Hemodynamic profile of arpromidine and its F2-substituted derivatives in comparison to impromidine in congestive heart failure

There is considerable evidence that congestive heart failure (CHF) is paralleled by a decrease in the number of sarcolemmal β-receptors due to excessive levels of circulating endogenous catecholamines [1, 2]. In contrast, the myocardial H2-receptor system is not affected. The first clinically available specific H2-receptor agonist impromidine proved to be a potent inotrope in patients with CHF which were insensitive to catecholamine stimulation [3, 4]. Though the overall results of these initial studies were beneficial, the narrow therapeutic range, high costs of synthesis and the arrhythmogenic potential of impromidine limited its broad clinical application in large scale clinical trials. Recently developed phenylpyridylalkylguanidines [5] were investigated underin vitro andin vivo conditions in the guinea pig under physiologic and pathophysiologic conditions using impromidine as reference. Compounds tested were arpromidine 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 underin vivo conditions where BU-E-76 was more potent than BU-E-75, arpromidine and impromidine, respectively, in augmenting LV dp/dt, LVP, cardiac output and systemic blood pressure, but all compounds were revealed to have less chronotropic and arrhythmogenic potential. In the vasopressin-induced acute heart failure model, BU-E-76 and BU-E-75 normalized within minutes all contractile parameters in contrast to arpromidine and impromidine. It is thus concluded that these new H2-receptor agonists may represent a promising therapeutic improvement for treatments of CHF patients, with a cardiovascular profile superior to impromidine and conventional catecholamines.