Vazodilatatorno delovanje donora azot monoksida i vodonik-sulfida na izolovanoj unutrašnjoj torakalnoj arteriji i veni safeni čoveka: uloga kalijumovih kanala

Abstract

Gasotransmiteri ostvaruju deo svojih uticaja na organizam regulacijom jonskih kanala, posebno kalijumovih (K+) kanala. Promenjena struktura/funkcija jonskih kanala, ali i poremećaji metabolizma i/ili nivoa gasotransmitera, povezani su sa nekoliko patofizioloških stanja, uključujući kardiovaskularne bolesti.Glavni cilj našeg istraživanja bio je ispitivanje mehanizama vazodilatatornog dejstva nikorandila, donora azot monoksida (NO), i natrijum-hidrogensulfida, donora vodonik-sulfida (H2S), na izolovanoj unutrašnjoj torakalnoj arteriji i veni safeni čoveka.Neiskorišćeni segmenti unutrašnje torakalne arterije i vene safene uzimani su od pacijenata tokom bajpas operacija. Ispitivanje je rađeno u in vitro uslovima u sistemu za izolovane organe. Koncentracijski-zavisne krive relaksacije konstruisane su na prekontrahovanim preparatima sa i bez endotela u prisustvu/odsustvu blokatora K+ kanala i/ili inhibitora signalnog puta cikličnog gvanozin-monofosfata (cGMP).Naši rezultati su pokazali da nikorandil i natrijum-hidrogensulfid prouzrokuju koncentracijski-zavisnu relaksaciju izolovane humane vene safene i unutrašnje torakalne arterije prekontrahovane fenilefrinom. Nikorandil izaziva endotel-nezavisnu, a natrijum-hidrogensulfid endotel-zavisnu relaksaciju oba krvna suda. Signalni put cGMP-a ima značajnu ulogu u vazorelaksantnom efektu nikorandila. Takođe, mehanizam dejstva natrijum-hidrogensulfida uključuje pojačanje NO/cGMP signalnog puta na oba krvna suda. Kalijumovi kanali doprinose relaksantnom dejstvu oba ispitivana agensa, s tim da postoje razlike u tipovima K+ kanala i njihovom relativnom značaju.S obzirom da se spazam vene safene i unutrašnje torakalne arterije i dalje javlja u kliničkim uslovima, a njegova prevencija i reverzija još uvek predstavljaju izazov, rezultati naše studije mogu ukazati na nove tarapijske ciljeve u lečenju spazma bajpas graftova i potencijalno dati farmakološku osnovu za razvoj novih vazodilatatornih lekova.

Gasotransmitters exert part of their impact on the organism via regulation of ion channels, especially potassium (K+) channels. Altered structure/function of ion channels, as well disorders of the metabolism and/or levels of the gasotransmitters are associated with several pathophysiological conditions, including cardiovascular diseases.The principal aim of our study was to investigate the mechanisms of vasodilator action of nicorandil, a nitric oxide (NO) donor, and of sodium hydrosulfide, a hydrogen sulfide (H2S) donor, on the isolated human internal thoracic artery and saphenous vein.Discarded segments of the internal thoracic artery and saphenous vein were collected from patients undergoing coronary artery bypass grafting. The investigation was performed in vitro in an isolated organs system. Concentration-response curves were constructed on pre-contracted preparations with and without endothelium in the presence/absence of K+ channel blockers and/or cyclic guanosine monophosphate (cGMP) pathway inhibitors.Our results showed that nicorandil and sodium hydrosulfide cause a concentration-dependent relaxation of the isolated human saphenous vein and internal thoracic artery pre-contracted by phenylephrine. Nicorandil exerts endothelium-independent and sodium hydrosulfide endothelium-dependent relaxation of both blood vessels. cGMP signalling pathway plays a significant role in the vasorelaxant effect of nicorandil. Also, sodium hydrosulfide mechanism of action involves enhancement of the NO/cGMP signalling pathway in both vessels. Potassium channels contribute to the relaxant effect of both investigated agents, although differences exist in K+ channel subtypes and their relative importance.Since the spasm of saphenous vein and internal thoracic artery still occurs in clinical settings, and its prevention and reversion is still challenging, the results of our study may indicate new targets in the treatment of bypass grafts spasm, and potentially provide a pharmacological basis for the development of new vasodilator drugs.