We examined whether human cardiac tissue contains diadenosine polyphosphates and investigated their physiological role. Extracts from human cardiac tissue from transplant recipients were fractionated by size exclusion-, affinity-, anion exchange- and reversed-phase chromatography. MALDI-MS analysis of two absorbing fractions revealed molecular masses of 676.2 Da and 756.0 Da. The UV spectra of both fractions were identical to that of adenosine. Postsource decay MALDI mass spectrometry indicated that the molecules with a mass of 676.2 Da and 757.0 Da contained AMP and ATP, respectively. As shown by enzymatic cleavage, both molecules consist of two adenosines interconnected by either two or three phosphates in 5'-positions of the riboses. Two substances can be identified as 5',5"'-P1,P2-diphosphate (Ap2A) and 5',5"'-P1, P3-triphosphate (Ap3A). Ap2A and Ap3A, together with ATP and ADP, are stored in myocardial-specific granules in biologically active concentrations. In the isolated perfused rat heart, Ap2A and Ap3A caused dose-dependent coronary vasodilations. In myocardial preparations, Ap2A and Ap3A attenuated the effect of isoproterenol, exerting a negative inotropic effect. The calcium current of guinea pig ventricular myocytes, stimulated by isoproterenol, was also attenuated by Ap2A and Ap3A. The presence of Ap2A and Ap3A in cardiac-specific granules and the actions of these substances on the myocardium and coronary vessels indicate a role for these substances as endogenous modulators of myocardial functions and coronary perfusion.
Fifteen novel amiloride analogues were synthesized and their diuretic properties compared to amiloride and triamterene in white wistar rats. Whereas none of the 6-substituted derivatives exhibited significant natriuretic and antikaliuretic effects, five of the compounds modified in the 2-position were found equal or better than standards. The results are discussed with respect to chemical structure and physiochemical properties.
A series of partially hydrogenated imidazo[1,2-c]pteridines IXa – IXc, XIa - XIf and XVa - XVc, pyrimidol[1,2-c]pteridines XIIa - XIId and XVIa - XVIc, and 1,3-diazepinol[1,2-c]pteridines XIIIa - XIIIc and XVII have been prepared from 2-amino-3-cyanopyrazines I via reactions of I with alkanediamines II - IV and subsequent condensation of the resulting intermediates V - VII with orthoesters VIII, aldehydes X and ketones XIV.
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