Some characteristics of the inotropic effects of histamine H1- and H2-receptor agonists in comparison with those of alpha- and beta-adrenoceptor agonists

Abstract

The positive inotropic effects of 2-pyridyl-ethylamine (PEA) and of 4-methylhistamine (4MeH) were studied in isolated guinea-pig ventricular strips electrically stimulated at a rate of 60 and 150/min. The increase in contractile tension induced by PEA (10(-7)-3 X 10(-4) M) in the presence of cimetidine (10(-5) M) was associated with a slight increase in time to peak tension and with a lengthening of the relaxation phase; the positive inotropic effect of PEA was significantly higher at a frequency of 60/min than at 150/min. Conversely, the inotropic response to 4MeH (10(-8)-3 X 10(-6) M) was not frequency dependent, and was associated with an evident decrease in relaxation time. Moreover, 4MeH consistently antagonized, in dose-dependent manner, the negative inotropic effects induced by the calcium antagonistic drug D600 and by lowering calcium concentration in the medium, and was able to restore the contractility abolished by treatment of preparations with a high K+ medium. On the other hand PEA, in the presence of cimetidine, scarcely antagonized the negative inotropic effects induced either by D600 or by low calcium solution, and was unable to restore the contractility of K+-depolarized preparations. The characteristics of the inotropic response of the H1-receptor agonist were very similar to those of the alpha-adrenoceptor agonist phenylephrine. This observation suggests that a common mechanism is probably involved in the inotropic effects mediated by H1 and by alpha receptors, and that this mechanism does not include a stimulation of the calcium transmembrane influx.

On the presence of H1-receptors in various sections of guinea-pig heart: A correlation between binding and functional studies

“…Thus, binding studies confirm the presence and the functional role of ventricular H~-receptors [7, 8,10] and support the results of REZNHARDT et al [14] and AMEmNI et al [7], who demonstrated an H lmediated positive inotropic effect in the right atrium. Thus, binding studies confirm the presence and the functional role of ventricular H~-receptors [7, 8,10] and support the results of REZNHARDT et al [14] and AMEmNI et al [7], who demonstrated an H lmediated positive inotropic effect in the right atrium.…”

“…Nevertheless, the effects on contractility cannot be considered a definite proof of the presence of Hi-receptors, since these effects are dependent on several experimental conditions such as the driving rate [8], and even difference of animal strain [15], thus leading to conflicting results.…”

H1- and H2-receptors in the guinea-pig heart: an electrophysiological study

“…On the other hand, we observed that PEA caused an unexpectedly small inotropic effect in the left atrium. This result can be explained if we bear in mind that the PEAmediated inotropic effect is strongly frequency dependent [19] as is the histamine one in the left atrium [22], and that VEgMA and MCNEILL [5] stimulated the left atrium at a much lower frequency than we did.…”

“…2) caused an increase in contraction force in ventricular strips; this increase was not modified by triprolidine (10 -6 M), an HFreceptor-blocking drug with no significant cocaine-like activity [18]. The lack of effect of triprolidine was not surprising since it has been demonstrated in our laboratory [19] that triprolidine shifts only the lower part of the PEA dose-response curve to the right, i.e. for PEA concentrations lower than 3 x 10 -5 M. Even if the strong frequency dependence of PEA-induced inotropic effect [19] makes a correct comparison between the results obtained in preparations driven at different frequencies impossible, it clearly appears that this effect is ~reater in the right ventricle than in the atria, and greater in the right than in the left atrium.…”

Histamine-Mediated Vasoconstriction and cAMP Levels in Coronary Arteries of the Isolated Rabbit Heart

“…Histamine, through an H ¡-receptor mechanism, apparently uncouples the P-receptor from the guanyl nucleotide binding protein [Sastre et al, 1987]. A similar H|-mediated inhibition of H2-receptors, which have similarities to P-receptors [Mantelli et al, 1982], is a distinct possibility. In addi tion, the fact that H|-receptor stimulation decreases cAMP from control levels suggests that H ¡-receptors inhibit endogenously acti vated P (or other) receptors.…”