Therapeutic value of H2-receptor stimulation in congestive heart failure. Hemodynamic effects of BU-E-76, BU-E-75 and arpromidine (BU-E-50) in comparison to impromidine.
Previous studies from our department revealed that congestive heart failure (CHF) is paralleled by a decrease in number of sarcolemmal beta-receptors due to excessive levels of circulating endogenous catecholamines. In contrast, the myocardial H2-receptor system proved to be not affected (Am. Heart J. 101; 569, 1981). The first clinically tested specific H2-receptor agonist impromidine (IMP) turned out to be a potent stimulator in patients with CHF which were insensitive to catecholamine stimulation (Pharmacol. Ther. 24; 165, 1984). Though the overall results of such an H2-receptor stimulation were salutary with favourable hemodynamic effects, the narrow therapeutic range, high costs of synthesis and the arrhythmogenic potential of IMP limited its broad clinical application in large scale trials. - Recently developed phenylpyridylalkylguanidines (J. Med. Chem. 32, 1963, 1989) were investigated under in vitro and in vivo conditions in the guinea-pig under physiologic and pathophysiologic conditions using IMP as reference. - Compounds tested were arpromidine (INN) (BU-E-50) and the difluorinated analogues BU-E-75 and BU-E-76, all guanidine-type H2-agonists with additional H1-antagonistic properties due to a pheniramine like moiety. In the isolated perfused heart all three new compounds were more potent in increasing cardiac contractile force and coronary flow but less effective on heart rate and less arrhythmogenic. The same could be established under in vivo conditions where BU-E-76 was more potent than BU-E-75, arpromidine and IMP, respectively, in augmenting LVdp/dt, LVP, cardiac output and systemic blood pressure, but all compounds revealed to have less chronotropic and arrhythmogenic potentials. In the vasopressin-induced acute heart failure model BU-E-76 and BU-E-75 normalized all contractile parameters in contrast to arpromidine and IMP. Within minutes it is concluded that the new H2-receptor agonists may represent a promising therapeutic improvement for treatment of CHF patients with a cardiovascular profile superior to IMP and conventional catecholamines.
Felix
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SB
I. Medical Clinic, Division Cardiology and Circulation, Technical University of Munich, FRG.
Buschauer
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A
Baumann
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D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006146:Guanidines / Q000494:pharmacology / Q000627:therapeutic use*; D006168:Guinea Pigs; D006333:Heart Failure / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D017446:Impromidine; D011970:Receptors, Histamine H2 / Q000187:drug effects / Q000502:physiology; D013318:Stroke Volume / Q000187:drug effects; D014667:Vasopressins
D002316:Cardiotonic Agents; D006146:Guanidines; D007093:Imidazoles; D011970:Receptors, Histamine H2; D014667:Vasopressins; C069358:BU-E 75; C069359:BU-E 76; C060591:arpromidine; D017446:Impromidine