The Combined Inotropic and Vasorelaxant Effect Of DHQ-11, A Conjugate of Flavonoid Dihydroquercetin with Isoquinoline Alkaloid 1-Aryl-6,7-Dimethoxy-1,2.3,4-Tetrahydroisoquinoline.
Pulat B. Usmanov1., Inoyat Z. Jumayev1*., Shavkat Yu. Rustamov1., Abdisalim A. Zaripov1., Adilbay T. Esimbetov., Sherzod N. Zhurakulov2 and Valentina I. Vinogradova2.1Institute of Biophysics and Biochemistry of National University of Uzbekistan, Tashkent, Uzbekistan.
2Institute of the Chemistry of Plant Substances, Uzbek Academy of Sciences, Tashkent, Uzbekistan.
Corresponding Author E-mail : inoyat8585@mail.ru
Abstract: This study investigated the positive inotropic andvasorelaxant activity ofDHQ-11, aconjugate of flavonoid dihydroquercetin with isoquinoline alkaloid 1-aryl-6,7-dimethoxy-1,2.3,4-tetrahydroisoquinoline.A study was performed using anterior papillary muscle removed from the left ventricle and thoracic aorta dissected from rats. DHQ-11 produceda concentration-dependent positive inotropic effect which was more potent than their parent compounds alone. The positive inotropic effect of conjugate DHQ-11was significantly attenuated by the β-adrenoreceptor inhibitor propranolol and L-type Ca2+ channel blocker nifedipine. Also,conjugate DHQ-11 markedly potentiated first post-rest responses indicating that it can modulate Ca2+ loading/release processes in the sarcoplasmic reticulum.These results suggest that positive inotropic effect produced by conjugate DHQ-11may be mediated through activation oftheβ-AR/AC/cAMP/PKA pathway that leads to increased Ca2+ influx and rises in Ca2+ loading/release in the SR, resulting in increased [Ca2+]i and enhanced contraction force. DHQ-11 significantly relaxed both high KCl- and phenylephrine-induced contractions of rat aortic rings whichwere significantly inhibited by lowering extracellular Ca2+ concentration and in the presence of verapamil.DHQ-11 significantly inhibited phenylephrine-induced contractions in a Ca2+-free medium, in the presence of verapamil. The vasorelaxant effect of the DHQ-11 was significantly reduced by the removal of endothelium and in the presenceof L-NAME and methylene blue as well as glibenclamide and TEA.These results suggest that the vasorelaxation produced by conjugate DHQ-11may be mediatedbyan endothelium-independent mechanism involving activation of KATP and BKCa channels and inhibition of L-type VDCCs and Ca2+ release from the sarcoplasmic reticulum and endothelium-dependent mechanism through activation of the NO/sGC/cGMP/PKG signaling pathway resulting in a decrease of intracellular Ca2+levels. These observations reveal that the conjugate DHQ-11 due to its high positive inotropic and vasorelaxant activity could be a promising compound for the design and development of new drugs for the treatment of heart failure.
Keywords: Alkaloids; Aorta; Calcium Channel; Endothelium; Nitric Oxide; Positive Inotropic Effect; Papillary Muscle; Vasorelaxation Back to TOC