| Heart failure (CHF) is due to ventricular dysfunction caused by a clinical syndrome characterized by cardiac output showed a decline in ventricular filling pressure increases, can cause respiratory depression, fatigue and edema. Therefore, its treatment decisions generally focus on three major factors of heart function, or preload, afterload (resistance) and myocardial contractility. Therefore, to change or increase in vascular tension of myocardial contractility drugs are beneficial in treating heart failure. Currently used inotropic drug digitalis glycosides still and phosphodiesterase inhibitors (milrinone, amrinone) dominated. Cardiac glycoside drugs prone to long-term toxicity, long-term application of phosphodiesterase inhibitors drug side effects, a higher mortality rate. Therefore, research and development of new positive inotropic drugs and drugs to protect heart muscle is particularly important. Yanbian University College of Pharmacy to find more positive inotropic effect, less side effects treatment of heart failure inotropic agents, changing the quinolone ring of benzyl phenyl substituents, were designed and synthesized quinolinone derivatives PHR0007, but its cardiac effects and action mechanism is not clear.This study used this isolated perfused beating atrial model, use of rabbits, weighing 1.8-2.0 kg, either male or female, by comparing inotropes milrinone observed PHR0007 different concentrations (1.0,30.0,100.0μmol/L) for atrial pulse pressure and stroke volume effects, and are using non-specific protein kinase inhibitor staurosporine, cAMP (cyclic adenosine monophosphate, cAMP)-dependent protein kinase (protein kinase A, PKA) selective inhibition Agent H-89, non-specific phosphodiesterase (phosphodiesterases, PDEs) inhibitor 3-isobutyl-1-methyl xanthine (3-isobutyl-1-methylxan-thine, IBMX) and adenylyl cyclase (activator of adenylyl cyclases, AC) activator forskolin of PHR0007 rabbit atrial positive inotropic effect of the mechanisms for the further development of cardiac drugs provide an important experimental basis. The results of the present study showed that:1.Effects of PHR0007(1.0μmol/L,30.0μmol/L, and 100.0μmol/L) significantly increased atrial pulse pressure (under 1μmol/L P>0.05 vs control cycle; under 30.0μmol/L P<0.001 vs control cycle; under 100μmol/L P<0.001 vs control cycle respectively) and atrial stroke volume (under 1μmol/L P>0.05 vs control cycle; under 30.0μmol/L P<0.001 vs control cycle; under 100.0μmol/L P<0.001 vs control cycle respectively)in beating rabbit atria compared with control baseline levels. and atrial pulse pressure with dose-dependent manner. The most effect of PHR0007on the atrial dynamics was observed in 30μmol/L. 2.Staurosporine(1.0μmol/L), an nonspecific inhibitor of protein kinase significantly decreased atrial pulse pressure and atrial stroke volume in beating rabbit atria (P<0.001 vs control cycle respectively), and the staurosporine completely blocked the effect of PHR0007 on atrial dynamics (P<0.001 vs staurosporine alone).3.H-89 (10.0μmol/L), a cAMP-dependent inhibitor of protein kinase A significantly decreased atrial pulse pressure and atrial stroke volume in beating rabbit atria (P<0.001 vs control cycle respectively), and the H-89 completely blocked the effect of PHR0007 on atrial dynamics (P<0.001 vs H-89 alone).4.Forskolin (1.0μmol/L), a directly activator of adenylyl cyclase failed to modulation of PHR0007-increased atrial pulse pressure secretion and atrial stroke volume secretion.5.PDEs blocker significantly change the effect of PHR0007-induced increased of atrial pulse pressure secretion and atrial stroke volume secretion.6.PHR0007 significantly increased atrial pulse pressure(P<0.001 vs milrinone) and atrial stroke volume(P<0.001 vs milrinone) in beating rabbit atria compared with milrinone.These results indicate that:PHR0007 increases atrial dynamics by dose-dependent manner in perfused beating rabbit atria via PDE-cAMP-PKA channels. |
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