Current Pharmaceutical Design - Volume 10, Issue 20, 2004

In this article we overview the most important antiarrhythmic and positive inotropic mechanisms based on pharmacological modification of an ion channel or a transport protein in the surface membrane of cardiac myocytes. First we briefly characterize the ion currents mediated by these proteins in atrial and ventricular cells. Since the level of expression of ion channels is markedly altered in various types of chronic heart diseases, such as atrial fibrillation or heart failure, cardiac remodelling characteristic of these cases is also discussed. The paper gives evaluation of the currently applied most important antiarrhythmic strategies and some insight into the perspectives of the future by reviewing a few but promising mechanisms and drugs that are currently investigated. Positive inotropic agents and mechanisms are similarly treated, focusing primarily on proarrhythmic risks or potential antiarrhythmic effects of these compounds. Based on the backgrounds and aims above, modification of the followings factors is discussed in details: INa, ICa, IKr, IKs, IK1, Ito, IKur, IK,Ach, IK,ATP, If, gap-junction channel, Na+ / K+ pump, Na+ / Ca2+ exchanger, Na+ / H+ exchanger, as well as the intracellular concentrations of sodium and calcium ions. In addition to the critical evaluation of each manipulation, the following general conclusions can be drawn. (1) Since large modifications in action potential parameters are usually disadvantageous at long time scale, combination of the various mechanisms, each represented at a moderate degree, appears to be better. (2) Regarding Class III. antiarrhythmic action, selective potassium channel blockers free of reverse rate-dependent properties should be preferred. (3) Partial inhibition of the Na+ / Ca2+ exchanger may result-paradoxically in an antiarrhythmic action under specific conditions, in addition to its positive inotropic effect. We believe that investigation of new antiarrhythmic mechanisms, rather than new compounds of the old families, might be most beneficial in order to effectively treat life threatening cardiac arrhythmias in the future.

It is not well known but the actions of opioid receptor agonist and antagonist drugs have not been well characterized in the heart and cardiovascular system. Under normal physiological conditions, opioid receptors have a limited role in the regulation of the cardiovascular system. Instead the primary focus of opioid receptor research, for many years, relates to the characterization of the actions as analgesics in the central nervous system (CNS). Recently, however a series of studies suggest that in particular the arylacetamide class of kappa (k) opioid receptor agonist drugs have significant opioid receptor independent actions on the heart and cardiovascular system. Some of the actions of these molecules may indeed be mediated by activation of peripheral opioid receptors; however, these new studies provide pharmacological evidence to the contrary and show using many different in vitro and in vivo animal models that these ‘non-opioid’ actions result from direct or opioid receptor-independent actions on cardiac tissue. This article will outline the molecular mechanism(s) that are responsible for the cardiovascular and cardiac actions these arylacetamide k opioid receptor agonists and characterize the role that these opioid receptors have in ischaemic arrhythmogenesis. In many instances it would appear that the effects of opioid agonists (and antagonists) in cardiovascular disease models of ischaemia may be mediated by opioid receptor-independent actions of these drugs.

Since Kerr described programmed cell death (apoptosis) as a process distinct from necrosis, there have been many studies of apoptosis in disease, especially of immunological origin. Because cardiac myocytes are terminally differentiated cells, they have typically been assumed to die exclusively by necrosis. However, during the last decade this view has been challenged by several studies demonstrating that a significant number of cardiac myocytes undergo apoptosis in myocardial infarction, heart failure, myocarditis, arrhythmogenic right ventricular dysplasia, and immun rejection after cardiac transplantation, as well as in other conditions of stress. These are potentially relevant observations, beacause apoptosis - unlike necrosis - can be blocked or reversed at early stages. Specific inhibition of this process may confer a considerable degree of cardioprotection, but requires a thorough understanding of the underlying mechanisms. Recent progress includes a better understanding of the importance of mitochondria-initiated events in cardiac myocyte apoptosis, of factors inducing apoptosis in heart failure and during hypoxia, and of the dual pro-apoptotic and antiapoptotic effects of hypertrophic stimuli such as β-adrenoceptor agonists, angiotensin converting enzime inhibitors, nitric oxide and calcineurin. The investigation of cytoprotective and apoptotic signal transduction pathways has revealed important new insights into the roles of the mitogen-activated protein kinases p38, extracellular signal regulated kinase and c-Jun N-terminal kinase in cardiac cell fate. Our present review focuses on the intracellular signal transduction pathways of cardiac myocyte apoptosis and the possibility of specific inhibition of the process.

The cardiovascular toxicity of older generation of tricyclic antidepressants (e.g. imipramine, desipramine, amitriptyline, clomipramine) and neuroleptics (e.g. haloperidol, droperidol, thioridazine, pimozide) is well established. These drugs inhibit cardiovascular Na+, Ca2+ and K+ channels often leading to life-threatening arrhythmia. To overcome the toxicity of old generation of antidepressants and antipsychotics, selective serotonin reuptake inhibitor antidepressants (SSRIs: fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, venlafaxin) and several new antipsychotics (e.g. clozapine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone, quetiapine) were introduced during the past decade. Although these new compounds are not more effective in treating psychiatric disorders than older medications, they gained incredible popularity since they have been reported to have fewer and more benign side effect profile (including cardiovascular) than predecessors. Surprisingly, an increasing number of case reports have demonstrated that the use of SSRIs and new antipsychotics (e.g. clozapine, olanzapine, risperidone, sertindole, aripiprazole, ziprasidone, quetiapine) is associated with cases of arrhythmias, prolonged QTc interval on electrocardiogram (ECG) and orthostatic hypotension in patients lacking cardiovascular disorders, raising new concerns about the putative cardiovascular safety of these compounds. In agreement with these clinical reports these new compounds indeed show marked cardiovascular depressant effects in different mammalian and human cardiovascular preparations by inhibiting cardiac and vascular Na+, Ca2+ and K+ channels. Taken together, these results suggest that the new generation of antidepressants and antipsychotics also have clinically important cardiac as well as vascular effects. Clinicians should be more vigilant about these potential adverse reactions and ECG control may be suggested during therapy, especially in patients with cardiovascular disorders. The primary goal of this review is to shed light on the recently observed clinically important cardiovascular effects of new antidepressants and antipsychotics and discuss the mechanism beyond this phenomenon.

The natriuretic peptides are a family of widely distributed polypeptide mediators that exert a range of actions in several body systems. In cardiovascular homeostasis, the endocrine roles of the cardiac-derived atrial and B-type natriuretic peptide (ANP and BNP) in regulating central fluid volume and blood pressure have been recognised for two decades. However, there is a growing realisation that natriuretic peptide actions go far beyond their endocrine effects and that local (autocrine / paracrine) regulatory actions within the heart and coronary vasculature may be of comparable importance, especially in disease states where tissue and circulating levels of the peptides rise markedly. In acute myocardial ischaemia, release of BNP occurs rapidly from ventricular myocardium, prompting speculation that the early activation of the natriuretic peptide receptor / cGMP signalling system may be an important autocrine / paracrine response in cardiac ischaemia. The autocrine / paracrine actions include inotropic effects, the acute regulation of coronary vascular tone and the attenuation of the susceptibility of myocardium to ischaemic injury. The effects of longer-term upregulation of natriuretic peptide expression in the heart could include the suppression of growth and proliferative responses in a variety of myocardial and vascular cells. In a variety of preparations, acute exposure of epicardial coronary arteries to pharmacological concentrations of natriuretic peptides evokes vasorelaxation, although in coronary microvessels, evidence for a vasorelaxant action of the peptides is less consistent. The mechanisms of the coronary vasorelaxant action are unclear but limited evidence suggests an endothelium-dependent component. In ischaemic myocardium, acute treatment with BNP prior to and during coronary artery occlusion exerts a markedly protective, concentration-dependent infarct-limiting action. This cytoprotective effect of the natriuretic peptide signalling pathway might conceivably represent an alternative endogenous salvage pathway in myocardium which is potentially exploitable therapeutically. Taken together, the acute actions of natriuretic peptides on the coronary vasculature and in myocardial ischaemia suggest a profile of activity that may be therapeutically beneficial in the management of patients with acute coronary syndromes.

Gastrointestinal (GI) smooth muscle cell activity is controlled by contractile cholinergic neurons and relaxant non-adrenergic non-cholinergic (NANC) neurons in the myenteric plexus between the circular and longitudinal muscle layer. Decreased or increased NANC relaxation might be involved in the pathophysiology of functional GI motility disorders. Vasoactive intestinal polypeptide (VIP) and nitric oxide (NO) are the primary inhibitory NANC neurotransmitters. As classic neurotransmitters, VIP is stored in vesicles in the nerve endings, while NO is synthetized on demand by the neuronal isoform of NO synthase (nNOS). The VIP / nNOS co-localization in myenteric neurons, reported for various regions of the GI tract in different species, suggests that VIP and NO are co-transmitters. At the presynaptic level, VIP and NO can induce each others release. Most clear-cut evidence for this mechanism was obtained in isolated myenteric ganglia where VIP induced NO release, and NO facilitated VIP release. At the postsynaptic level, many studies support that VIP and NO are parallel co-transmitters, acting via the adenylate cyclase / 3'5' adenosine cyclic monophosphate (cAMP) and guanylate cyclase / 3'5' cyclic guanosine monophosphate pathway respectively. Mainly based on results obtained in isolated GI smooth muscle cells, a serial postsynaptic VIP / NO interaction model was proposed, whereby VIP is the principle neurotransmitter, acting partially via a VPAC receptor and the adenylate cyclase / cAMP pathway but also by induction of muscular NO production. Recent results suggest that the capacity of VIP to release NO from isolated smooth muscle cells is related to the induction of inducible NOS (iNOS) in the cells during the isolation procedure. The relative contribution of NO and VIP to GI NANC relaxation differs upon tissue and nerve firing frequency, so that interference with either of them will lead to varying effects.

Regulation of myometrial functions during gestation, labor and birth are in the forefront of research in reproductive sciences. The complexity of the problem is reflected by our scant understanding of the intimate cellular and molecular events underlying these phenomena, despite extensive efforts spanning several decades. Unlike other smooth muscles, the myometrium is, to a large extent, under hormonal control. Of these, the steroid hormones, progesterone and estrogen, play dominant roles in terms of uterine growth, the maintenance of quiescence during gestation and the preparation of the uterus for labor and delivery. In addition to steroid hormones, there are a number of factors that modulate myometrial contractility (oxytocin, prostaglandins, endothelin, platelet activating factor) and relaxation (corticotropin releasing hormone, prostacyclin, nitric oxide). Although notable advances have been made towards understanding some of the key steps in receptor signaling that define the actions of these factors, a good deal of new information is needed to fully understand this fundamental life process. Pharmaceutical agents have been used extensively to induce labor or to prolong pregnancy in the case of preterm labor that represents the major cause of perinatal morbidity and mortality. Because preterm labor is a syndrome of multiple etiologies, pharmacologic agents will have to be targeted accordingly. This review attempts to present a critical overview of these topics.

Human arylamine N-acetyltransferases 1 and 2 (NAT1 and NAT2) are polymorphic phase II xenobioticmetabolising enzymes (XME) that acetylate arylamine compounds. They therefore play an important role in the detoxication and / or metabolic activation of certain therapeutic drugs, occupational chemicals and carcinogens. Although the use of the term “xenobiotic” implies that XME form a separate and distinct class of enzymes, possible endogenous substrates may exist. Unlike NAT2, NAT1 is produced in most tissues. Polymorphism at the NAT1 locus has been associated with the existence of at least 26 allelic variants, generating phenotypic variations in terms of NAT1 catalytic activity. This genetic variation affects the acetylator status of individuals, leading to interindividual differences in drug response and predisposition to disease in humans. Recent studies have shown that non-genetic factors may also regulate NAT1 activity at the posttranslational level, with potentially important consequences for drug toxicity. In this minireview, we summarise what is currently known about the regulation of NAT1 activity by non-genetic factors, including substrates and oxidative stress. Recent findings presented here may account for the genotype / phenotype relationship for the NAT1 locus being less clear-cut than that for human NAT2.

Hepatocyte growth factor (HGF) is a cytokine whose multipotent actions are mediated by c-Met receptor. This review focuses on effects of HGF on myocardial infarction (MI) and heart failure. Circulating concentrations of HGF and myocardial concentrations of HGF and c-Met mRNA and protein are substantially increased following acute MI. HGF has been shown to be cardioprotective towards acute cardiac ischemia-reperfusion injury. Gene transfection of HGF into rat hearts attenuates acute ischemia injury. Administration of HGF protein reduces infarct size and increases cardiac performance in a rat model of acute ischemia / reperfusion. In contrast, acute blockade of endogenous HGF increases infarct size and mortality. These acute effects of HGF appear to be related to angiogenic and anti-apoptotic mechanisms. Recent studies demonstrate that post-MI treatment with HGF gene or protein attenuates chronic cardiac remodeling and dysfunction. In rats, HGF gene transfer following large MI results in preserved cardiac function and geometry in association with angiogenesis and reduced apoptosis, and treatment with recombinant HGF also significantly improves cardiac performance measured 8 weeks after MI. In mice, post-MI HGF gene therapy improves cardiac remodeling and dysfunction through hypertrophy of cardiomyocytes, infarct wall thickening, preservation of vessels, and antifibrosis. In addition, gene transfer of HGF improves cardiac remodeling, angiogenesis and regional myocardial function in the chronic ischemic myocardium of dogs. Together, these preclinical data highlight the significant acute and chronic cardioprotective effects of HGF following ischemic heart failure. Clinical trials are needed to investigate the therapeutic potential of HGF for postinfarction heart failure in humans.