cord injuries or after stroke.

Renal sympathetic nerve ablation for treatment-resistant hypertension.

Hypertension is a major risk factor for increased cardiovascular events with accelerated sympathetic nerve activity implicated in the pathogenesis and progression of disease. Blood pressure is not adequately controlled in many patients, despite the availability of effective pharmacotherapy. Novel procedure- as well as device-based strategies, such as percutaneous renal sympathetic nerve denervation, have been developed to improve blood pressure in these refractory patients. Renal sympathetic denervation not only reduces blood pressure but also renal as well as systemic sympathetic nerve activity in such patients. The reduction in blood pressure appears to be sustained over 3 years after the procedure, which suggests absence of re-innervation of renal sympathetic nerves. Safety appears to be adequate. This approach may also have potential in other disorders associated with enhanced sympathetic nerve activity such as congestive heart failure, chronic kidney disease and metabolic syndrome. This review will focus on the current status of percutaneous renal sympathetic nerve denervation, clinical efficacy and safety outcomes and prospects beyond refractory hypertension.

Consequences of the ablation of nonpeptidergic afferents in an animal model of trigeminal neuropathic pain.

Damage to peripheral nerves causes significant remodeling of peripheral innervation and can lead to neuropathic pain. Most nociceptive primary afferents are unmyelinated (C fibers) and subdivided into peptidergic and nonpeptidergic fibers. Previous studies have found nerve injury in the trigeminal system to induce changes in small-diameter primary afferent innervation and cause significant autonomic sprouting into the upper dermis of the lower-lip skin of the rat. In this study, we used the ribosomal toxin, saporin, conjugated to the lectin IB4 to specifically ablate the nonpeptidergic nociceptive C fibers, to see if loss of these fibers was enough to induce autonomic fiber sprouting. IB4-saporin treatment led to specific and permanent ablation of the IB4-positive, P2X(3)-immunoreactive fibers and led to sprouting of parasympathetic fibers into the upper dermis, but not of sympathetic fibers. These changes were associated with significant increase in glial-derived nerve growth factor levels in the lower-lip skin. While IB4-saporin treatment had no effect on evoked mechanical thresholds when von Frey hairs were applied to the lower-lip skin, ablation of nonpeptidergic fibers in a chronic constriction injury model caused significant sympathetic and parasympathetic fiber sprouting, and led to an exacerbated pain response. This was an unexpected finding, as it has been suggested that nonpeptidergic fibers play a major role in mechanical pain, and suggests that these fibers play a complex role in the development of neuropathic pain.

Relative contributions of afferent vagal fibers to resistance to diet-induced obesity.

BACKGROUND: We previously demonstrated vagal neural pathways, specifically subdiaphragmatic afferent fibers, regulate expression of the intestinal sodium-glucose cotransporter SGLT1, the intestinal transporter responsible for absorption of dietary glucose. We hypothesized targeting this pathway could be a novel therapy for obesity. We therefore tested the impact of disrupting vagal signaling by total vagotomy or selective vagal de-afferentation on weight gain and fat content in diet-induced obese rats. METHODS: Male Sprague-Dawley rats (n = 5-8) underwent truncal vagotomy, selective vagal de-afferentation with capsaicin, or sham procedure. Animals were maintained for 11 months on a high-caloric Western diet. Abdominal visceral fat content was assessed by magnetic resonance imaging together with weight of fat pads at harvest. Glucose homeostasis was assessed by fasting blood glucose and HbA1C. Jejunal SGLT1 gene expression was assessed by qPCR and immunoblotting and function by glucose uptake in everted jejunal sleeves. RESULTS: At 11-months, vagotomized rats weighed 19% less (P = 0.003) and de-afferented rats 7% less (P = 0.19) than shams. Vagotomized and de-afferented animals had 52% (P < 0.0001) and 18% reduction (P = 0.039) in visceral abdominal fat, respectively. There were no changes in blood glucose or glycemic indexes. SGLT1 mRNA, protein and function were unchanged across all cohorts at 11-months postoperatively. CONCLUSIONS: Truncal vagotomy led to significant reductions in both diet-induced weight gain and visceral abdominal fat deposition. Vagal de-afferentation led to a more modest, but clinically and statistically significant, reduction in visceral abdominal fat. As increased visceral abdominal fat is associated with excess morbidity and mortality, vagal de-afferentation may be a useful adjunct in bariatric surgery.

Return of spinal reflex after spinal cord surgery for brachial plexus avulsion injury.

Motor but not sensory function has been described after spinal cord surgery in patients with brachial plexus avulsion injury. In the featured case, motor-related nerve roots as well as sensory spinal nerves distal to the dorsal root ganglion were reconnected to neurons in the ventral and dorsal horns of the spinal cord by implanting nerve grafts. Peripheral and sensory functions were assessed 10 years after an accident and subsequent spinal cord surgery. The biceps stretch reflex could be elicited, and electrophysiological testing demonstrated a Hoffman reflex, or Hreflex, in the biceps muscle when the musculocutaneous nerve was stimulated. Functional MR imaging demonstrated sensory motor cortex activities on active as well as passive elbow flexion. Quantitative sensory testing and contact heat evoked potential stimulation did not detect any cutaneous sensory function, however. To the best of the authors' knowledge, this case represents the first time that spinal cord surgery could restore not only motor function but also proprioception completing a spinal reflex arch.

Liver afferents contribute to water drinking-induced sympathetic activation in human subjects: a clinical trial.

UNLABELLED: Water drinking acutely increases sympathetic activity in human subjects. In animals, the response appears to be mediated through transient receptor potential channel TRPV4 activation on osmosensitive hepatic spinal afferents, described as osmopressor response. We hypothesized that hepatic denervation attenuates water drinking-induced sympathetic activation. We studied 20 liver transplant recipients (44±2.6 years, 1.2±0.1 years post transplant) as model of hepatic denervation and 20 kidney transplant recipients (43±2.6 years, 0.8±0.1 years post transplant) as immunosuppressive drug matched control group. Before and after 500 ml water ingestion, we obtained venous blood samples for catecholamine analysis. We also monitored brachial and finger blood pressure, ECG, and thoracic bioimpedance. Plasma norepinephrine concentration had changed by 0.01±0.07 nmol/l in liver and by 0.21±0.07 nmol/l in kidney transplant recipients (p<0.05 between groups) after 30-40 minutes of water drinking. While blood pressure and systemic vascular resistance increased in both groups, the responses tended to be attenuated in liver transplant recipients. Our findings support the idea that osmosensitive hepatic afferents are involved in water drinking-induced sympathetic activation in human subjects. TRIAL REGISTRATION: ClinicalTrials.gov NCT01237431.

Cardiac spinal deafferentation reduces the susceptibility to sustained ventricular tachycardia in conscious rats.

The response to myocardial ischemia is complex and involves the cardio-cardiac sympathetic reflex. Specifically, cardiac spinal (sympathetic) afferents are excited by ischemic metabolites and elicit an excitatory sympathetic reflex, which plays a major role in the genesis of ventricular arrhythmias. For example, brief myocardial ischemia leads to ATP release, which activates cardiac spinal afferents through stimulation of P2 receptors. Clinical work with patients and preclinical work with animals document that disruption of this reflex protects against ischemia-induced ventricular arrhythmias. However, the role of afferent signals in the initiation of sustained ventricular tachycardia has not been investigated. Therefore, we tested the hypothesis that cardiac spinal deafferentation reduces the susceptibility to sustained ventricular tachycardia in adult (12-15 wk of age), conscious, male Sprague-Dawley rats. To test this hypothesis, the susceptibility to ventricular tachyarrhythmias produced by occlusion of the left main coronary artery was determined in two groups of conscious rats: 1) deafferentation (bilateral excision of the T1-T5 dorsal root ganglia) and 2) control (sham deafferentation). The ventricular arrhythmia threshold (VAT) was defined as the time from coronary occlusion to sustained ventricular tachycardia resulting in a reduction in arterial pressure. Results document a significantly higher VAT in the deafferentation group (7.0 ± 0.7 min) relative to control (4.3 ± 0.3 min) rats. The decreased susceptibility to tachyarrhythmias with deafferentation was associated with a reduced cardiac metabolic demand (lower rate-pressure product and ST segment elevation) during ischemia.

Structural preservation of deafferented cortex induced by electrical stimulation of a sensory peripheral nerve.

Any manipulation to natural sensory input has direct effects on the morphology and physiology of the Central Nervous System. In the particular case of amputations, sensory areas of the brain undergo degenerative processes with a marked reduction in neuronal activity and global disinhibition. This is probably due to a deregulation of the circuits devoted to the control of the cortical activity. These changes are detected in the organization of the representational maps, the metabolic labeling by 2-deoxyglucose or cytochrome oxidase, the density of afferent and efferent axonal connections and the reduced expression of inhibitory neurotransmitters. In the present study, performed in animals, we have evaluated the therapeutic potential of Brain Machine Interfaces in reversing or limiting the degenerative/deregulation processes of amputations. Applying electrical stimulation on amputated peripheral nerves, we have achieved to maintain in approximately normal values 1) the cortical activity and 2) the expression of GABA-associated molecules of the inhibitory interneurons of the primary somatosensory cortex.

[Effect of inferior vestibular and part of mandibular branch of trigeminal neurotomy on sound-induced masseter reflex potentials].

OBJECTIVE: To evaluate the influence of inferior vestibular and part of mandibular branch of trigeminal neurotomy on sound-induced masseter reflex potentials. METHOD: Twenty guinea pigs were randomly divided into four groups, including 5 normal control guinea pigs, 5 received unilateral inferior vestibular neurotomy, 5 received unilateral inferior alveolar nerve neurotomy, and 5 received auriculotemporal nerve neurotomy. Click sound-induced masseter reflex potentials were recorded in four groups, respectively. RESULT: The thresholds of negative peak (NP) of click sound-induced masseter reflex potentials in normal control group were (90.00 +/- 8.16) dBnHL. The response rates of the NP of the masseter reflex potentials using 100, 90, 80 and 70 dBnHL monaural acoustic stimulation with unilateral recording were 100%, 70%, 40% and 0, respectively. The mean latencies of the NP were (6.55 +/- 0.25) ms, (6.61 +/- 0.16) ms and (6.70 +/- 0.13) ms, when elicited by 100,90 and 80 dBnHL acoustic stimulation respectively. There was no significant difference between the stimulus intensity and the mean latency of the NP (P > 0.05). Negative peak of click sound-induced masseter reflex potentials was not observed in the inferior vestibular neurotomy group. The NP was preserved in the inferior alveolar nerve and auriculotemporal nerve neurotomy groups. There were no significant difference of the mean thresholds and latencies of NP between normal control group and inferior alveolar nerve and auriculotemporal nerve neurotomy group (P > 0.05). CONCLUSION: Click sound-induced masseter reflex potentials originates from vestibular afferents. Afferent of inferior alveolar nerve and auriculotemporal nerve can not influence the vestibular evoked masseter reflex potentials.

Histological modifications of the rat prostate following transection of somatic and autonomic nerves.

It is known that hormones influence significantly the prostate tissue. However, we reported that mating induces an increase in androgen receptors, revealing a neural influence on the gland. These data suggested that somatic afferents (scrotal and genitofemoral nerves) and autonomic efferents (pelvic and hypogastric nerves) could regulate the structure of the prostate. Here we assessed the role of these nerves in maintaining the histology of the gland. Hence, afferent or efferent nerves of male rats were transected. Then, the ventral and dorsolateral regions of the prostate were processed for histology. Results showed that afferent transection affects prostate histology. The alveoli area decreased and increased in the ventral and dorsolateral prostate, respectively. The epithelial cell height increased in both regions. Efferent denervation produced dramatic changes in the prostate gland. The tissue lost its configuration, and the epithelium became scattered and almost vanished. Thus, afferent nerves are responsible for spinal processes pertaining to the trophic control of the prostate, activating its autonomic innervation. Hence, our data imply that innervation seems to be synergic with hormones for the healthy maintenance of the prostate. Thus, it is suggested that some prostate pathologies could be due to the failure of the autonomic neural pathways regulating the gland.

Histological modifications of the rat prostate following transection of somatic and autonomic nerves

It is known that hormones influence significantly the prostate tissue. However, we reported that mating induces an increase in androgen receptors, revealing a neural influence on the gland. These data suggested that somatic afferents (scrotal and genitofemoral nerves) and autonomic efferents (pelvic and hypogastric nerves) could regulate the structure of the prostate. Here we assessed the role of these nerves in maintaining the histology of the gland. Hence, afferent or efferent nerves of male rats were transected. Then, the ventral and dorsolateral regions of the prostate were processed for histology. Results showed that afferent transection affects prostate histology. The alveoli area decreased and increased in the ventral and dorsolateral prostate, respectively. The epithelial cell height increased in both regions. Efferent denervation produced dramatic changes in the prostate gland. The tissue lost its configuration, and the epithelium became scattered and almost vanished. Thus, afferent nerves are responsible for spinal processes pertaining to the trophic control of the prostate, activating its autonomic innervation. Hence, our data imply that innervation seems to be synergic with hormones for the healthy maintenance of the prostate. Thus, it is suggested that some prostate pathologies could be due to the failure of the autonomic neural pathways regulating the gland.

Sabe-se que os hormônios influenciam significativamente o tecido prostático. Entretanto, nós demonstramos que o acasalamento induz um aumento nos receptores androgênicos, revelando uma influência neural sobre a glândula. Esses dados sugerem que os aferentes somáticos (nervos escrotal e genito-femural) e os eferentes autonômicos (nervos pélvicos e hipo-gástricos) poderiam regular a estrutura da próstata. Neste trabalho, avaliou-se a função destes nervos na manutenção da histologia da glândula. Dessa forma, os nervos aferentes e eferentes de ratos machos foram seccionados As regiões ventral e dorsolateral da próstata foram processadas para histologia. Os resultados mostraram que a transecção aferente afeta a histologia da próstata. A área alveolar diminuiu e aumentou na próstata dorsal e dorsolateral, respectivamente. A altura da célula epitelial aumentou em ambas as regiões. A desenervação eferente produziu alterações dramáticas na glândula prostática. O tecido perdeu a sua configuração e o epitélio tornou-se difuso e quase desapareceu. Assim, os nervos aferentes são responsáveis por processos espinhais que pertencem ao controle trófico da próstata, ativando sua inervação autonômica. Dessa forma, nossos dados sugerem que a inervação parece ser sinérgica com os hormônios para a manutenção saudável da próstata. Assim, sugere-se que algumas patologias prostáticas poderiam ser ocasionadas devido a falhas nas vias neurais autonômicas que regulam esta glândula.

Renal sympathetic nerve ablation: the new frontier in the treatment of hypertension.

The sympathetic nervous system plays an important role in circulatory and metabolic control and has clearly been established as a major contributor to the development of hypertension, as elevated sympathetic nerve activity initiates and sustains the elevation of blood pressure. Increased sympathetic outflow to the heart, resulting in increased cardiac output and neurally mediated vasoconstriction of peripheral blood vessels, is an obvious example of a neural pathophysiologic pathway leading to elevated blood pressure. The consequences of increased sympathetic outflow to the kidneys, perhaps most important in this context, are sodium and water retention, increased renin release, and alterations of renal blood flow-effects that contribute substantially to both acute and long-term blood pressure elevations. Accordingly, renal sympathetic nerve ablation appears to be a logical therapeutic approach for the treatment of hypertension. Recent reports on a novel catheter-based renal nerve ablation procedure reviewed in this article are promising.

Prefrontal beta2 subunit-containing and alpha7 nicotinic acetylcholine receptors differentially control glutamatergic and cholinergic signaling.

One-second-long increases in prefrontal cholinergic activity ("transients") were demonstrated previously to be necessary for the incorporation of cues into ongoing cognitive processes ("cue detection"). Nicotine and, more robustly, selective agonists at alpha4beta2* nicotinic acetylcholine receptors (nAChRs) enhance cue detection and attentional performance by augmenting prefrontal cholinergic activity. The present experiments determined the role of beta2-containing and alpha7 nAChRs in the generation of prefrontal cholinergic and glutamatergic transients in vivo. Transients were evoked by nicotine, the alpha4beta2* nAChR agonist ABT-089 [2-methyl-3-(2-(S)-pyrrolindinylmethoxy) pyridine dihydrochloride], or the alpha7 nAChR agonist A-582941 [2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole]. Transients were recorded in mice lacking beta2 or alpha7 nAChRs and in rats after removal of thalamic glutamatergic or midbrain dopaminergic inputs to prefrontal cortex. The main results indicate that stimulation of alpha4beta2* nAChRs evokes glutamate release and that the presence of thalamic afferents is necessary for the generation of cholinergic transients. ABT-089-evoked transients were completely abolished in mice lacking beta2* nAChRs. The amplitude, but not the decay rate, of nicotine-evoked transients was reduced by beta2* knock-out. Conversely, in mice lacking the alpha7 nAChR, the decay rate, but not the amplitude, of nicotine-evoked cholinergic and glutamatergic transients was attenuated. Substantiating the role of alpha7 nAChR in controlling the duration of release events, stimulation of alpha7 nAChR produced cholinergic transients that lasted 10- to 15-fold longer than those evoked by nicotine. alpha7 nAChR-evoked cholinergic transients are mediated in part by dopaminergic activity. Prefrontal alpha4beta2* nAChRs play a key role in evoking and facilitating the transient glutamatergic-cholinergic interactions that are necessary for cue detection and attentional performance.