Effects of carvedilol on nitric oxide (NO) activity/expression in patient with chronic heart failure (CHF)

Abstract

Previous studies have reported increased myocardial inducible nitric oxide synthase (iNOs) expression and activity in chronic heart failure (ChF). Nitric oxide (NO) is a free radical which reacts with various molecules to cause multiple biological effects. Carvedilol is a α1-, β1-, and β2-adrenergic antagonist, used in therapy of hypertension and ChF. recently, it has been shown that carvedilol has an effect as NO quenching agent. Carvedilol presents several other mechanisms of action that converge to improve the symptomatology of hypertension and CHF. In addition to the adrenergic antagonism, carvedilol is also an antioxidant and endothelin suppressor. The molecular mechanism for the NO quenching potency of carvedilol remains to be determined. In cardiac cells the major pathway responsible for the regulation of iNOS activity/expression involves the activation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (Akt). Thus, in our current ongoing and future studies, we will test the hypothesis that in disease states such as CHF where the PI3K/Akt pathway is interrupted, the regulation of iNOS activity/expression will be abolished. as a corollary of this primary hypothesis, we postulate that in CHF carvedilol stimulates cardiovascular iNOS via a mechanism involving activation of PI3K/akt cascade and further amplifies iNOS activity/expression. Moreover, since the PI3K/akt pathway have been acknowledged as a critically important mediator of cardiac iNOS regulation, PI3K/akt are identified as one of key targets for novel therapeutic interventions to minimize irreversible tissue damage associated with CHF and hypertension. A safer technology to regulate in vivo synthesis of PI3K/akt by generic manipulation would be a welcome work.

Azot oksid (NO) je slobodni radikal čije reakcije dovode do različitih bioloških dejstava. Karvedilol je antagonist α1-, β1-,i β2 adrenergičkih receptora koji se koristi u terapiji hipertenzije i nedavno je pokazano da hemijski reaguje sa NO. Pored adrenergičke blokade karvedilol doprinosi poboljšanju hipertenzije i HSI drugim mehanizmima. Takođe, pokazano je da karvedilol ima ulogu antioksidansa i ulogu u supresiji endotelina. Precizan mehanizam interakcije karvedilola i NO do sada nije u potpunosti razjašnjen. aktivnost/ekspresija inducibilne azot oksid sintetaze (iNOS) u kardiomiocitima dominantno je regulisana aktivacijom fosfatidilinozitol 3-kinaze (PI3K) i protein kinaze B (akt). U našim tekućim i planiranim istraživanjima, polazimo od hipoteze da je u HSI poremećen PI3K/akt signalni put, a time konsekventno i smanjena aktivnost/ekspresija iNOS-a. Takođe, naša hipoteza se bazira na pretpostavci da karvedilol u HSI stimuliše iNOS u kardiovaskularnom sistemu preko aktivacije PI3K/Akt kaskade. U zaključku, regulacija PI3K/Akt signalnog puta ima veoma bitnu ulogu u regulaciji iNOS-a u stanjima HSI. S obzirom da PI3K/Akt signalni put ima biološku ulogu kao kritično-važni signalni put u delovanju adrenergičkih lekova, kao što je karvedilol, to ga čini ključnim za terapeutske intervencije u cilju minimalizacije ireverzibilnih tkivnih i ćelijskih oštećenja koja su asocirana sa HSI i hipertenzijom.