Modulation of the heart's electrical properties by the anticonvulsant drug retigabine.

Retigabine, currently used as antiepileptic drug, has a wide range of potential medical uses. Administration of the drug in patients can lead to QT interval prolongation in the electrocardiogram and to cardiac arrhythmias in rare cases. This suggests that the drug may perturb the electrical properties of the heart, and the underlying mechanisms were investigated here. Effects of retigabine on currents through human cardiac ion channels, heterologously expressed in tsA-201 cells, were studied in whole-cell patch-clamp experiments. In addition, the drug's impact on the cardiac action potential was tested. This was done using ventricular cardiomyocytes isolated from Langendorff-perfused guinea pig hearts and cardiomyocytes derived from human induced pluripotent stem cells. Further, to unravel potential indirect effects of retigabine on the heart which might involve the autonomic nervous system, membrane potential and noradrenaline release from sympathetic ganglionic neurons were measured in the absence and presence of the drug. Retigabine significantly inhibited currents through hKv11.1 potassium, hNav1.5 sodium, as well as hCav1.2 calcium channels, but only in supra-therapeutic concentrations. In a similar concentration range, the drug shortened the action potential in both guinea pig and human cardiomyocytes. Therapeutic concentrations of retigabine, on the other hand, were sufficient to inhibit the activity of sympathetic ganglionic neurons. We conclude that retigabine- induced QT interval prolongation, and the reported cases of cardiac arrhythmias after application of the drug in a typical daily dose range, cannot be explained by a direct modulatory effect on cardiac ion channels. They are rather mediated by indirect actions at the level of the autonomic nervous system.

A selective Akt inhibitor produces hypotension and bradycardia in conscious rats due to inhibition of the autonomic nervous system.

Akt is a serine-threonine kinase that is amplified in a variety of human cancers, and as with other anticancer agents, some Akt inhibitors have produced functional cardiovascular effects such as marked hypotension that may limit their clinical benefit. Although identified in preclinical studies, the mechanism(s) responsible for these effects are often not fully characterized; potential targets include Akt signaling disruption in cardiac tissue, vascular smooth muscle, and/or autonomic system signaling. A selective Akt inhibitor was found to produce a rapid and marked hypotension and bradycardia in conscious rats. Isolated right atrial tissue and isolated thoracic aortic rings were used to examine direct effects of Akt inhibition on cardiac and vascular tissues, respectively. In addition, rats surgically prepared with telemetry units for monitoring blood pressure and heart rate were used to investigate potential effects on the autonomic nervous system (ANS). Whereas this Akt inhibitor did not produce any significant effect on atrial tissue, it did cause vasorelaxation of aortic rings. More significantly, in conscious rats, the Akt inhibitor inhibited the neural pressor response to the known nicotinic acetylcholine receptor (nAchR) agonist dimethylphenylpiperazinium (DMPP). In fact, the response observed was comparable to the response observed with the known ganglionic blocker hexamethonium. Thus, the hypotension and bradycardia produced by the Akt inhibitor is primarily due to blockade of nAchRs in autonomic ganglia. This finding highlights the importance of evaluating the ANS for cardiovascular effects associated with new chemical entities as well as suggesting a novel direct effect of an Akt inhibitor on nAchRs.

Castration in rats impairs performance during acquisition of a working memory task and exacerbates deficits in working memory produced by scopolamine and mecamylamine.

RATIONALE: Although much research has focused on the effects of ovarian hormones on learning and memory in females, less information is available regarding the effects of testicular hormones on learning and memory in males. Additionally, despite evidence of an interaction of testicular hormones and the cholinergic system in areas of the brain implicated in learning and memory, no information is available regarding the behavioral consequences of that interaction. OBJECTIVES: We assessed the effect of castration in male rats on working memory during acquisition of a radial maze. We also assessed the interactive effects of castration and scopolamine, a muscarinic receptor antagonist, as well as mecamylamine, a nicotinic receptor antagonist, on behavior. METHODS: Young adult male rats were castrated or underwent sham surgeries. Beginning 10 days after surgeries, performance on a task of working memory was assessed across 24 days of acquisition in an eight-arm radial maze. Following acquisition, scopolamine and mecamylamine dose-effect curves were established. RESULTS: Castration of male rats significantly decreased arm-choice accuracy during acquisition. Castration significantly exacerbated impairments in arm-choice accuracy produced by scopolamine as well as mecamylamine, without altering the disruptive effects of the drugs on the rate at which rats entered the arms of the maze. CONCLUSIONS: These results indicate that castration in male rats impairs working memory during acquisition of a spatial maze task. Additionally, these results suggest that the absence of testicular hormones increases the sensitivity of male rats to the impairing effects of scopolamine as well as mecamylamine on working memory.

Cardiovascular effects of an organophosphate toxin isolated from Ptychodiscus brevis.

The dose-dependent hypotensive and bradycardic effects induced by an ichthyotoxic organophosphate compound isolated from the marine dinoflagellate Ptychodiscus brevis were studied. These effects were not antagonized by atropine, but potentiated by alpha-adrenoceptor blocker and hexamethonium. The toxin abolished the vasopressor effect elicited by phenylephrine, indicating an alpha-adrenergic blocking activity. The cardiovascular depressor responses were antagonized by tetraethylammonium while blockade of cholinergic and histaminergic receptors or inhibition of prostaglandin synthesis failed to modify these effects. The results indicate that the cardiovascular depressor effects of the toxin are probably mediated through alpha-adrenergic and ganglionic blockade accompanied by modulation of potassium channel activity.

2,2'-Phthaloyl-,2,2'-isophthaloyl-, and 2,2'-terephthaloylbis[1,1,1-trimethylhydrazinium] dihydroxide, bis(inner salts): synthesis, partition coefficients, toxicity and effect on ganglionic transmission.

2,2'-Phthaloyl-, 2,2'-isophthaloyl, and 2,2'-terephthaloyl-boff++[1,1,1-trimethylhydrazinium] dihydroxide, bis(inner salts) 7, 8, and 9 and their hydrazide and hydrazinium diiodide precursors were synthesized and tested for toxicity and their ability to block sympathetic ganglionic transmission. Only the 2,2'-phthaloyl and isophthaloylhydrazinium diiodides 4 and 5 produced weak inhibition of nerve transmission (35% at 2.15 X 10(-3) M). The inner salts were appreciably less toxic than the hydrazinium diiodides in brine shrimp testing. The log P (log10, chloroform pH 7 buffer system) values of all compounds were determined and those of the inner salts and hydrazinium diiodides were in the range of -3.03 to -3.60.

Efficacy and toxicity of drug combinations in treatment of physostigmine toxicosis.

Atropine, in combination with 1 of 6 other drugs, was tested in mice for the ability to prevent death by an otherwise lethal dose of the cholinesterase inhibitor, physostigmine. The atropine dose (4 mg/kg, i.p.) was kept constant, while the dose of the other drug in the pair was tested in 5 geometrically spaced doses, ranging down to 1/16 of the maximum dose (which caused no gross behavioral signs). Atropine alone saved 20% of the mice. The combination of atropine and benactyzine saved 100% of the mice at all 5 doses of benactyzine; similar complete protection was afforded by the combination of atropine and the largest dose of an oxime, TMB4 (15 mg/kg). Over 80% survivals were achieved with the larger doses of atropine combinations involving hexamethonium, mecamylamine, and diazepam. No enhanced protection occurred with atropine combinations with the oxime, 2-PAM. The toxicity of the effective combinations, when used in high doses without physostigmine challenge, revealed that deaths occurred over a narrow range of doses of all combinations except atropine/diazepam. An additive toxic effect of atropine was suggested with its combinations with TMB4, mecamylamine, and diazepam, whereas no additive toxicity occurred with combinations involving hexamethonium or benactyzine (i.e., the LD50 of the combinations was about the same as for hexamethonium or benzactyzine alone). The combinations with the best therapeutic safety ratio were with diazepam (no deaths at a dose 10 times that which saved 100% of mice) and benactyzine (no deaths at a more than 50-fold dose).

[Long-term experiments on toleration of the ganglionic blockader hygronium]. / O perenosimosti gangliolitika gigroniia v khronicheskom éksperimente.

In tests set up on albino rats, guinea pigs and rabbits the chronic toxicity of hygronium--a new original ganglion blocking agent of a short-term action was studied. With its daily intraperitoneal administration for 14 days in doses of 10 and 40 mg/kg (1/10 and 1/3 DL50) the drug produces in some of the animals, chiefly in rabbits and guinea pigs receiving 40 mg/kg, readily reversible histological changes in some of their internal organs. Hygronium does not cause any local irritating effect