Effects of in vitro, acute and chronic treatment with fluoxetine on the sympathetic neurotransmission of rat vas deferens.

It is described that fluoxetine treatment is able to induce ejaculatory disorders. However, the exact mechanism is still not fully understood. Therefore, this study was carried out to further evaluate the anti-ejaculatory effects of fluoxetine, using different approaches (in vitro or in vivo treatments), on the sympathetic neurotransmission of the rat vas deferens. Vas deferens from male Wistar rats were used to check the in vitro effects of fluoxetine 10-6M, 3.10-6M or 10-5M. Animals were also acutely (20mg/kg, i.p. 4h or 24h) or chronically (10mg/kg, i.p., 30days) treated with fluoxetine or drug-free vehicle. The vas deferens from non-treated and treated animals were isolated and mounted in an isolated organ bath for the study of the contractions induced by adrenergic agonists, tyramine, 5-HT, Ca2+ or electrical field stimulation. In vitro or acute treatment with fluoxetine decreased the contraction induced by agonists, Ca2+ or electrical field stimulation. The chronic treatment with fluoxetine decreased the contractions induced agonists, tyramine or Ca2+, but did not modify the contractions induced by electrical field stimulation. We have shown that in vitro or in vivo fluoxetine treatment is able to alter the sympathetic neurotransmission of the rat vas deferens which could be related to alterations in the calcium signalling.

Reduction of motor disorder in 6-OHDA-induced severe parkinsonism rats by post treatment with granulocyte-colony stimulating factor.

Granulocyte-colony stimulating factor (G-CSF) induced regeneration of dopaminergic neurons and improved behavior deficit in moderate Parkinson's disease (PD) model mice. Post treatment of G-CSF in severe PD model has not been addressed. A very severe PD model in rats was induced by a high dose 6-hydroxydopamine (6-OHDA) injected into the right medial forebrain bundle to evaluate therapeutic effects of G-CSF. G-CSF (50 microg/kg/day for five days) was given on the 9th day after the 6-OHDA injection. Rotational behavior was examined on the 9th and 28th days. Rats were killed on the 28th day and survival dopaminergic neurons in the substantia nigra, dopaminergic axons and dopaminergic receptor 2 in the striatum were examined. We, for the first time, demonstrated that post treatment with G-CSF reduced abnormal rotational behavior and increased the lesion to non-lesion ratio of dopaminergic fibers in the striatum, but the treatment promoted neither the increase in survival dopaminergic neurons nor the increase in dopaminergic receptor 2 expression. We conclude that post treatment with G-CSF can reduce the abnormal rotational behavior of severe PD rats primarily through relative increases in dopaminergic fibers of the lesion side in the striatum. Results of our study suggest therapeutic potentials of G-CSF for treating severe PD patients.

Complex fractionated electrograms in the right atrial free wall and the superior/posterior wall of the left atrium are affected by activity of the autonomic nervous system.

BACKGROUND: Complex fractionated atrial electrograms (CFAEs) are supposed to be related to structural and electrical remodeling. Animal studies suggest a role of the autonomic nervous system (ANS). However, this has never been studied in humans. OBJECTIVE: The goal of this study was to investigate the influence of ANS on CFAEs in patients with idiopathic atrial fibrillation (AF). METHODS: Thirty-six patients (28 men, 55 ± 9 years) were included before undergoing catheter ablation. In the 24 hours preceding the procedure, 20 patients were in AF (group 1) and 16 were in sinus rhythm (SR, group 2). With 2 decapolar catheters, 1 in the right atrium (RA) and 1 in the left atrium (LA), 20 unipolar electrograms were simultaneously recorded during a 100-second AF-period (in group 2 after induction of AF). After atropine and metoprolol administration, a second 100-second AF-period was recorded 30 minutes later. Five patients of group 2 served as controls and did not receive atropine and metoprolol prior to the second recording. CFAEs were assessed and the prevalence of CFAEs was expressed as percentage of the recording time. RESULTS: The prevalence of CFAEs was greater in group 1 than in group 2 in both RA and LA (P = 0.026, P < 0.001, respectively). Atropine and metoprolol significantly reduced CFAEs in group 1 (P < 0.001) and prevented the time-dependent increase of CFAEs in group 2. CONCLUSION: The prevalence of CFAEs is greater in long-lasting AF episodes. Atropine and metoprolol administration reduces CFAEs in both atria. Thus, CFAEs are at least partly influenced by the ANS.

Antagonizing L-type Ca2+ channel reduces development of abnormal involuntary movement in the rat model of L-3,4-dihydroxyphenylalanine-induced dyskinesia.

BACKGROUND: Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) leads to debilitating involuntary movements, termed L-DOPA-induced dyskinesia. Striatofugal medium spiny neurons (MSN) lose their dendritic spines and cortico-striatal glutamatergic synapses in PD and in experimental models of DA depletion. This loss of connectivity is triggered by a dysregulation of intraspine Cav1.3 L-type Ca2+ channels. Here we address the possible implication of DA denervation-induced spine pruning in the development of L-DOPA-induced dyskinesia. METHODS: The L-type Ca2+ antagonist, isradipine was subcutaneously delivered to rats at the doses of .05, .1, or .2 mg/kg/day, for 4 weeks, starting the day after a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion. Fourteen days later, L-DOPA treatment was initiated. RESULTS: Isradipine-treated animals displayed a dose-dependent reduction in L-DOPA-induced rotational behavior and abnormal involuntary movements. Dendritic spine counting at electron microscopy level showed that isradipine (.2 mg/kg/day) prevented the 6-OHDA-induced spine loss and normalized preproenkephalin-A messenger RNA expression. Involuntary movements were not reduced when isradipine treatment was started concomitantly with L-DOPA. CONCLUSIONS: These results indicate that isradipine, at a therapeutically relevant dose, might represent a treatment option for preventing L-DOPA-induced dyskinesia in PD.

Trichopus zeylanicus combats fatigue without amphetamine-mimetic activity.

Chronic fatigue is a complex and little understood symptom for which there is no safe and effective pharmacotherapy. The present study was conducted to investigate the effectiveness of Trichopus zeylanicus whole plant powder on fatigue in young Sprague Dawley rats, and aged normal and long-living mutant Ames dwarf mice. Fatigue was evaluated by subjecting the animals to a forced swim test. Trichopus zeylanicus (250 and 500 mg/kg) treated young Sprague-Dawley rats resisted fatigue at a significant level (p < 0.005) compared with controls by an extended swim time in the forced swim test. Oral Trichopus zeylanicus (500 mg/kg) treatment for 2 weeks significantly increased the mobility time in the aged mutant (p < 0.05) and normal mice (p < 0.01) and significantly increased the swim time in the forced swim test in the aged normal mice (p < 0.05). Amphetamine-mimetic activity in Trichopus zeylanicus was excluded by suitable tests. These results show that Trichopus zeylanicus whole plant powder has anti-fatigue effects in young Sprague-Dawley rats and aged normal and mutant Ames dwarf mice providing scientific evidence for the Kani tribal practice in India.

Clonidine injections into the lateral nucleus of the amygdala block acquisition and expression of fear-potentiated startle.

Numerous studies of aversive learning with different animal models have shown that the noradrenergic system has an important role in the acquisition, consolidation and expression of aversive learning. We used intracerebral clonidine injections to investigate the role of the noradrenergic amygdaloid system in the fear-potentiated startle paradigm. Clonidine is a noradrenergic alpha2-receptor agonist which can decrease noradrenergic transmission by stimulating presynaptic alpha2-receptors. Rats received injections of 0, 2.5, 5 and 10 nmol clonidine into the lateral amygdala (i) before fear-conditioning, (ii) immediately after fear-conditioning, (iii) before testing and (iv) before both fear-conditioning and the testing of conditioned fear. Clonidine injections blocked the acquisition and expression of conditioned fear. The effect on acquisition was not caused by state-dependency or possible side-effects of clonidine on consolidation. Given that clonidine decreases amygdaloid noradrenaline release, these results show a crucial role of noradrenergic transmission within the amygdala in classical fear-conditioning. Surprisingly, both the acquisition and the expression of conditioned fear were blocked after amygdaloid injections of clonidine, suggesting that amygdaloid noradrenaline is necessary to induce both unconditioned and conditioned fear.

Effects of selective autonomic blockade on T-wave alternans in humans.

BACKGROUND: T-wave alternans (TWA) is an important noninvasive measure of ventricular arrhythmia vulnerability. This study tested the hypothesis that the autonomic nervous system influences TWA measurement in high-risk subjects with coronary artery disease. METHODS AND RESULTS: T-wave alternans was measured in 60 patients with coronary artery disease, left ventricular dysfunction, and inducible sustained ventricular tachycardia during electrophysiological studies. All patients had TWA measured at baseline with atrial pacing at 100 bpm (600 ms), 109 bpm (550 ms), and 120 bpm (500 ms). After a 10-minute recovery period, TWA was measured again after sympathetic blockade (esmolol, n=20), parasympathetic blockade (atropine, n=20), or no intervention (control subjects, n=20). The prevalence of significant TWA was unchanged compared with baseline after atropine infusion and in the control group. In contrast, the amplitude of TWA in the vector magnitude lead was significantly reduced after esmolol infusion (P<0.001), and the number of positive TWA tests was reduced by 50% (70% versus 35%, P<0.05). CONCLUSIONS: Our findings have important implications for the use of TWA to risk-stratify patients for life-threatening ventricular arrhythmias and provide a new potential mechanism for the reduction in sudden cardiac death conferred by beta-blockers among patients with coronary artery disease and congestive heart failure.

In vivo electrophysiologic studies in endothelial nitric oxide synthase (eNOS)-deficient mice.

INTRODUCTION: Endothelial nitric oxide synthase (eNOS) mediates attenuation of the L-type calcium channel and modulates myocyte contractility. Arrhythmogenic afterdepolarizations are seen in vitro in ouabain-treated isolated myocytes from eNOS-deficient mice. The aim of these studies was to characterize the baseline electrophysiologic (EP) phenotype of eNOS-deficient mice and their potential susceptibility to cardiac conduction abnormalities and inducible arrhythmias. METHODS AND RESULTS: Surface ECG and in vivo intracardiac EP studies were performed in 27 mice lacking the eNOS gene and 21 wild-type littermate control mice. Baseline studies were performed in 10 eNOS-deficient mice and 10 wild-type controls. Subsequently, 17 eNOS-deficient mice and 11 wild-type controls were pretreated with digoxin, and ECG and EP testing were repeated. Data analysis revealed no significant differences in ECG intervals or cardiac conduction parameters, except sinus cycle length was higher in eNOS-deficient mice than wild-type mice (P < 0.01). After digoxin pretreatment, 7 of 17 eNOS-deficient mice had inducible ventricular tachycardia and 2 others had frequent ventricular premature beats, compared with only 3 of 11 wild-type mice with inducible ventricular tachycardia. In addition, 2 digoxin-treated eNOS-deficient mice and 1 wild-type mouse had inducible nonsustained atrial fibrillation. CONCLUSION: Mice with a homozygous targeted disruption of the eNOS gene have slower heart rates but no other distinguishable EP characteristics under basal sedated conditions. Partial inhibition of the Na+/K+ ATPase pump with digoxin administration increases ventricular ectopic activity in eNOS-/- mice, a phenotype analogous to afterdepolarizations seen in vitro in this eNOS-deficient mouse model.

The effects of intrinsic nitric oxide on cardiac neural regulation in cats.

UNLABELLED: In this study, we aimed to elucidate the effects of intrinsic nitric oxide (NO) on cardiac neural regulation. Twenty-two cats were anesthetized with 1.5% isoflurane and allocated to Group I (intact; n = 7), Group D (denervated baroreceptors and vagi; n = 8), or Group B (autonomic blockade with i.v. hexamethonium, propranolol, and atropine; n = 7). Cardiac sympathetic nerve activity (CSNA), mean arterial pressure (MAP), sinus heart rate (HR), and A-H and H-V intervals during pacing (150 bpm) were measured before and after i.v. administration of a NO synthase inhibitor, NG-nitro-L-arginine (L-NNA, 30 mg/kg) and after reversal with an excessive dose of L-arginine (300 mg/kg), before and during intermittent electrical stimulation of the posterior hypothalamus. L-NNA significantly increased MAP in Groups I and B, but not in Group D. L-NNA significantly decreased HR and lengthened A-H in Group I, but not in other groups. L-arginine further decreased HR and lengthened A-H unexpectedly. The reasons for these findings could not be determined in this study. L-NNA did not change CSNA. Hypothalamic stimulation did not potentiate L-NNA-induced changes in CSNA, hemodynamic variables, and atrioventricular conduction. In conclusion, intrinsic NO may modulate atrioventricular conduction and sinus rate through a vagal cholinergic, rather than a nonautonomic mechanism. IMPLICATIONS: Elucidating the roles of intrinsic nitric oxide (NO) on cardiac neural regulation is important. In intact, vagotomized, and baroreceptor-denervated or pharmacologically autonomic blockaded cats, an NO synthesis inhibitor was administered, and atrioventricular conduction and cardiac sympathetic neural discharge were measured. The results suggest a vagal cholinergic mechanism of intrinsic NO.

Analysis of 50 patients with atypical odontalgia. A preliminary report on pharmacological procedures for diagnosis and treatment.

Atypical odontalgia is a distressing and unusual chronic orofacial pain condition. It is often difficult to diagnose because it is associated with a lack of clinical and radiographic abnormalities. The condition is poorly understood on a pathophysiological basis, and patients often undergo repetitive and unnecessary dental procedures in attempts to alleviate pain. In this study, 50 patients diagnosed with odontalgia were evaluated by pharmacological procedures, including topical anesthetic application and phentolamine infusion. Results of these pharmacological procedures suggest that atypical odontalgia is a neuropathic pain of the oral cavity that may have a component of sympathetically maintained pain. Therapeutic trials of topical capsaicin were carried out to assess its efficacy for pain reduction. Topical capsaicin was effective in most patients.

Decreased heart rate by acupuncture stimulation in humans via facilitation of cardiac vagal activity and suppression of cardiac sympathetic nerve.

The effect of acupuncture stimulation applied to a Ximen point (P4) of a forearm on heart rate was studied in healthy volunteer human subjects. Acupuncture stimulation decreased heart rate, or gave no significant response. The decreased response of heart rate following acupuncture was attenuated by administration of atropine and propranolol. Therefore, the acupuncture-induced response of decrease in heart rate was concluded to be a result of a reciprocal coordination of an increase in cardiac vagal activity and a decrease in cardiac sympathetic activity.

Current management of the neonatal abstinence syndrome: a critical analysis of the evidence.

OBJECTIVE: To systematically and critically analyse and summarise the published evidence for the rational choice of pharmacologic treatment of the neonatal abstinence syndrome (NAS), a frequently observed condition in neonates born to mothers who are dependent on physically addicting drugs. DESIGN: Studies comparing different pharmacological agents for the treatment of NAS were identified utilising MEDLINE and additionally the references cited in pertinent articles. The identified studies were critically analysed regarding their study designs and outcome measures. The reported data for the comparative efficacy of the drugs were summarised and evaluated. RESULTS: Fourteen studies were identified, most of them comparing treatment of NAS with phenobarbital, paregoric or diazepam. However, none of these studies was conducted in a double-blind fashion. Frequently, treatment allocations were not properly randomised. Prenatal drug exposure varied and was often not sufficiently verified. Outcome measures and their evaluations differed widely. Due to the different study objectives and flaws in study design, a combined analysis of the published data in the form of a meta-analysis was not deemed possible. When attempting to compare efficacy, diazepam appears to be less efficacious in treating NAS than phenobarbital or paregoric. The relative efficacy of paregoric and phenobarbital appears to depend upon the antenatal exposure of the neonate and on the outcome measure of the study. Only two studies evaluate the efficacy of pure opioids, none of them in direct comparison to paregoric. It remains questionable whether paregoric, which contains the central stimulant camphor and a large amount of alcohol, should be the opioid of choice for the treatment of NAS. CONCLUSION: Most published studies were conducted prior to the development of clinical epidemiology and modern study design and thus yielded only very limited comparative data on the benefits of different treatment protocols. There is very little evidence regarding the efficacy of different pharmacological therapy regimens to treat NAS. More studies are required to produce the evidence needed to allow a rational choice between treatment modalities of NAS and thus to ensure optimal care of the neonates suffering from this condition.

[Differential approach to restoring motor function of the intestines in peritonitis]. / Differentsirovannyi podkhod k vosstanovleniiu motornoi funktsii kishechnika pri peritonite.

The authors have made a comparative estimation of the effectiveness of different methods of treatment of 330 patients with peritonitis with special reference to subdivision of motor disorders into 4 stages (compensated, subcompensated, decompensated stages and enteroplegia). It was established that sympatholytic drugs and continuous peridural anesthesia were effective in the compensated stage. Continuous intubation of the gastro-intestinal tract with the help of a rigid probe ensuring decompression in the postoperative period was the operation of choice in decompensated disturbances of the motor-evacuatory function.

The efficacy and safety of long-term antihypertensive therapy with nifedipine.

The antihypertensive effect and safety of long-term therapy with nifedipine were evaluated in 132 hypertensive patients, including 100 aged patients who received nifedipine alone or with other antihypertensive agents for a mean duration of 28.6 months. A prompt hypotensive effect was observed 1 month after the initiation of nifedipine therapy. The hypotensive effect persisted for the entire follow-up period and was related to the pretreatment mean blood pressure level. Late drug tolerance was not observed. Dizziness, facial flushing and other unpleasant sensations were observed in 7.5% and ankle edema in 9.8% of the patients. The therapy did not significantly influence serum creatinine levels. Hypotension and side effects were the cause of discontinuation in 10.6% and 4.5% of patients, respectively. We conclude that long-term antihypertensive therapy with nifedipine is both effective and safe, not only in adult patients but also in the high-risk aged patient.