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. In rat ventricular papillary muscle cells R (1-30 µM) caused a significant reduction of APA and maximum velocity of depolarization (V(max)) which was accompanied by lengthening of APD(90). In single canine ventricular myocytes at concentrations ≥10 µM R decreased the amplitude of phase-1 repolarization, the plateau potential and reduced V(max). R suppressed several ion currents in a concentration-dependent manner under voltage clamp conditions. The EC(50) value for this inhibition was 25.2±2.7 µM for the transient outward K(+ ) current (I(to)), 72.3±9.3 µM for the rapid delayed rectifier K(+ ) current (I(Kr)), and 82.5±9.4 µM for the L-type Ca(2+ ) current (I(Ca)) with Hill coefficients close to unity. The inward rectifier K(+ ) current (I(K1)) was not affected by R up to concentrations of 100 µM. Suppression of I(to), I(Kr), and I(Ca) has been confirmed under action potential voltage clamp conditions as well. The observed alterations in the AP morphology and densities of ion currents may predict serious proarrhythmic risk in case of intoxication with R as a consequence of overdose or decreased elimination of the drug, particularly in patients having multiple cardiovascular risk factors, such as elderly diabetic patients.

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. KEY RESULTS: At concentrations ≥10 µM rosiglitazone decreased the amplitude of phase-1 repolarization, reduced the maximum velocity of depolarization and caused depression of the plateau potential. These effects developed rapidly and were readily reversible upon washout. Rosiglitazone suppressed several transmembrane ion currents, concentration-dependently, under conventional voltage clamp conditions and altered their kinetic properties. The EC(50) value for this inhibition was 25.2 ± 2.7 µM for the transient outward K(+) current (I(to)), 72.3 ± 9.3 µM for the rapid delayed rectifier K(+) current (I(Kr)) and 82.5 ± 9.4 µM for the L-type Ca(2+) current (I(Ca) ) with Hill coefficients close to unity. The inward rectifier K(+) current (I(K1)) was not affected by rosiglitazone up to concentrations of 100 µM. Suppression of I(to), I(Kr), and I(Ca) was confirmed also under action potential voltage clamp conditions. CONCLUSIONS AND IMPLICATIONS: Alterations in the densities and kinetic properties of ion currents may carry serious pro-arrhythmic risk in case of overdose with rosiglitazone, especially in patients having multiple cardiovascular risk factors, like elderly diabetic patients.

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. Recent studies provide evidence that the two headache types are caused by different mechanisms: immediate headaches are connected to vasodilation caused by nitric oxide (NO) release, while migraines are triggered by other actions such as the release of calcitonin gene-related peptide or glutamate, or changes in ion channel function mediated by cyclic guanosine monophosphate or S-nitrosylation. Migraines usually need anti-attack medication, such as triptans, but these drugs are contraindicated in most medical conditions that are treated using nitrates. In conclusion, these data recommend the correction of summaries of nitrate product characteristics, and also suggest a need to develop new types of anti-migraine drugs, effective in migraine attacks, that could be used in patients with risk for angina pectoris.

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. Therefore, a study of diabetes-related immune processes was considered of interest in histidine decarboxylase knockout (HDC-KO) mice. AIM OF THE STUDY: The aim of our study was i) to characterize antibody production in response to vaccination with p277 or hsp65 in wild type (WT) BALB/c and HDC-KO mice, and ii) to establish a possible correlation between vaccination and the changes in the pattern of STZ diabetes. MATERIALS AND METHODS: An ELISA was employed to measure the hsp65- and p277-specific antibody levels. To induce diabetes multiple low-dose of STZ was used. RESULTS: Vaccination with p277 and hsp65 altered the pattern of STZ diabetes both in HDC-KO and WT animals, characterized by a transient increase followed by sustained reduction of blood sugar levels as compared to controls. However, vaccination with hsp65 and p277 caused a significant anti-p277 and anti-hsp65 antibody level increase only in WT animals. CONCLUSION: Multiple low-doses of STZ were able to induce diabetes in HDC-KO mice and the development of diabetes was prevented by vaccination with hsps. This protection developed in spite of the fact that vaccination caused a significant antibody level increase only in WT animals. To explain the therapeutic effect of vaccination we need further examination of the HDC KO strain.

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. METHODS: Diabetes was induced by a single injection of alloxan (145 mg kg(-1) i.v.). After the development of diabetes (3 weeks), electrophysiological studies were performed using whole cell voltage clamp and ECG measurements. RESULTS: The QT(c) interval in diabetic rabbits was moderately but statistically significantly longer than measured in the control animals (155 +/- 1.8 ms vs. 145 +/- 2.8 ms, respectively, n = 9-10, P < 0.05). This QT(c)-lengthening effect of diabetes was accompanied by a significant reduction in the density of the slow delayed rectifier K(+) current, I(Ks) (from 1.48 +/- 0.35 to 0.86 +/- 0.17 pA pF(-1) at +50 mV, n = 19-21, P < 0.05) without changes in current kinetics. No differences were observed either in the density or in the kinetics of the inward rectifier K(+) current (I(K1)), the rapid delayed rectifier K(+) current (I(Kr)), the transient outward current (I(to)) and the L-type calcium current (I(CaL)) between the control and alloxan-treated rabbits. CONCLUSION: It is concluded that type 1 diabetes mellitus, although only moderately, lengthens ventricular repolarization. Diabetes attenuates the repolarization reserve by decreasing the density of I(Ks) current, and thereby may enhance the risk of sudden cardiac death.

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. AIM OF THE STUDY: To determine Th1 (IFN-gamma) and Th2 (IL-13) cytokine levels in T1 diabetic and control subjects as well as to determine whether there is a shift towards Th1 or Th2 immune response. MATERIALS AND METHODS: ELISPOT (Enzyme-linked ImmunoSPOT) analysis was employed to differentiate antigen specific T-cell responses of a Th1 (IFN-gamma) or Th2 (IL-13) type. 11 T1 diabetic patients and 9 healthy controls were investigated. For T-cell stimulation, we used a polyclonal mitogen or Tetanus toxoid (TT) as positive controls and two peptide antigens Hsp60 AA394-408 and Hsp60 AA437-460. RESULTS: In case of Hsp60 AA437-460 we found significantly decreased Th2 response in patients, although there was no significant difference in Th1 response. In case of Hsp60 AA394-408 and positive controls there was no significant difference. CONCLUSION: Comparing the control and diabetic subjects a significant shift towards Th1 response in T1 diabetes mellitus for Hsp60 AA437-460 was observed.

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. In a concentration-dependent manner, nifedipine, diltiazem, fluoxetine, and citalopram elicited relaxation of LMMPs contracted by electrical field stimulation (EC50 values of 4 x 10(-7) M, 1.4 x 10(-6) M, 1.4 x 10(-5), and 6.8 x 10(-6) M, respectively). Nifedipine, diltiazem, fluoxetine, and citalopram also relaxed LMMPs contracted with a depolarizing concentration of KCl (48 mM; EC50 values of 1.8 x 10(-8) M, 1.4 x 10(-7) M, 3.7 x 10(-6) M, and 6.3 x 10(-6), respectively), a response that could be reversed by increasing the extracellular Ca2+ concentration (2.5-30 mM). These data suggest that fluoxetine and citalopram elicit relaxation of intestinal smooth muscle, likely by inhibiting Ca2+ channel(s). This effect may be of clinical importance.

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. Unfortunately, these compounds block cholinergic, histaminergic and alpha-1-adrenergic receptor sites, interact with a number of other medications and bring about numerous undesirable side effects. Several chemically unrelated agents have been developed and introduced in the past decade to supplement the early antidepressants. These include selective inhibitors of the reuptake of serotonin (the selective serotonin reuptake inhibitors (SSRIs)) or noradrenaline (reboxetine) or both (SNRIs: milnacipran and venlafaxine), as well as drugs with distinct neurochemical profiles such as mirtazapine, nefazodone, moclobemide and tianeptine. All these newer compounds are the results of rational developmental strategies to find drugs that were as effective as the TCAs but of higher safety and tolerability profile. In spite of the remarkable structural diversity, most currently introduced antidepressants are monoamin based and modulating monoamine activity as a therapeutic strategy continues to dominate antidepressant research. It must be emphasised, however, that these newer antidepressants are far from the ideal ones, also resulting in undesirable side effects and requiring 2-6 weeks of treatment to produce therapeutic effect. Furthermore, approximately 30% of the population do not respond to current therapies. An important new development has been the emergence of potential novel mechanisms of action beyond the monoaminergic synapse. The results of recent novel developmental approaches have suggested that modulation of N-methyl-D-aspartate (NMDA), neuropeptide (substance P and corticotrophin-releasing factor) receptors and the intracellular messenger system may provide an entirely new set of potential therapeutic targets. This paper discusses the advances from monoamine-based treatment strategies and looks at the future developments in the treatment of depression.

Cardiac electrophysiological effects of citalopram in guinea pig papillary muscle comparison with clomipramine.

The effect of citalopram, a selective serotonin reuptake inhibitor (SSRI) antidepressant, was studied on cardiac action potential configuration and compared with that of the tricyclic antidepressant (TCA) clomipramine. Conventional microelectrode techniques were used in right ventricular papillary muscle preparations of the guinea pig. Citalopram caused a concentration-dependent (10-100 microM) shortening of action potential duration (APD), depression of plateau and overshoot potential, and reduction of maximum velocity of depolarization (V(max)). No significant changes in resting membrane potential were observed. Similar results were obtained with clomipramine; however, reduction of V(max) and overshoot was more pronounced with clomipramine, whereas citalopram caused relatively greater shortening of APD. Effects of both drugs were partly reversible. The results indicate that the SSRI antidepressant citalopram, similarly to TCA compounds, alters cardiac action potential configuration in guinea pig ventricular muscle, probably owing to inhibition of cardiac Na(+) and Ca(2+) channels. Differences in cardiac side effects of the two drugs may be related to their different actions on cardiac action potential configuration.

Electrophysiological effects of fluoxetine in mammalian cardiac tissues.

Fluoxetine is a widely used antidepressant compound having selective serotonin reuptake inhibitor properties. In this study, the actions of fluoxetine were analyzed in guinea pig, rat, rabbit and canine ventricular myocardiac preparations using conventional microelectrode and whole cell voltage clamp techniques. Low concentrations of fluoxetine (1-10 micromol/l) caused significant shortening of action potential duration (APD) and depression of the plateau potential in guinea pig and rabbit papillary muscles and single canine ventricular myocytes. In rat papillary muscle, APD was not affected by fluoxetine (up to 100 micromol/l), however, the drug decreased the force of contraction with EC50 of 10 micromol/l. Fluoxetine (10 micromol/l) also decreased the maximum velocity of depolarization and action potential overshoot in each species studied. At this concentration no effect was observed on the resting membrane potential; high concentration (100 micromol/l), however, caused depolarization. In voltage clamped canine ventricular myocytes, fluoxetine caused concentration-dependent block of the peak Ca2+ current at 0 mV with EC50 of 5.4+/-0.94 micromol/l and Hill coefficient of 1.1+/-0.14 (n=6). In addition, 10 micromol/l fluoxetine shifted the midpoint of the steady-state inactivation curve of the Ca2+ current from -20.7+/-0.65 to -26.7+/-1 mV (P<0.001, n=8) without changing its slope factor. These effects of fluoxetine developed rapidly and were fully reversible. Fluoxetine did not alter voltage-dependence of activation or time constant for inactivation of I(Ca). Fluoxetine had no effect on the amplitude of K+ currents (I(K1) and I(to)). The inhibition of cardiac Ca2+ and Na+ channels by fluoxetine may explain most cardiac side effects observed occasionally with the drug. Our results suggest that fluoxetine may have antiarrhythmic (class I + IV type), as well as proarrhythmic properties (due to impairment of atrioventricular or intraventricular conduction and shortening of repolarization). Therefore, in depressed patients with cardiac disorders, ECG control may be suggested during fluoxetine therapy.

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. For electron microscopic study the hearts were perfused according to Langendorff technique. WEB 2086 (5 x 10(-9)-5 x 10(-7) M) significantly shortened the duration of atrial AP without changing the ventricular one, however, BN 52021 decreased both of them. The shortening of atrial and ventricular AP duration (APD) by both PAF antagonits were abolished by 4-aminopyridine (10(-3) M), a blocker of one type of K+ channels (IKto). Glibenclamide (10(-6) M) the blocker of ATP-dependent K channels prevented the shortening effect of BN 52021 (10(-6) M) on ventricular APD. Electron microscopic study of myocardial samples from hearts subjected to 30 min hypoxia/reoxygenation showed intracellular oedema, intramitochondrial swelling and fragmentation of mitochondrial christae, separation of intercalated disc. Pretreatment with WEB 2086 (5 x 10(-7) M) warded off nearly all damage caused by hypoxia/reoxygenation. Both WEB 2086 and NO synthase inhibitor NG-nitro-L-arginine methyl esther (L-NAME) (10(-3) M) abolished the negative inotropic effect of PAF (10(-7), 10(-6) M). L-NAME prevented the shortening of APD induced by 10(-7) M PAF. These results suggest that PAF may be responsible for myocardial ischemia and the beneficial effects of PAF antagonists in this pathological process could be due to their possible K+ channel stimulator property. These data support the possibility that NO contributes to the cardiac electromechanical alterations induced by PAF.

Fluoxetine dilates isolated small cerebral arteries of rats and attenuates constrictions to serotonin, norepinephrine, and a voltage-dependent Ca(2+) channel opener.

BACKGROUND AND PURPOSE: Recent clinical observations question that the antidepressant effect of fluoxetine (Prozac) can be explained solely with serotonin reuptake inhibition in the central nervous system. We hypothesized that fluoxetine affects the tone of vessels and thereby modulates cerebral blood flow. METHODS: A small branch of rat anterior cerebral artery (195+/-15 microm in diameter at 80 mm Hg perfusion pressure) was isolated, cannulated, and pressurized (at 80 mm Hg), and changes in diameter were measured by videomicroscopy. RESULTS: Fluoxetine dilated small cerebral arteries with an EC(50) of 7.7+/-1.0x10(-6) mol/L, a response that was not affected by removal of the endothelium or application of 4-aminopyridine (an inhibitor of aminopyridine-sensitive K(+) channels), glibenclamide (an inhibitor of ATP-sensitive K(+) channels), or tetraethylammonium (a nonspecific inhibitor of K(+) channels). The presence of fluoxetine (10(-6) to 3x10(-5) mol/L) significantly attenuated constrictions to serotonin (10(-9) to 10(-5) mol/L) and norepinephrine (10(-9) to 10(-5) mol/L). Increasing concentrations of Bay K 8644 (a voltage-dependent Ca(2+) channel opener, 10(-10) to 10(-6) mol/L) elicited constrictions, which were markedly reduced by 2x10(-6) and 10(-5) mol/L fluoxetine, whereas 3x10(-5) mol/L fluoxetine practically abolished the responses. CONCLUSIONS: Fluoxetine elicits substantial dilation of isolated small cerebral arteries, a response that is not mediated by endothelium-derived dilator factors or activation of K(+) channels. The finding that fluoxetine inhibits constrictor responses to Ca(2+) channel opener, as well as serotonin and norepinephrine, suggests that fluoxetine interferes with the Ca(2+) signaling mechanisms in the vascular smooth muscle. We speculate that fluoxetine increases cerebral blood flow in vivo, which contributes to its previously described beneficial actions in the treatment of mental disorders.

Serotonin reuptake inhibitor, fluoxetine, dilates isolated skeletal muscle arterioles. Possible role of altered Ca2+ sensitivity.

1. Inhibitors of serotonin reuptake in the central nervous system, such as fluoxetine, may also affect the function of vascular tissues. Thus, we investigated the effect of fluoxetine on the vasomotor responses of isolated, pressurized arterioles of rat gracilis muscle (98 +/- 4 microns in diameter at 80 mmHg perfusion pressure). 2. We have found that increasing concentrations of fluoxetine dilated arterioles up to 155 +/- 5 microns with an EC50 of 2.5 +/- 0.5 x 10(-6) M. 3. Removal of the endothelium, application of 4-aminopyridine (4-AP, an inhibitor of aminopyridine sensitive K+ channels), or use of glibenclamide (an inhibitor of ATP-sensitive K+ channels) did not affect the vasodilator response to fluoxetine. 4. In the presence of 10(-6), 2 x 10(-6) or 10(-5) M fluoxetine noradrenaline (NA, 10(-9)-10(-5) M) and 5-hydroxytryptamine (5-HT, 10(-9)-10(-5)M)-induced constrictions were significantly attenuated resulting in concentration-dependent parallel rightward shifts of their dose-response curves (pA2 = 6.1 +/- 0.1 and 6.9 +/- 0.1, respectively). 5. Increasing concentrations of Ca2+ (10(-4) 3 x 10(-2) M) elicited arteriolar constrictions (up to approximately 30%), which were markedly reduced by 2 x 10(-6)M fluoxetine, whereas 10(-5)M fluoxetine practically abolished these responses. 6. In conclusion, fluoxetine, elicits substantial dilations of isolated skeletal muscle arterioles, a response which is not mediated by 4-AP- and ATP-sensitive K+ channels or endothelium-derived dilator factors. The findings that fluoxetine had a greater inhibitory effect on Ca2+ elicited constrictions than on responses to NA and 5-HT suggest that fluoxetine may inhibit Ca2+ channel(s) or interfere with the signal transduction by Ca2+ in the vascular smooth muscle cells.

Electrophysiological changes in rat ventricular and atrial myocardium at different stages of experimental diabetes.

Action potential configuration in ventricular and atrial myocardium, as well as rate-dependent changes in ventricular action potential duration (APD) were studied and compared in healthy and diabetic rats. Diabetes was induced by a single injection of streptozotocin (STZ, 65 mg kg(-1) i.v.). Conventional microelectrode techniques were applied to record action potentials after the establishment of diabetes (2, 6, 10 and 18 weeks after STZ-treatment). Untreated age-matched animals were used as controls. Both depolarization and repolarization were significantly retarded following STZ-treatment. However, the time course of development of diabetic changes in atrial and ventricular myocardium was different. APD was significantly lengthened from week 2 of diabetes in ventricular, but only from week 6 in atrial preparations. In atrial myocardium, lengthening of APD was more pronounced at early rather than late phases of repolarization. The maximum rate of depolarization (Vmax) was significantly reduced from the 6th week of diabetes in both preparations. No differences were observed in action potential amplitude (except at week 18) and in the resting membrane potential in diabetic rats. Diabetic ventricular preparations showed a positive APD-frequency relationship at any level of repolarization, in contrast to control muscles, where APD25 and APD50 values lengthened. But APD75 and APD90 values were not changed significantly with increase in the pacing frequency. The results indicate that development of diabetic alterations are not fully identical in atrial and ventricular myocardium of the rat, probably owing to differences in density and kinetics of ionic currents responsible for atrial and ventricular action potentials.

Post-partum prolongation of the atrial repolarization in rabbit.

Female sexual steroids are known to modify the expression of various K+ channels and thus they can alter cardiac repolarization. In the present work, using conventional microelectrode techniques, action potential characteristics were studied in atrial myocardium isolated from virgin, late pregnant, early (1-3 days) post-partum and late (2-3 weeks) post-partum rabbits. No changes in action potential configuration were observed during pregnancy. However, the duration, overshoot and amplitude of action potentials were significantly increased in the early (1-3 days) post-partum period. Resting potential and maximum rate of depolarization remained unchanged. The observed changes were transient, normal action potential characteristics were obtained at weeks 2-3 post-partum. 4-aminopyridine (1 mmol L(-1)). caused a marked lengthening of action potential duration in all preparations obtained from non-pregnant and pregnant rabbits, whereas this 4-aminopyridine-induced prolongation was moderate in those preparations excised from the hearts of early post-partum animals. Action potential configuration was not affected by pinacidil (10 micromol L(-1)) or glibenclamide (5 micromol L(-1)) in non-pregnant or pregnant animals. In preparations obtained from early post-partum rabbits, pinacidil significantly shortened action potential duration, which was reverted by glibenclamide. The lengthening of action potential duration together with the decreased sensitivity to 4-aminopyridine observed in early post-partum animals may probably be caused by reduction of the transient outward K+ current at this stage. The results also suggest that electrophysiological alterations in the early post-partum period may probably be more pronounced than those associated with pregnancy itself.

Electrophysiological effects of homocysteine in isolated rat right ventricular papillary muscles and left atria.

There is clinical and epidemiological evidence that elevated plasma homocysteine (Hcy) levels are associated with increased myocardial infarction mortality; however, very little is known about Hcy's direct cardiac effects. Thus, we aimed to characterize the cellular electrophysiologic effects of Hcy, a sulfur-containing amino acid in isolated rat hearts. A conventional microelectrode technique was used in left atria and right ventricular papillary muscles. At concentrations higher than 10(6) M, Hcy significantly decreased the maximum rate of rise of the depolarization phase (Vmax) in both cardiac preparations in a dose-dependent manner. Hcy at 10(-4)-5 x 10(-4) M concentrations increased the action potential duration (APD) at late stages of repolarization (at 75% and 90% of APD) both in atria and in ventricles. There was a slight decrease in action potential amplitude in ventricular papillary muscles and atria at concentrations higher that 10(-5) M. The resting membrane potential and the early repolarization phase (APD25 and APD50) remained unchanged in every preparation studied at all concentrations of Hcy administered. The present data suggest that homocysteine may decrease the Na+ channel activity in in vitro cardiac preparations. reserved.

Speculations on difference between tricyclic and selective serotonin reuptake inhibitor antidepressants on their cardiac effects. Is there any?

The cardiovascular effects and toxicity of tricyclic antidepressants (TCAs) have been well documented in medical literature. The most common manifestation of such effects is slowing of intraventricular conduction, manifested by prolonged PR, QRS and QT intervals on the standard electrocardiogram (ECG) and postural hypotension. In contrast to TCAs, selective serotonin reuptake inhibitors (SSRIs), including fluoxetine and citalopram, are considered to cause less effect on cardiac impulse conduction. In addition, these compounds induced significantly less anticholinergic, antihistaminergic and cardiotoxic side-effects than TCAs. However, there is an increasing number of case reports on dysrhythmias, like atrial fibrillation or bradycardia and syncope associated with fluoxetine and another SSRI treatment and overdose. Although such reports have not been common, they do raise concerns. In cardiac tissues isolated from canine, rabbit, rat and guinea pig hearts we have found that fluoxetine and citalopram inhibited cardiac Na+ and Ca2+ channels. These direct cardiac electrophysiological effects were similar to those of observed for tricyclic antidepressants clomipramine and imipramine. The inhibition of cardiac Ca2+ and Na+ channels by fluoxetine may explain most cardiac side-effects observed occasionally with the drug and mild but significant bradycardia reported during chronic treatment. Our results suggest that fluoxetine and citalopram may have antiarrhythmic (class I + IV type), as well as proarrhythmic properties (due to impairment of atrioventricular or intraventricular conduction and shortening of repolarization). Taking all these into consideration, in depressed patients having also severe cardiac disorders, ECG control may be suggested during fluoxetine and probable another SSRI therapy. The primary goal of this review is to compare these direct cardiac effects of fluoxetine and citalopram to those of previously reported for TCAs. This paper also summarizes the recently observed effects of fluoxetine apparently not related to the blockage of 5-HT transporter based on literature.

Increased myogenic tone in skeletal muscle arterioles of diabetic rats. Possible role of increased activity of smooth muscle Ca2+ channels and protein kinase C.

OBJECTIVE: The diabetes mellitus-induced microangiopathy is still not clearly characterized. In this study we aimed to elucidate the effect of streptozotocin (STZ)-induced diabetes on myogenic response of isolated rat skeletal muscle arterioles and the mechanisms responsible for its alterations. METHODS: Male rats were divided into two groups: (1) control rats (C, plasma glucose: 6.4 +/- 0.5 mmol/l, n = 40) (2) diabetic rats (DM, 65 mg/kg STZ i.v., plasma glucose: 25.7 +/- 0.7 mmol/l, n = 40). Changes in diameter of isolated, cannulated gracilis skeletal muscle arterioles (approximately 130 microns in diameter) were measured by video-microscopy. RESULTS: Step increases in perfusion pressure (PP; from 10 to 140 mmHg) elicited significantly greater constrictions in DM than in C gracilis arterioles, in the presence of the endothelium (E). Also, a step increase in PP (from 40 to 100 mmHg) elicited greater and faster constrictions in DM vs. C arterioles. There were no significant differences in the pressure-passive diameter (in Ca2+ free solution) curves of arterioles. Dilations to acetylcholine were impaired in arterioles of DM as compared to those of C rats (EC50, C: 4.0 +/- 0.9 x 10(-9) mol/l, DM: 4.8 +/- 2.0 x 10(-8) mol/l (p < 0.01), and unaffected by inhibition of nitric oxide synthesis with L-NNA (10(-4) mol/l). Arteriolar constrictions to norepinephrine (NE) were significantly greater in DM compared to those of C rats (EC50, C: 6.2 +/- 0.6 x 10(-7) mol/l, DM: 8.0 +/- 2.0 x 10(-8) mol/l, p < 0.01) both in the presence and absence of E. In the absence of the E, constrictions to increases in pressure, or Ca2+ (0.25-7.5 mmol/l), or the voltage-dependent Ca(2+)-channel agonist Bay K 8644 (EC50; DM: 4.2 +/- 1.5 x 10(-10) mol/l, C: 1.7 +/- 0.8 x 10(-9) mol/l, p < 0.05) or the protein kinase C activator phorbol 12-myristate 13-acetate (PMA, EC50; DM: 6 +/- 2 x 10(-9) mol/l, C: 2 +/- 1 x 10(-8) mol/l, p < 0.05) were significantly greater in arterioles of DM compared to those of C rats. CONCLUSION: The novel findings of our study are that in diabetes mellitus the myogenic response of rat skeletal muscle arterioles is enhanced, which seems to be independent from the impaired endothelial function present simultaneously, and likely due to the increased activity of voltage-dependent Ca2+ channels and/or upregulation of protein kinase C in arteriolar smooth muscle.