Guanabenz inhibits alveolar bone resorption in a rat model of periodontitis.

Increase of sympathetic activity has been known to exacerbate osteoporosis through promotion of bone resorption. However, it is largely unknown about involvement of sympathetic activity in exacerbation of periodontitis. In this study, we investigated whether α2-adrenergic receptor (α2-AR) agonist guanabenz which decreases sympathetic activity, attenuates alveolar bone resorption in rats having high sympathetic activity with periodontitis. Volumes of residual alveolar bone and attachment levels in periodontium were examined using micro-computed tomography and hematoxylin-eosin staining, respectively. Furthermore, osteoclast numbers per bone surface and osteoclast surface per bone surface were measured using tartrate-resistant acid phosphatase staining. To examine the suppressive effects of guanabenz on pro-inflammatory cytokines, expression levels of tyrosine hydroxylase (TH), TNF-α, IL1-ß, and IL-6 in periodontium were measured using immunohistostaining. Administration of guanabenz attenuated loss of alveolar bone and attachment levels in rats having high sympathetic activity. Furthermore, its administration suppressed osteoclast numbers in rats having high sympathetic activity. TH, TNF-α, IL-1ß, and IL-6 positive cells in periodontium in rats treated with guanabenz for 12 weeks, were lower than those in control rats having high sympathetic activity. This study demonstrated administration of α2-AR agonist guanabenz attenuates alveolar bone resorption through decrease of sympathetic activity in rats.

Guanabenz and Clonidine, α2-Adrenergic Receptor Agonists, Inhibit Choroidal Neovascularization.

BACKGROUND: Neovascular age-related macular degeneration (AMD) with choroidal neovascularization (CNV) is a leading cause of blindness in elderly people. Anti-vascular endothelial growth factor (anti-VEGF)-drugs are used to treat AMD patients; however, some patients are resistant to these therapies. OBJECTIVE: The purpose of this study was to investigate the anti-angiogenic effects of α2-adrenergic agonists, including guanabenz and clonidine. METHODS: We evaluated the anti-angiogenic effects of α2-adrenergic agonists in human retinal microvascular endothelial cells (HRMECs). A proliferation assay was conducted, and the migration ratio was evaluated. In a laser-induced CNV model, guanabenz and clonidine were delivered via intraperitoneal injection or implantation of an osmotic pump device. Fourteen days following CNV induction, CNV lesion size and fundus fluorescein angiography (FFA) were evaluated. RESULTS: Guanabenz and clonidine inhibited VEGF-induced retinal endothelial cell growth and migration. In the CNV model mice, CNV lesion sizes were reduced by intraperitoneal administration of guanabenz or clonidine. Data, including body weight, systolic blood pressure, and heart rate showed that guanabenz (0.5 and 2.0 mg/kg/day) had little effect on these parameters; conversely, a high dose of clonidine (1.0 mg/kg/day) did affect these parameters. Additionally, clonidine did not affect CNV size, but continuous administration of guanabenz attenuated both CNV size and leakage from neovessels. CONCLUSION: Our study suggests a key role for α2-adrenergic receptors during CNV formation. Therefore, we suggest that α2-adrenergic receptor agonists may represent novel therapeutic drugs for patients with neovascular AMD.

Administration of small-molecule guanabenz acetate attenuates fatty liver and hyperglycemia associated with obesity.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic triglycerides (TG) and hyperglycemia arising due to persistent insulin resistance, and is profoundly linked to obesity. However, there is currently no established treatment for NAFLD in obese human subjects. We previously isolated Helz2, the expression of which was upregulated in human and mouse NAFLD, and its deletion activated the hepatic expression of functional leptin receptor long form (Leprb) and suppressed NAFLD development and body weight (BW) gain in obese mice. A high-throughput assay of small-molecule drugs revealed that guanabenz acetate (Ga), originally used to treat hypertension, possesses a high affinity constant against HELZ2, and its administration activates LEPRB expression in HepG2 cells in vitro. The chronic oral administration of Ga shows the selective leptin sensitization in the liver via upregulation of hepatic Leprb expression, which affects expression of genes involved in lipogenesis and fatty acid ß-oxidation and diminishes hepatocyte hypertrophy with droplets enriched in TG in high-fat diet-induced obese mice. This activity significantly improves insulin resistance to decrease hyperglycemia and hepatocyte and adipocyte weights, resulting in BW reduction without reducing food intake. Regarding drug repositioning, Ga has the potential to effectively treat NAFLD and hyperglycemia in obese patients.

Sephin1 Reduces Prion Infection in Prion-Infected Cells and Animal Model.

Prion diseases are fatal infectious neurodegenerative disorders in human and animals caused by misfolding of the cellular prion protein (PrPC) into the infectious isoform PrPSc. These diseases have the potential to transmit within or between species, and no cure is available to date. Targeting the unfolded protein response (UPR) as an anti-prion therapeutic approach has been widely reported for prion diseases. Here, we describe the anti-prion effect of the chemical compound Sephin1 which has been shown to protect in mouse models of protein misfolding diseases including amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) by selectively inhibiting the stress-induced regulatory subunit of protein phosphatase 1, thus prolonging eIF2α phosphorylation. We show here that Sephin1 dose and time dependently reduced PrPSc in different neuronal cell lines which were persistently infected with various prion strains. In addition, prion seeding activity was reduced in Sephin1-treated cells. Importantly, we found that Sephin1 significantly overcame the endoplasmic reticulum (ER) stress induced in treated cells, as measured by lower expression of stress-induced aberrant prion protein. In a mouse model of prion infection, intraperitoneal treatment with Sephin1 significantly prolonged survival of prion-infected mice. When combining Sephin1 with the neuroprotective drug metformin, the survival of prion-infected mice was also prolonged. These results suggest that Sephin1 could be a potential anti-prion drug selectively targeting one component of the UPR pathway.

Guanabenz Reverses a Key Behavioral Change Caused by Latent Toxoplasmosis in Mice by Reducing Neuroinflammation.

Toxoplasma gondii is an intracellular parasite that has infected one-third of humans. The infection is permanent because the replicative form (tachyzoite) converts into a latent tissue cyst form (bradyzoite) that evades host immunity and is impervious to current drugs. The continued presence of these parasitic cysts hinders treatment and leads to chronic infection that has been linked to behavioral changes in rodents and neurological disease in humans. How these behavioral changes occur, and whether they are due to parasite manipulation or the host response to infection, remains an outstanding question. We previously showed that guanabenz possesses antiparasitic activity; here, we show that guanabenz reproducibly lowers brain cyst burden up to 80% in chronically infected male and female BALB/cJ mice when given intraperitoneally but not when administered by gavage or in food. Regardless of the administration route, guanabenz reverses Toxoplasma-induced hyperactivity in latently infected mice. In contrast, guanabenz increases cyst burden when given to chronically infected C57BL/6J mice yet still reverses Toxoplasma-induced hyperactivity. Examination of the brains from chronically infected BALB/cJ and C57BL/6J mice shows that guanabenz decreases inflammation and perivascular cuffing in each strain. Our study establishes a robust model for cyst reduction in BALB/cJ mice and shows for the first time that it is possible to reverse a key behavioral change associated with latent toxoplasmosis. The rescue from parasite-induced hyperactivity correlates with a decrease in neuroinflammation rather than reduced cyst counts, suggesting that some behavioral changes arise from host responses to infection.IMPORTANCEToxoplasma gondii is a common parasite of animals, including up to one-third of humans. The single-celled parasite persists within hosts for the duration of their life as tissue cysts, giving rise to chronic infection. Latent toxoplasmosis is correlated with neurological dysfunction in humans and results in dramatic behavioral changes in rodents. When infected, mice and rats adapt behaviors that make them more likely to be devoured by cats, the only host that supports the sexual stage of the parasite. In this study, we establish a new mouse model of tissue cyst depletion using a drug called guanabenz and show that it is possible to reverse a key behavior change back to normal in infected animals. We also show that the mechanism appears to have nothing to do with parasite cyst burden but rather the degree of neuroinflammation produced by chronic infection.

Modulation of α-adrenoceptor signalling protects photoreceptors after retinal detachment by inhibiting oxidative stress and inflammation.

BACKGROUND AND PURPOSE: Currently available treatments do not halt progression of photoreceptor death and subsequent visual impairment related to retinal detachment (RD) which is observed in various retinal disorders. This study investigated the neuroprotective effects of two adrenoceptor ligands, the α1 -adrenoceptor antagonist doxazosin and the α2 -adrenoceptor agonist guanabenz, against photoreceptor cell death in RD. EXPERIMENTAL APPROACH: We used a model of experimental RD in Brown-Norway rats induced by subretinal injection of sodium hyaluronate. Oxidative stress biomarkers and cytokine production were quantified with elisa. Protein expression levels and immunofluorescent labelling were determined in rats with RD and controls for mechanistic elucidation. The effects of systemic (i.p.) administration of doxazosin or guanabenz on photoreceptor apoptosis, retinal histology and electroretinography were evaluated in rats with RD and compared to the effects in vehicle controls. KEY RESULTS: Photoreceptors were the major source of RD-induced ROS overproduction in the rat retina through the regulation of NADPH oxidase. Systemic administration of doxazosin or guanabenz decreased the RD-induced production of ROS and proinflammatory cytokines, including IL-1ß and the chemokine CCL2, and suppressed retinal gliosis, resulting in attenuation of photoreceptor death and preservation of retinal structures and functions in RD. CONCLUSIONS AND IMPLICATIONS: Our findings point to α-adrenoceptors as novel therapeutic targets to provide photoreceptor protection and suggest that both doxazosin and guanabenz, two FDA-approved drugs, could be further explored to treat retinal diseases.

Inhibition of Eukaryotic Initiation Factor 2 Alpha Phosphatase Reduces Tissue Damage and Improves Learning and Memory after Experimental Traumatic Brain Injury.

Patients who survive traumatic brain injury (TBI) are often faced with persistent memory deficits. The hippocampus, a structure critical for learning and memory, is vulnerable to TBI and its dysfunction has been linked to memory impairments. Protein kinase RNA-like ER kinase regulates protein synthesis (by phosphorylation of eukaryotic initiation factor 2 alpha [eIF2α]) in response to endoplasmic reticulum (ER) stressors, such as increases in calcium levels, oxidative damage, and energy/glucose depletion, all of which have been implicated in TBI pathophysiology. Exposure of cells to guanabenz has been shown to increase eIF2α phosphorylation and reduce ER stress. Using a rodent model of TBI, we present experimental results that indicate that postinjury administration of 5.0 mg/kg of guanabenz reduced cortical contusion volume and decreased hippocampal cell damage. Moreover, guanabenz treatment attenuated TBI-associated motor, vestibulomotor, recognition memory, and spatial learning and memory dysfunction. Interestingly, when the initiation of treatment was delayed by 24 h, or the dose reduced to 0.5 mg/kg, some of these beneficial effects were still observed. Taken together, these findings further support the involvement of ER stress signaling in TBI pathophysiology and indicate that guanabenz may have translational utility.

Attenuation of malignant phenotypes of breast cancer cells through eIF2α-mediated downregulation of Rac1 signaling.

Blocking dephosphorylation of eukaryotic translation initiation factor 2α (eIF2α) is reported to alter proliferation and differentiation of various cells. Using salubrinal and guanabenz as an inhibitory agent of dephosphorylation of eIF2α, we addressed a question whether an elevated level of phosphorylated eIF2α attenuates malignant phenotypes of triple negative breast cancer cells (TNBCs) that lack estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2. We determined effects of salubrinal and guanabenz on in vitro phenotype of 4T1 mammary tumor cells and MDA-MB-231 human breast cancer cells and evaluated their effects on in vivo tumor growth using BALB/c mice injected with 4T1 cells. The results revealed that these agents block the proliferation and survival of 4T1 and MDA-MB-231 cells, as well as their invasion and motility. Silencing eIF2α revealed that eIF2α is involved in the reduction in invasion and motility. Furthermore, salubrinal-driven inactivation of Rac1 was suppressed in the cells treated with eIF2α siRNA, and treatment with Rac1 siRNA reduced cell invasion and motility. In vivo assay revealed that subcutaneous administration of salubrinal reduced the volume and weight of tumors induced by 4T1 cells. Collectively, the results indicate that these agents can attenuate malignant phenotype and tumor growth of breast cancer cells through the eIF2α-mediated Rac1 pathway. Since salubrinal and guanabenz are known to inhibit bone resorption, this study provides a potential use of eIF2α-mediated Rac1 regulation in suppressing the growth and metastasis of breast cancer.

Functional selectivity of central Gα-subunit proteins in mediating the cardiovascular and renal excretory responses evoked by central α(2) -adrenoceptor activation in vivo.

BACKGROUND AND PURPOSE: Activation of brain α(2) -adrenoceptors in conscious rodents decreases heart rate (HR) and mean arterial blood pressure (MAP) and increases urine output and urinary sodium excretion. In vitro, α(2) -adrenoceptor stimulation activates Gα(i(1-3)) , Gα(o) and Gα(s) -subunit protein-gated signal transduction pathways. Here we have investigated whether these same Gα-subunit protein-gated pathways mediate the cardiovascular and renal excretory responses to central α(2) -adrenoceptor activation in conscious Sprague-Dawley rats. EXPERIMENTAL APPROACH: Rats were pre-treated by intracerebroventricular injection (i.c.v.) with an oligodeoxynucleotide (ODN) targeted to a Gα(i1) , Gα(i2) , Gα(i3) , Gα(o) , Gα(s) or a scrambled (SCR) ODN sequence (25 µg, 24 h). On the day of study, the α(2) -adrenoceptor agonist guanabenz (50 µg) or saline vehicle, was injected i.c.v. into ODN-pre-treated conscious rats. MAP and HR were recorded, and urine was collected for 150 min. KEY RESULTS: In vehicle- and SCR ODN-pre-treated rats, i.c.v. guanabenz decreased MAP and HR, and produced marked diuretic and natriuretic responses. Selective ODN-mediated down-regulation of brain Gα(i2) -subunit proteins abolished the central guanabenz-induced hypotension and natriuresis. In contrast, following selective Gα(s) down-regulation, the characteristic hypotensive response to i.c.v. guanabenz was converted to an immediate increase in MAP. The bradycardic and diuretic responses to i.c.v. guanabenz were not blocked by pre-treatment with any ODN. CONCLUSIONS AND IMPLICATIONS: There was functional selectivity of Gα(i2) and Gα(s) subunit protein-gated signal transduction pathways in mediating the hypotensive and natriuretic, but not bradycardic or diuretic, responses evoked by central α(2) -adrenoceptor activation in vivo.

Allergic lung inflammation affects central noradrenergic control of cholinergic outflow to the airways in ferrets.

Brain stem noradrenergic cell groups mediating autonomic responses to stress project to airway-related vagal preganglionic neurons (AVPNs). In ferrets, their activation produces withdrawal of cholinergic outflow to the airways via release of norepinephrine and activation of alpha(2A)-adrenergic receptors (alpha(2A)-AR) expressed by AVPNs. In these studies, we examined the effects of allergen exposure of the airway (AE) with ovalbumin on noradrenergic transmission regulating the activity of AVPNs and, consequently, airway smooth muscle tone. Experiments were performed in vehicle control (Con) and AE ferrets. Microperfusion of an alpha(2A)-AR agonist (guanabenz) in close proximity to AVPNs elicited more pronounced effects in Con than AE ferrets, including a decrease in unit activity and reflexly evoked responses of putative AVPN neurons with a corresponding decrease in cholinergic outflow to the airways. Although no differences were found in the extent of noradrenergic innervation of the AVPNs, RT-PCR and Western blot studies demonstrated that AE and repeated exposure to antigen significantly reduced expression of alpha(2A)-ARs at message and protein levels. These findings indicate that, in an animal model of allergic asthma, sensitization and repeated challenges with a specific allergen diminish central inhibitory noradrenergic modulation of AVPNs, possibly via downregulation of alpha(2A)-AR expression by these neurons.

The detection and biotransformation of guanabenz in horses: a preliminary report.

Guanabenz (2,6-dichlorobenzylidene-amino-guanidine) is a centrally acting antihypertensive drug whose mechanism of action is via alpha2 adrenoceptors or, more likely, imidazoline receptors. Guanabenz is marketed as an antihypertensive agent in human medicine (Wytensin tablets, Wyeth Pharmaceuticals). Guanabenz has reportedly been administered to racing horses and is classified by the Association of Racing Commissioners International as a class 3 foreign substance. As such, its identification in a postrace sample may result in significant sanctions against the trainer of the horse. The present study examined liquid chromatographic/tandem quadrupole mass spectrometric (LC-MS/MS) detection of guanabenz in serum samples from horses treated with guanabenz by rapid i.v. injection at 0.04 and 0.2 mg/kg. Using a method adapted from previous work with clenbuterol, the parent compound was detected in serum with an apparent limit of detection of approximately 0.03 ng/ml and the limit of quantitation was 0.2 ng/ml. Serum concentrations of guanabenz peaked at approximately 100 ng/ml after the 0.2 mg/kg dose, and the parent compound was detected for up to 8 hours after the 0.04 mg/kg dose. Urine samples tested after administration of guanabenz at these dosages yielded evidence of at least one glucuronide metabolite, with the glucuronide ring apparently linked to a ring hydroxyl group or a guanidinium hydroxylamine. The LC-MS/MS results presented here form the basis of a confirmatory test for guanabenz in racing horses.

Therapeutic effects of evening administration of guanabenz and clonidine on morning hypertension: evaluation using home-based blood pressure measurements.

OBJECTIVE: To clarify the effects of bedtime administration of the centrally acting alpha(2)-agonists, guanabenz and clonidine, on morning hypertension. METHODS: Patients with morning hypertension were assigned to receive once-daily evening administration of guanabenz (2 mg/day, n = 81; 4 mg/day, n = 2) or clonidine (75 microg/day, n = 40; 150 microg/day, n = 10) for 4 weeks, and the blood pressure (BP)-lowering effects of these drugs in the morning and evening were evaluated by assessing self-monitored BP in the home environment. The subjects were then subdivided into different groups according to their evening BP, and the effects of guanabenz and clonidine on evening BP were evaluated further for each group. In addition, as a substitute for the trough/peak ratio, the evening/morning (E/M) ratio was calculated to assess the duration of action of the two alpha(2)-agonists. RESULTS: Evening dosing with guanabenz or clonidine lowered morning BP significantly. Both drugs decreased evening BP in the subgroup of subjects with a high evening BP, but not in those with a normal evening BP. The individual E/M ratios for guanabenz, but not for clonidine, were significantly greater in those with a high evening BP than in those with a normal evening BP. In the early treatment period, treatment with guanabenz resulted in a higher diastolic E/M ratio in those subjects with a high evening diastolic BP than did treatment with clonidine. CONCLUSION: The results suggest that evening administration of the central alpha(2)-agonists guanabenz and clonidine effectively suppresses the morning BP elevation in treated hypertensive patients.

Alpha-2 adrenergic receptor agonists block stress-induced reinstatement of cocaine seeking.

The alpha-2 adrenergic receptor agonists, clonidine, lofexidine and guanabenz, blocked stress- but not cocaine-induced reinstatement of cocaine seeking at doses that suppressed footshock-induced release of noradrenaline in prefrontal cortex and amygdala. Rats were trained to self-administer cocaine (0.5 mg/kg/infusion, i.v; 10-12 days) and, after a drug-free period (7-13 days), were returned to the self-administration chambers for daily extinction and reinstatement test sessions. Both intermittent footshock (15 min, 0.6 mA) and cocaine priming (20 mg/kg, i.p.) reinstated extinguished drug seeking. Pretreatment with either clonidine (20, or 40 microg/kg, i.p.) or lofexidine (50, 100, 150, or 200 microg/kg, i.p.) attenuated footshock- but not cocaine-induced reinstatement of cocaine seeking. Guanabenz (640 microg/kg, i.p.), an alpha-2 agonist with low affinity for imidazoline type-1 receptors, also attenuated footshock- but not cocaine-induced reinstatement of cocaine seeking. The results point to an important role for NE systems in the effects of footshock on relapse to cocaine seeking.

Influence of arterial baroreceptors and intracerebroventricular guanabenz on synchronized renal nerve activity.

The contributions of changes in the number of active fibres and the peak interval of synchronized neural discharges to arterial baroreflex regulated alterations in renal sympathetic nerve activity were examined in intact conscious rats. Stimulation of central nervous system alpha 2 adrenoreceptors with intracerebroventricular guanabenz (10, 20, 40 micrograms) was used to alter renal sympathetic nerve activity by a non-reflex mechanism in both intact and sinoaortic denervated (SAD) rats. Synchronized renal sympathetic nerve discharge was analysed with the sympathetic peak detection algorithm. When arterial pressure was increased from 50 mmHg to 150 mmHg in intact rats, the peak height (number of simultaneously active fibres) of synchronized discharges decreased in a sigmoidal fashion while the peak interval remained unchanged. Guanabenz produced a dose dependent inhibition of renal sympathetic nerve activity due to both a decrease in peak height and an increase in peak interval of synchronized discharges in both intact and SAD rats. Arterial baroreflex mediated changes in renal sympathetic nerve activity are due to changes in the number of simultaneously active nerve fibres. Central nervous system alpha 2 adrenoreceptor stimulation decreases renal sympathetic nerve activity by decreasing the number of active fibres and increasing the peak interval, acting on additional neural pathways not involved in buffering acute arterial pressure changes.

Metabolism-based inactivation of penile nitric oxide synthase activity by guanabenz.

Guanabenz (Wytensin) was shown to inactivate nitric oxide synthase (NOS) activity in vitro and in vivo. In in vitro studies with the use of a cytosolic fraction from penile tissue, the inactivation was found to depend on NADPH, time, and the concentration of guanabenz. The L-, but not the D-, isomer of arginine could protect from the inactivation, suggesting an active site-directed event. The kinetics of inactivation could be described by an apparent dissociation constant for the initial reversible complex (Ki) and a pseudo first-order inactivation constant (kinact) of 38.5 microM and 0.179 min-1, respectively. In in vivo studies, guanabenz was shown to inhibit penile cytosolic NOS activity in a dose- and time-dependent manner. Treatment of rats with guanabenz (5 mg/kg/day) for 4 days caused a decrease of approximately one-half in the NOS activity of the penile cytosolic fraction with a concomitant loss in the amount of immunodetectable NOS protein. Treatment for 4 days at a dose of 0. 5 mg/kg/day showed a similar decrease in activity, whereas a dose of 0.05 mg/kg/day showed no effects. Due to the multitude of processes that are regulated by NO, the inactivation of NOS is a potential mechanism to be considered in a variety of biological effects associated with drugs.

Differential effects of rANF and chronic guanabenz to presynaptic and postsynaptic alpha 2-adrenoceptor-mediated cardiovascular response in pithed rats.

1. In normal rats, intracerebroventricular (i.c.v.) guanabenz induced a decrease in blood pressure (BP) and heart rate (HR), and this hypotension or bradycardia was not changed by rANF pretreatment (3 micrograms i.c.v.). 2. In pithed rats, intravenous (i.v.) guanabenz, an alpha 2-adrenoceptor agonist, produced an increase in mean blood pressure (MBP) in a dose-dependent manner. The pressor response by guanabenz was attenuated by infusion of rANF. This attenuation was additive when incubated in combination with yohimbine. 3. In pithed rats, the pressor response due to the increase of sympathetic outflow with electrical stimulation was partially blocked by rANF infusion or chronic guanabenz treatment. This reduction was not augmented by chronic guanabenz plus rANF treatment. 4. The inhibitory action of guanabenz in tachycardia evoked by electrical stimulation at the C7-T1 site was attenuated by rANF, but not by chronic treatment with guanabenz.

Substance P suppresses the activity of alpha 2-adrenoceptors of the nucleus reticularis gigantocellularis involved in cardiovascular regulation in the rat.

We evaluated possible interactions between substance P (SP) and the alpha 2-adrenoceptors in the nucleus reticularis gigantocellularis (NRGC) of the medulla oblongata involved in cardiovascular regulation. Adult, male Sprague-Dawley rats anesthetized with pentobarbital sodium (40 mg/kg, i.p., with 10 mg/kg/h i.v. supplements) were used. The circulatory suppressant efficacy of a centrally acting alpha 2-adrenoceptor agonist, guanabenz, was used as the experimental index. Bilateral microinjection of SP (300 or 600 pmol) into the NRGC, a medullary site that is critically involved in the cardiovascular depressive actions of guanabenz, significantly diminished the hypotensive and bradycardiac efficacy of the aminoguanidine compound (100 micrograms/kg, i.v.). This implied reduction in alpha 2-adrenoceptor activity in the NRGC by SP was antagonized by its selective receptor antagonist, [D-Pro2,D-Trp7,9]-SP (1200 pmol). Similarly, attenuation by SP of the cardiovascular suppressant effects of guanabenz was also reversed by immunocytochemically verified depletion of dopamine-beta-hydroxylase-immunoreactive nerve terminals in the NRGC, elicited by the selective noradrenergic neurotoxin, DSP4 (50 micrograms). These data suggest that SP may exert an inhibitory action on the alpha 2-adrenoceptors in the NRGC that are involved in central cardiovascular regulation, possibly via a presynaptic modulation on noradrenergic neurotransmission.

Attenuation of the cardiovascular and catecholamine responses to tracheal intubation with oral guanabenz.

We conducted a randomized, placebo-controlled, and double-blind study to evaluate the efficacy of oral guanabenz, an alpha 2-adrenergic agonist, in attenuating the cardiovascular and catecholamine responses to laryngoscopy and tracheal intubation in 30 normotensive (ASA physical status 1) patients undergoing elective surgery. They were allocated to one of three groups (n = 10 for each): placebo, 4 mg, or 6 mg of guanabenz groups. These tablets were administered 2 h before the induction of anesthesia. Anesthesia was induced with thiopental 5.0 mg/kg intravenously (IV), and tracheal intubation was facilitated by the administration of vecuronium, 0.2 mg/kg IV. During anesthesia, ventilation was assisted or controlled with 1% enflurane and 50% nitrous oxide in oxygen. Laryngoscopy lasting 30 s was attempted 2 min after the administration of thiopental and vecuronium. Patients receiving placebo showed a significant increase in mean arterial blood pressure, heart rate, and plasma catecholamine concentrations in response to tracheal intubation. These changes were significantly smaller in patients receiving either dose of guanabenz (P < 0.05). Oral administration of guanabenz before induction of anesthesia is a simple and effective method for attenuating the pressor and tachycardic responses to laryngoscopy and tracheal intubation with the drug acting at least partly via inhibition of the increases in plasma catecholamines concentrations.