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.