Mechanism of Cardiovascular Actions of Heptanolamines

Abstract

It has been suggested that heptaminol and methylheptaminol should be used as myocardial stimulants because they have cardiotonic actions similar to those of cardiac glycosides. However, as these aliphatic amines show definite sympathomimetic effects, the mechanism of their actions on the heart was investigated, in order to determine whether digitalis-like properties are involved in these effects. The pattern of pharmacological actions of heptaminol and methylheptaminol was compared with that of catechol amines, tyramine and k-strophanthin. The influence of atropine, hexamethonium, cocaine and reserpine was also investigated. The results show that both heptanolamines have a long-lasting cardiostimulant action which is abolished by cocaine and absent in reserpine pretreated animals. The pharmacological activity of these drugs may be entirely attributed to an indirect sympathomimetic action of the tyramine type, probably due to release of endogenous catechol amines. None of the experimental findings is consistent with the alleged digitalis-like action of these compounds.Among the aliphatic amines, the heptylamines with an alcoholic function on carbon two have been the object of a more detailed pharmacological study, as they show cardiostimulating properties which are particularly intense and long-lasting. The two most active compounds of the series, heptaminol (6-amino-2-methyl-2-heptanol; 2831 RP; Heptamyl; Cortensor) and methylheptaminol (6-methylamino-2-methyl-2-heptanol; 3738 RP; Aranthol), have been employed in the therapy of various clinical conditions including heart failure. Their use in heart failure is based on the experimental work of Loubatieres (1949aLoubatieres ( & b, 1951 and Loubatieres, Bouyard, Macabies & Mouralis (1949), who observed digitalis-like cardiotonic effects on the cat papillary muscle preparation fatigued by repeated electrical stimulation and on the dog ventricle ii situ. Coraboeuf & Boistel (1953), recording the action potentials of cardiac tissue by means of intracellular microelectrodes, concluded that heptaminol shows powerful cardiotonic effects.These heptanolamines, however, exhibit pharmacological actions which may be interpreted as depending on an activation of sympathetic receptors (Jackson, 1947;Walton, Belkin & Brodie, 1947;Huggins, Handley & La Forge, 1949;Marsh & Herring, 1951; Garrett, 1954; v. Haxthausen, 1955;Hille & Teske, 1957). It thus seems necessary to characterize the nature of their cardiostimulating action, in order to ascertain whether, as well as their sympathomimetic action, there is also a digitalis-like component which may significantly contribute to the cardiac effects.

Alteration of the L‐type calcium current in guinea‐pig single ventricular myocytes by heptaminol hydrochloride

“…Other mechanisms have been proposed to explain the cardiotonic effects of heptaminol: (1) the cardiovascular actions of heptanolamines were attributed to an indirect sympathomimetic action due to release of endogenous catecholamines (Garrett et al, 1962). This cannot explain our observations, since we are concerned with single isolated cells and the results described so far show mainly a reduction of peak Ic.…”

“…Since the early 1950's (Loubatieres, 1951), heptaminol (6amino 2-methyl heptanol) has been described as a cardiotonic molecule, mainly in cardiac ischaemic preparations and in drug-induced hypotension. Although some indications have been given about the mechanisms underlying these effects (Coraboeuf & Boistel, 1953;Garrett et al, 1962;Berthiau et al, 1989; see also Allard et al, 1991 on skeletal muscle), the action of heptaminol on ionic currents remains less understood. Due to the structure of its molecule, heptaminol is related both to alcohol and amine hydrocarbon derivatives.…”

“…Although some indications have been given about the mechanisms underlying these effects (Coraboeuf & Boistel, 1953;Garrett et al, 1962;Berthiau et al, 1989; see also Allard et al, 1991 on skeletal muscle), the action of heptaminol on ionic currents remains less understood. Due to the structure of its molecule, heptaminol is related both to alcohol and amine hydrocarbon derivatives.…”

Condensation of heptaminol hydrochloride for its spectrofluorimetric determination in pure form and tablets: application in human plasma

“…Its mechanism of action has not been defined, and could be due indirect sympathomimetic action, probably due to release of endogenous catechol amines. [1] Various methods have been reported for determining heptaminol in its dosage forms and in plasma. Spectrophotometric [2][3][4] , spectrofluorimetric [4][5][6][7][8] , chromatographic [9][10][11][12][13][14][15][16][17][18][19][20][21][22]] and capillary electrophoretic [23]…”

Utility of ninhydrin reagent for spectrofluorimetric determination of heptaminol in human plasma

“…Heptaminol (HEP) (6‐amino‐2‐methyl‐2‐heptanol hydrochloride, Figure ) is an amino alcohol drug that affects the cardiovascular system due to its positive inotropic action that causes an increase in the coronary blood flow accompanied by a slight peripheral vasoconstriction making it most commonly used for the treatment of orthostatic hypotension …”