Search

The endogenous gasotransmitter hydrogen sulphide (HS) is an important regulator of the cardiovascular system, particularly of myocardial function. Moreover, HS exhibits cardioprotective activity against ischemia/reperfusion (I/R) or hypoxic injury, and is considered an important mediator of "ischemic preconditioning", through activation of mitochondrial potassium channels, reduction of oxidative stress, activation of the endogenous "anti-oxidant machinery" and limitation of inflammatory responses. Accordingly, HS-donors, i.e. pro-drugs able to generate exogenous HS, are viewed as promising therapeutic agents for a number of cardiovascular diseases. The novel HS-donor 4-carboxy phenyl-isothiocyanate (4CPI), whose vasorelaxing effects were recently reported, was tested here in different experimental models of myocardial I/R. In Langendorff-perfused rat hearts subjected to I/R, 4CPI significantly improved the post-ischemic recovery of myocardial functional parameters and limited tissue injury. These effects were antagonized by 5-hydroxydecanoic acid (a blocker of mitoK channels). Moreover, 4CPI inhibited the formation of reactive oxygen species. We found the whole battery of HS-producing enzymes to be present in myocardial tissue: cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST). Notably, 4CPI down-regulated the post-ischemic expression of CSE. In Langendorff-perfused mouse hearts, 4CPI reduced the post-ischemic release of norepinephrine and the incidence of ventricular arrhythmias. In both rat and mouse hearts, 4CPI did not affect the degranulation of resident mast cells. In isolated rat cardiac mitochondria, 4CPI partially depolarized the mitochondrial membrane potential; this effect was antagonized by ATP (i.e., the physiological inhibitor of K channels). Moreover, 4CPI abrogated calcium uptake in the mitochondrial matrix. Finally, in an in vivo model of acute myocardial infarction in rats, 4CPI significantly decreased I/R-induced tissue injury. In conclusion, HS-donors, and in particular isothiocyanate-based H2S-releasing drugs like 4CPI, can actually be considered a suitable pharmacological option in anti-ischemic therapy.

Brief periods of ischemia are known to confer to the myocardium an increased resistance to the injury due to a later and more prolonged ischemic episode. This phenomenon, known as ischemic preconditioning (IPreC), is ensured by different biological mechanisms. Although an exhaustive comprehension of them has not been reached yet, it is widely accepted that mitochondria are pivotally involved in controlling cell life and death, and thus in IPreC. Among the several signaling pathways involved, as triggers and/or end effectors, in the mitochondrial mechanisms of cardioprotection, an important role is played by the activation of potassium channels located in the mitochondrial inner membrane (mitoK) of cardiomyocytes. Presently, different types of mitoK channels have been recognized in the heart, such as ATP-sensitive (mitoKATP) and calcium-activated (mitoBK(Ca) and mitoSK(Ca)) potassium channels. Consistently, drugs modulating mitoK, on one hand, have been employed as useful experimental tools for early basic studies on IPreC. On the other hand, activators of mitoK are promising and innovative therapeutic agents for limiting the myocardial injury due to ischemic episodes. In this review, we report the experimental evidence supporting the role of mitoK in signaling pathways in the mechanisms of cardioprotection and an overview on the most important molecules acting as modulators of these channels, with their profiles of selectivity. Some innovative pharmaceutical strategies for mitochondriotropic drugs have been also reported. Finally, an appendix describing the main experimental approaches usually employed to study mitoK in isolated mitochondria or in intact cells has been added.

Hydrogen sulphide (H(2)S) is emerging as an important endogenous modulator, which exhibits the beneficial effects of nitric oxide (NO) on the cardiovascular (CV) system, without producing toxic metabolites. H(2)S is biosynthesized in mammalian tissues by cystathionine-β-synthase and cystathionine-γ-lyase. H(2)S exhibits the antioxidant properties of inorganic and organic sulphites, behaving as a scavenger of reactive oxygen species. There is also clear evidence that H(2)S triggers other important effects, mainly mediated by the activation of ATP-sensitive potassium channels (K(ATP)). This mechanism accounts for the vasorelaxing and cardioprotective effects of H(2)S. Furthermore, H(2)S inhibits smooth muscle proliferation and platelet aggregation. In non-CV systems, H(2)S regulates the functions of the central nervous system, as well as respiratory, gastroenteric, and endocrine systems. Conversely, H(2)S deficiency contributes to the pathogenesis of hypertension. Likewise, impairment of H(2)S biosynthesis is involved in CV complications associated with diabetes mellitus. There is also evidence of a cross-talk between the H(2)S and the endothelial NO pathways. In particular, recent observations indicate a possible pathogenic link between deficiencies of H(2 S activity and the progress of endothelial dysfunction. These biological aspects of endogenous H(2)S have led several authors to look at this mediator as "the new NO" that has given attractive opportunities to develop innovative classes of drugs. In this review, the main biological actions of H(2)S are discussed. Moreover, some examples of H(2)S-donors are shown, as well as some hybrids, in which H(2)S-releasing moieties are added to well-known drugs, for improving their pharmacodynamic profile or reducing the potential for adverse effects, are reported.