title: Pharmacological characterization of the vascular effects of aryl isothiocyanates: is hydrogen sulfide the real player?
abstract: Hydrogen sulfide (H₂S) is an endogenous gasotransmitter, which mediates important physiological effects in the cardiovascular system. Accordingly, an impaired production of endogenous H₂S contributes to the pathogenesis of important cardiovascular disorders, such as hypertension. Therefore, exogenous compounds, acting as H₂S-releasing agents, are viewed as promising pharmacotherapeutic agents for cardiovascular diseases. Thus, this paper aimed at evaluating the H₂S-releasing properties of some aryl isothiocyanate derivatives and their vascular effects. The release of H₂S was determined by amperometry, spectrophotometry and gas/mass chromatography. Moreover, the vascular activity of selected isothiocyanates were tested in rat conductance (aorta) and coronary arteries. Since H₂S has been recently reported to act as an activator of vascular Kv7 potassium channels, the possible membrane hyperpolarizing effects of isothiocyanates were tested on human vascular smooth muscle (VSM) cells by spectrofluorescent dyes. Among the tested compounds, phenyl isothiocyanate (PhNCS) and 4-carboxyphenyl isothiocyanate (PhNCS-COOH) exhibited slow-H₂S-release, triggered by organic thiols such as L-cysteine. These compounds were endowed with vasorelaxing effects on conductance and coronary arteries. Moreover, these two isothiocyanates caused membrane hyperpolarization of VSM cells. The vascular effects of isothiocyanates were strongly abolished by the selective Kv7-blocker XE991. In conclusion, the isothiocyanate function can be viewed as a suitable slow H₂S-releasing moiety, endowed with vasorelaxing and hypotensive effects, typical of this gasotransmitter. Thus, such a chemical moiety can be employed for the development of novel chemical tools for basic studies and promising cardiovascular drugs.
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, via Bonanno, 6, I-56126 Pisa, Italy. Electronic address: alma.martelli@farm.unipi.it.
authors.forename: Alma
authors.initials: A
authors.lastname: Martelli
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, via Bonanno, 6, I-56126 Pisa, Italy. Electronic address: lara.testai@farm.unipi.it.
authors.forename: Lara
authors.initials: L
authors.lastname: Testai
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, via Bonanno, 6, I-56126 Pisa, Italy. Electronic address: valentina.citi@libero.it.
authors.forename: Valentina
authors.initials: V
authors.lastname: Citi
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, via Bonanno, 6, I-56126 Pisa, Italy. Electronic address: alice.marino@for.unipi.it.
authors.forename: Alice
authors.initials: A
authors.lastname: Marino
authors.affiliation: Dipartimento di Chimica e Chimica Industriale, Università di Pisa, via Risorgimento, 35, I-56126 Pisa, Italy.
authors.forename: Francesca G
authors.initials: FG
authors.lastname: Bellagambi
authors.affiliation: Dipartimento di Chimica e Chimica Industriale, Università di Pisa, via Risorgimento, 35, I-56126 Pisa, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ghimenti
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, via Bonanno, 6, I-56126 Pisa, Italy. Electronic address: breschi@farm.unipi.it.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Breschi
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, via Bonanno, 6, I-56126 Pisa, Italy. Electronic address: calderone@farm.unipi.it.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calderone
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D066298:In Vitro Techniques; D017879:Isothiocyanates / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D017879:Isothiocyanates; D006862:Hydrogen Sulfide
keywords: 2-isopropyl phenylisothiocyanate; 2-trifluorometyl phenylisothiocyanate; 4-carboxyphenyl isothiocyanate (PubChem CID: 242946); 4-carboxyphenylisothiocyanate; AB; ACh; AngII; CF; CSE; DADS; DMSO; DiBac4(3); Diallyl disulfide (PubMed CID: 16590); GYY4137; GYY4137 (PubMed CID: 53393943); H(2)S; H(2)S-releasing drugs; HASMC; HR; Hydrogen sulfide; Hydrogen sulfide (PubChem CID: 402); Hypertension; Isothiocyanate; LVDP; NA; NO; PhNCS; PhNCS-CF(3); PhNCS-CH(3); PhNCS-COOH; PhNCS-iPr; Phenyl isothiocyanate (PubChem CID: 7673); SBP; SMGS; VSM; Vascular smooth muscle; acetylcholine; angiotensin II; assay buffer; bisoxonol dye bis-(1,3-dibutylbarbituric acid); coronary flow; cystathionine-gamma-lyase; diallyl disulfide; dimethylsulfoxide; heart rate; human aortic smooth muscle cell; hydrogen sulfide; l-NAME; l-nitroarginine methyl ester; left ventricular developed pressure; metyl-phenylisothiocyanate; morpholin-4-ium-4-methoxyphenyl-morpholino-phosphinodithioate; nitric oxide; noradrenaline; phenylisothiocyanate; smooth muscle growth supplement; systolic blood pressure; vascular smooth muscle