Apparent superiority of H2-receptor stimulation and simultaneousβ-blockade over conventional treatment withβ-sympathomimetic drugs in post-acute myocardial infarction: Cardiac effects of impromidine — a new specific H2-receptor agonist — in the surviving catecholamine-insensitive myocardium

Abstract

Left ventricular infarction (AMI) was produced in experimental animals and the contractile response to beta-adrenergic and H2-histaminergic stimulation by isoproterenol and impromidine tested in the isolated perfused heart preparation. Adenylate cyclase activity as well as binding characteristics of [3H]-dihydroalprenolol ([3H]-DHA), [3H]-methyl-tiotidine ([3H]-TIOT) and [3H]-quinuclidinyl benzilate ([3H]-QNB) to cardiac beta 1-, H2- and cholinergic muscarinic receptors were determined in sarcolemmal membrane preparations of the right ventricle of the same hearts. In addition, an attempt was made to elucidate the therapeutic value of post-AMI treatment with impromidine in the presence and absence of beta-blockade, in contrast to administration of prenalterol and the conventional therapy with beta-sympathomimetic drugs, e.g. dobutamine. Three days post-AMI the dose-response curve for isoproterenol of right ventricular dP/dtmax was significantly depressed, while the inotropic effect of impromidine was not impaired. Stimulation of adenylate cyclase activity by isoproterenol was reduced by 80% whereas impromidine and NaF stimulation rates were unaltered. Receptor-binding studies indicated a 90% loss and 10-times lowered affinity (KD) of the remaining beta-receptors while specific [3H]-TIOT- and [3H]-QNB-binding was unchanged. Administration of dobutamine increased mortality rates and extension of infarct size, led to a further decrease in contractile response to isoproterenol, induced complete insensitivity of adenylate cyclase to isoproterenol stimulation and caused pronounced additional reduction of number and affinity of [3H]-DHA-binding sites. In contrast, all above alterations were prevented by treatment with either prenalterol or combined administration of impromidine plus metoprolol. It is concluded, that these alterations in the non-ischemic, uninvolved myocardium post-AMI are the result of catecholamine-induced specific damage of sarcolemmal beta-receptors. Furthermore, treatment with H2-agonists in combination with beta-blocking agents may have beneficial effects, whereas conventional therapy with beta-sympathomimetic drugs tends to worsen the already depressed function of the beta-adrenergic stimulation mechanism.

Acylguanidines as Bioisosteres of Guanidines: NG-Acylated Imidazolylpropylguanidines, a New Class of Histamine H2 Receptor Agonists

“…Toward the synthesis of N G -acylated guanidines, a guanidine building block is coupled to carboxylic acids to make use of common coupling reagents. The protected alkylated guanidines were prepared starting from alcohols (10,12) or amine 20 (Scheme 1). 29 Guanidine hydrochloride was treated with sodium hydroxide and benzyloxycarbonyl chloride to yield a nucleophilic guanidinylation reagent (13) toward alcohols.…”

“…Compared to amine-type H 2 R agonists such as histamine, dimaprit, and amthamine, guanidine-type compounds are much more potent. Impromidine (Figure ), which is about 50 times more potent than histamine at the guinea pig right atrium, was investigated for the treatment of patients suffering from severe catecholamine-insensitive congestive heart failure. , Arpromidine (Figure ) and related N -[3-(1 H -imidazol-4-yl)propyl]guanidines were developed as positive inotropic vasodilators (“cardiohistaminergics”) and were superior to impromidine in terms of potency and hemodynamic profile when tested in the guinea pig under physiological conditions and in a pathophysiological model of severe congestive heart failure (vasopressin-induced acute heart failure). ,, Arpromidine and related guanidine-type agonists represent the most potent H 2 R agonists known so far, achieving up to 400 times the potency of histamine on the spontaneously beating guinea pig right atrium. The binding site of histamine in the H 2 R was identified by in vitro mutagenesis studies and modeling approaches based on the crystal structure of rhodopsin .…”

Structure-Activity Relationships of Histamine H2 Receptor Ligands+

“…By using impromidine, Baumann and co-workers demonstrated that H 2 R stimulation may be an effective treatment in patients suffering from severe catecholamine-insensitive congestive heart failure [67]. Arpromidine (9) and related N-…”

Resposta cronotrópica ao teste cardiopulmonar após o uso de cimetidina

“…Histamine has several effects on cardiac performance, mediated by H 1 and H 2 receptors 3,4 . The latter are responsible for the positive chronotropic effect of histamine and are found mainly in the right atrium and around the sinus node 5 .…”