eng Oriental Scientific Publishing Company Biomedical and Pharmacology Journal 0974-6242 2021-06-30 14 2 651 661 10.13005/bpj/2167 39044 article Pulat B. Usmanov 1 InoyatZ. Jumayev 1 Shavkat Yu. Rustamov 1 AbdisalimA. Zaripov 1 Adilbay T. Esimbetov 1 SherzodN. Zhurakulov 2 Institute of Biophysics and Biochemistry of National University of Uzbekistan, Tashkent, Uzbekistan. Institute of the Chemistry of Plant Substances, Uzbek Academy of Sciences, Tashkent, Uzbekistan. 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 K_ATP and BK_Ca 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. https://biomedpharmajournal.org/vol14no2/the-combined-inotropic-and-vasorelaxant-effect-of-dhq-11-a-conjugate-of-flavonoid-dihydroquercetin-with-isoquinoline-alkaloid-1-aryl-67-dimethoxy-12-34-tetrahydroisoquinoline/ Alkaloids  Aorta  Calcium Channel  Endothelium  Nitric Oxide  Positive Inotropic Effect  Papillary Muscle  Vasorelaxation