Effects of pioglitazone on cardiac ion currents and action potential morphology in canine ventricular myocytes.

Despite its widespread therapeutical use there is little information on the cellular cardiac effects of the antidiabetic drug pioglitazone in larger mammals. In the present study, therefore, the concentration-dependent effects of pioglitazone on ion currents and action potential configuration were studied in isolated canine ventricular myocytes using standard microelectrode, conventional whole cell patch clamp, and action potential voltage clamp techniques. Pioglitazone decreased the maximum velocity of depolarization and the amplitude of phase-1 repolarization at concentrations ≥3 μM.

Can the electrophysiological action of rosiglitazone explain its cardiac side effects?

Recent large clinical trials found an association between the antidiabetic drug rosiglitazone therapy and increased risk of cardiovascular adverse events. The aim of this report is to elucidate the cardiac electrophysiological properties of rosiglitazone (R) on isolated rat and murine ventricular papillary muscle cells and canine ventricular myocytes using conventional microelectrode, whole cell voltage clamp, and action potential (AP) voltage clamp techniques. In histidine-decarboxylase knockout mice as well as in their wild types R (1-30 µM) shortened AP duration at 90% level of repolarization (APD(90)) and increased the AP amplitude (APA) in a concentration-dependent manner.

Effects of rosiglitazone on the configuration of action potentials and ion currents in canine ventricular cells.

Background And Purpose: In spite of its widespread clinical application, there is little information on the cellular cardiac effects of the antidiabetic drug rosiglitazone in larger experimental animals. In the present study therefore concentration-dependent effects of rosiglitazone on action potential morphology and the underlying ion currents were studied in dog hearts.

Experimental Approach: Standard microelectrode techniques, conventional whole cell patch clamp and action potential voltage clamp techniques were applied in enzymatically dispersed ventricular cells from dog hearts.

Headache-type adverse effects of NO donors: vasodilation and beyond.

Although nitrate therapy, used in the treatment of cardiovascular disorders, is frequently associated with side-effects, mainly headaches, the summaries of product characteristics of nitrate-containing medicines do not report detailed description of headaches and even do not highlight the possibility of nitrate-induced migraine. Two different types of nitrate-induced headaches have been described: (i) immediate headaches that develop within the first hour of the application, are mild or medium severity without characteristic symptoms for migraine, and ease spontaneously; and (ii) delayed, moderate or severe migraine-type headaches (occurring mainly in subjects with personal or family history of migraine), that develop 3-6 h after the intake of nitrates, with debilitating, long-lasting symptoms including nausea, vomiting, photo- and/or phono-phobia. These two types of headaches are remarkably different, not only in their timing and symptoms, but also in the persons who are at risk.

Electrophysiological characteristics of heart ventricular papillary muscles in diabetic histidine decarboxylase knockout and wild-type mice.

Objective: The diabetes-induced action potential (AP) abnormalities have been studied mainly in rats where significant prolongation of repolarization and reduced maximum rate of depolarization (Vmax) was detected. Histidine decarboxylase knockout (HDC-KO) mice lack endogenous histamine and they are characterized by impaired glucose tolerance. Furthermore they have autoantibodies reactive to glutamic acid decarboxylase (GAD).

Effects of vaccination with heat shock proteins on streptozotocin induced diabetes in histidine decarboxylase knockout mice.

Rationale: Type 1 diabetes mellitus (T1D) is an immune mediated disease in which heat shock proteins (hsps) may be involved in the development of the disease. Furthermore, vaccination with different hsps prevented the development of multiple low-dose streptozotocin (STZ) induced autoimmune diabetes in C57BL/KSJ mice. Histamine influences many aspects of the immune response, including Th1/Th2 balance and antibody production.

Role of slow delayed rectifier K+-current in QT prolongation in the alloxan-induced diabetic rabbit heart.

Aim: In diabetes mellitus, several cardiac electrophysiological parameters are known to be affected. In rodent experimental diabetes models, changes in these parameters were reported, but only limited relevant information is available in other species, having cardiac electrophysiological properties more resembling the human, including the rabbit. The present study was designed to analyse the effects of experimental type 1 diabetes on ventricular repolarization and the underlying transmembrane potassium currents in rabbit hearts.

Serotonin and epilepsy.

In recent years, there has been increasing evidence that serotonergic neurotransmission modulates a wide variety of experimentally induced seizures. Generally, agents that elevate extracellular serotonin (5-HT) levels, such as 5-hydroxytryptophan and serotonin reuptake blockers, inhibit both focal and generalized seizures, although exceptions have been described, too. Conversely, depletion of brain 5-HT lowers the threshold to audiogenically, chemically and electrically evoked convulsions.

Diabetes mellitus attenuates the repolarization reserve in mammalian heart.

Objective: In diabetes mellitus several cardiac electrophysiological parameters are known to be affected. In rodent experimental diabetes models changes in these parameters were reported, but no such data are available in other mammalian species including the dog. The present study was designed to analyse the effects of experimental type 1 diabetes on ventricular repolarization and its underlying transmembrane ionic currents and channel proteins in canine hearts.

Th1 and Th2 cell responses of type 1 diabetes patients and healthy controls to human heat-shock protein 60 peptides AA437-460 and AA394-408.

Rationale: Type 1 diabetes mellitus (T1) is considered to be an immune mediated disease. Based on previous findings it might be suggested that heat shock protein 60 (Hsp60) could be involved in the mediation of the development of the disease. Furthermore a bias toward Th1 immune response was observed in T1D patients where the level of Th1 cytokines was elevated, while the level of Th2 was decreased.

Norfluoxetine and fluoxetine have similar anticonvulsant and Ca2+ channel blocking potencies.

Norfluoxetine is the most important active metabolite of the widely used antidepressant fluoxetine but little is known about its pharmacological actions. In this study the anticonvulsant actions of norfluoxetine and fluoxetine were studied and compared to those of phenytoin and clonazepam in pentylenetetrazol-induced mouse epilepsy models. Pretreatment with fluoxetine or norfluoxetine (20mg/kg s.

Effects of norfluoxetine on the action potential and transmembrane ion currents in canine ventricular cardiomyocytes.

Norfluoxetine is the most important active metabolite of the widely used antidepressant compound fluoxetine. Although the cellular electrophysiological actions of fluoxetine are well characterized in cardiac cells, little is known about the effects of its metabolite. In this study, therefore, the effects of norfluoxetine on action potential (AP) configuration and transmembrane ion currents were studied in isolated canine cardiomyocytes using the whole cell configuration of patch clamp techniques.

Cardiovascular side effects of new antidepressants and antipsychotics: new drugs, old concerns?

The cardiovascular toxicity of older generation of tricyclic antidepressants (e.g. imipramine, desipramine, amitriptyline, clomipramine) and neuroleptics (e.

[Cardiac effects of antipsychotics: mechanism of arrhythmias and sudden cardiac death].

The review summarizes experimental and clinical data showing the cardiac side effects of antipsychotic drugs. Some antipsychotics may correlate with prolongation of QT interval, induce ventricular tachycardia, torsades de pointes, TdP, and sudden death. The author surveys the cellular actions of the drugs, the electrophysiological mechanisms and the recent data referring the drug's effects on ionic currents, mainly potassium currents.

Trends in the development of new antidepressants. Is there a light at the end of the tunnel?

Since the introduction of tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) in mid-1950's, treatment of depression has been dominated by monoamine hypotheses. The well-established clinical efficacy of TCAs and MAOIs is due, at least in part, to the enhancement of noradrenergic or serotonergic mechanisms, or to both. Unfortunately, their very broad mechanisms of action also include many unwanted effects related to their potent activity on cholinergic, adrenergic and histaminergic receptors.

[Cardiovascular effects of selective serotonin reuptake inhibitor antidepressants].

This paper reviews the cardiovascular effects of fluoxetine and other selective serotonin reuptake inhibitors comparing with those of tricyclic antidepressants. The authors survey the electrophysiological mechanisms and the recent data referring on drug's actions on different ionic currents/channels. The paper primarily focuses on preclinical data, showing various effects of fluoxetine and citalopram on cardiac and smooth muscle preparations and on cardiac ionic currents.

Differential effects of fluoxetine enantiomers in mammalian neural and cardiac tissues.

Racemic fluoxetine is a widely used SSRI antidepressant compound having also anticonvulsant effect. In addition, it was shown that it blocked several types of voltage gated ion channels including neural and cardiac calcium channels. In the present study the effects of enantiomers of fluoxetine (R(-)-fluoxetine and S(+)-fluoxetine) were compared on neuronal and cardiac voltage-gated Ca2+ channels using the whole cell configuration of patch clamp techniques, and the anticonvulsant action of these enantiomers was also evaluated in a mouse epilepsy model.

Electrophysiological effects of risperidone in mammalian cardiac cells.

In this study, the effects of risperidone, the widely used antipsychotic drug, on isolated canine ventricular myocytes and guinea-pig papillary muscles were analyzed using conventional microelectrode and whole cell voltage-clamp techniques. Risperidone concentration-dependently lengthened action potential duration in guinea-pig papillary muscles (EC(50)=0.29+/-0.

New trends in the development of oral antidiabetic drugs.

A large number of oral antidiabetic agents are available today. This article provides a short review of the pharmacology and some clinical aspects of various oral antidiabetic drugs. It focuses mainly on the newest developing drugs (therapy of the near future) and on the most commonly used older groups for the common approach of every-day practice (sulphonylureas).

Serotonin reuptake inhibitors fluoxetine and citalopram relax intestinal smooth muscle.

Selective serotonin reuptake inhibitor antidepressants (SSRIs) exert depressant effects on cardiac myocytes and vascular smooth muscle cells by inhibiting Ca2+ channels. We hypothesized that the SSRIs fluoxetine and citalopram affect the contractile activity of intestinal smooth muscle by interfering with Ca2+ entry and (or) signaling pathways. The effects of fluoxetine and citalopram on contractions of guinea-pig ileum longitudinal muscle-myenteric plexus preparations (LMMP) were compared with the effects of the voltage-operated Ca2+ channel inhibitors nifedipine and diltiazem.

The role of platelet-activating factor (PAF) antagonists and nitric oxide in cardiac actions of PAF. Electrophysiological and morphological study.

Electrophysiological and ultrastructural effects of platelet-activating factor (PAF) antgonists, WEB 2086 and BN 52021 were compared in isolated guinea-pig hearts preparations. We studied the possible role of nitric oxide (NO) in electromechanical actions of PAF. Isometric twitches and intracellular action potentials (APs) were recorded from guinea-pig right ventricular papillary muscles and left atria.

Current trends in the development of new antidepressants.

Early antidepressant medications e.g. tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are effective because they enhance either noradrenergic or serotonergic mechanisms, or both.