96 Meta-analysis of placebo-controlled trials of Levosimendan in acute myocardial infarction

The treatment of acute myocardial infarction is the early revascularization strategy. Heart failure and cardiogenic shock may complicate acute myocardial infarction nevertheless the best disposable strategy applied. Levosimendan is relatively new drug to treat heart failure with a peculiar mechanism of action: calcium sensitization of myocardial fibres. Levosimendan has a direct inotropic effect but also pleiotropic effects; through the K+ATP channels opening it has also a vasodilator effect with may participate concretely to the global effects of the drug. Literature has focused the attention on the anti-heart failure and anti-cardiogenic shock properties of Levosimendan, but it may have effects also preventing the development of myocardial insufficiency in the acute setting of acute myocardial infarction. Scope of the meta-analysis is to evaluate the effect of Levosimendan on acute myocardial infarction in placebo-controlled trials. Based on the eight studies selected we found a beneficial effect of Levosimendan on acute and long-term mortality of patients affected by acute myocardial infarction with no significative increase in adverse events (Figure 1). With caution in interpreting the results of this meta-analysis, our data support the idea that Levosimendan may already have a role in the treatment of acute ischaemic heart disease. Further studies, specifically designed to investigate the early role in the treatment of ischaemic heart failure, are needed.

Meta-Analysis of Placebo-Controlled Trials of Levosimendan in Acute Myocardial Infarction

The treatment of acute myocardial infarction is early revascularization. Heart failure and cardiogenic shock may complicate acute myocardial infarction despite applying the best available strategy. Levosimendan is a relatively new drug to treat heart failure with a peculiar mechanism of action: calcium sensitization of myocardial fibres. Levosimendan has a direct inotropic effect but also pleiotropic effects; through the K+ATP channel’s opening, it also has a vasodilator effect which may participate concretely in the global effects of the drug. The focus of the literature is on the anti-heart failure and anti-cardiogenic shock properties of Levosimendan, but it may have effects also preventing the development of myocardial insufficiency in acute myocardial infarction. The aim of the meta-analysis is to evaluate the effect of Levosimendan on acute myocardial infarction in placebo-controlled trials. Based on the eight studies selected, we found a beneficial effect of Levosimendan on acute and long-term mortality of patients affected by acute myocardial infarction. With caution in interpreting the results of this meta-analysis, our data support the idea that Levosimendan may already have a role in the treatment of acute ischemic heart disease. Further studies specifically designed to investigate the early role in the treatment of ischemic heart failure are needed.

Enhanced KCl-mediated contractility and Ca2+ sensitization in porcine collateral-dependent coronary arteries persist after exercise training

Small coronary arteries distal to chronic occlusion displayed enhanced contractile responses, which were further augmented after exercise training and attributable to enhanced calcium sensitization without alterations in calcium channel current. The calcium sensitization mediators Rho-kinase and CaMKII significantly contributed to enhanced contraction in collateral-dependent arteries of exercise-trained, but not sedentary, pigs. Exercise-enhanced contractile responses may increase resting arterial tone, creating an enhanced coronary flow reserve that is accessible during periods of increased metabolic demand.

Botulinum toxin type A suppresses arterial vasoconstriction by regulating calcium sensitization and the endothelium-dependent endothelial nitric oxide synthase/soluble guanylyl cyclase/cyclic guanosine monophosphate pathway: An in vitro study

Botulinum toxin type A (BTX-A) is a potent neurotoxin that causes relaxation of striated muscle by inhibiting the release of acetylcholine at the neuromuscular junction. Some studies have suggested that BTX-A treatment for Raynaud syndrome is safe and effective with few adverse reactions. However, the underlying mechanism remains unclear. In the present study, we used both arterial rings isolated from rabbits and human microvascular endothelial cells (HMEC-1) to evaluate the mechanism underlying the effects of BTX-A on arterial vasoconstriction induced by 5-hydroxytryptamine. The roles of calcium sensitization and the endothelial nitric oxide synthase (eNOS)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway were investigated. BTX-A caused a concentration-dependent decrease in the contraction of endothelium-intact arteries and significantly reduced calcium sensitization in the arteries. Inhibitors of eNOS (L-NAME) and sGC (methylene blue) both significantly abolished the vasodilatory action of BTX-A. Furthermore, BTX-A increased eNOS activity and the cGMP level in dose- and time-dependent manners and increased eNOS and sGC protein levels in a time-dependent manner in HMEC-1. Taken together, these findings indicate that BTX-A suppresses arterial vasoconstriction by regulating smooth muscle calcium sensitization and the eNOS/sGC/cGMP pathway. Impact statement Raynaud syndrome (RS), usually caused by cold or mental stress, may lead to cyanosis and reactive hyperemia accompanied by pain or paresthesia. Although a variety of drugs have been used to alleviate the symptoms, the effects have not been satisfactory, so there is an urgent need to explore new alternative treatments. The present study investigated the mechanism underlying the effects of botulinum toxin type A (BTX-A) on arterial vasoconstriction, which may provide new approaches for RS. We found that BTX-A suppresses arterial vasoconstriction by regulating smooth muscle calcium sensitization and the endothelial nitric oxide synthase (eNOS)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway. These findings clarify the underlying mechanism of the effects of BTX-A on arterial vasoconstriction and provide new theoretical support for the use of BTX-A on RS. It may also help us to develop new medicines which regulate calcium sensitization and the eNOS/sGC/cGMP pathway against RS.

The absence of sympathoexcitation during the development of hypertension in Cyp1a1 Ren-2 transgenic rats

The insertion of mouse renin gene (Ren-2) into the genome of normotensive rats causes a spontaneous rise of blood pressure (BP), leading to an angiotensin II (Ang II)-dependent form of hypertension in transgenic (mRen-2)27 rats (TGR). However, enhanced sympathetic BP component was demonstrated in heterozygous TGR aged 20 weeks. In the present study we used another model, i.e. Cyp1a1-Ren-2 transgenic rats (iTGR) in which hypertension can be induced by natural xenobiotic indole-3 carbinol (I3C) added to the diet. We investigated whether the development of high blood pressure (BP) in 5-month-old iTGR animals fed I3C diet for 10 days is solely due to enhanced Ang II-dependent vasoconstriction or whether enhanced sympathetic vasoconstriction also participates in BP maintenance in this form of hypertension. Using acute sequential blockade of renin-angiotensin system (RAS), sympathetic nervous system (SNS) and NO synthase (NOS) we have demonstrated that the observed gradual increase of BP in iTGR fed I3C diet was entirely due to the augmentation of Ang II-dependent BP component without significant changes of sympathetic BP component. Thus, the hypertension in iTGR resembles to that of homozygous TGR in which high BP was entirely dependent on Ang II-dependent vasoconstriction. Moreover, our measurements of acute BP response to Rho kinase inhibitor fasudil in animals subjected to a combined blockade of RAS, SNS and NOS indicated the attenuation of basal calcium sensitization in both iTGR and homozygous TGR.