Vascular Effects of p-Carboxyphenyl-Isothiocyanate, a novel H2S-donor

Hydrogen sulfide (H2S), is a pivotal mediator in cardiovascular physiology. This gasotransmitter evokes vasorelaxing effects through different mechanisms of action, such as the inhibition of phosphodiesterases and activation of vascular KATP and Kv7 potassium channels. Indeed, impaired production of H2S contributes to the pathogenesis of important cardiovascular disorders [1]. Therefore, exogenous compounds, acting as H2S-releasing agents, are viewed as promising therapeutic agents for cardiovascular diseases. This work aimed at evaluating the H2S-releasing properties of the p-Carboxyphenyl-Isothiocyanate (PhNCS-COOH) derivative and its vascular effects. H2S release was first determined by the amperometric approach, and unequivocally confirmed by gas chromatography/mass spectrometry. Unlike NaHS, a fast H2S-donor widely used in the laboratory but unsuitable for clinical use, PhNCS-COOH exhibited a slow H2S-releasing profile, similar to the slow-releasing reference drugs diallyldisulfide (DADS) and GYY4137. H2S release from PhNCS-COOH occurred only in the presence of an excess of L-Cysteine: this thiol-dependency has been viewed as a particularly advantageous property, because it allows this compound to release H2S only in a biological environment. The vascular activity of PhNCS-COOH was tested in rat aorta and coronary arteries. Like NaHS, PhNCS-COOH displayed concentration-dependent vasorelaxing effects on endothelium-denuded rat aortic rings. These effects were significantly antagonized by the Kv7 blocker XE991. PhNCS-COOH also inhibited the vasoconstricting effect of noradrenaline (NA), with greater potency than NaHS. In addition, the isothiocyanate derivative increased basal coronary flow similarly to NaHS. Furthermore PhNCS-COOH was more effective than NaHS in counteracting the coronary vasoconstriction induced by angiotensin II. Since H2S is known to hyperpolarize vascular smooth muscle by activating KATP and Kv7 channels [1,2], we evaluated its effects on the membrane potential of human aortic smooth muscle cells (HASMC) using a membrane potential sensitive fluorescent dye. Like the reference Kv7 activator Retigabine, PhNCS-COOH evoked a marked hyperpolarization, largely due to the activation of Kv7 channels [3]. In conclusion, PhNCS-COOH can be viewed as a new suitable slow H2S-releasing drug, endowed with vasorelaxing effects, typical of the endogenous gasotransmitter. PhNCS-COOH might be employed as a novel chemical tool in basic studies and in the development of original drugs in cardiovascular diseases.