Influence of histamine receptors on basal left ventricular contractile tone in humans: assessment using the H2 receptor antagonist famotidine and the beta-adrenoceptor antagonist esmolol as pharmacologic probes.

Histamine has a positive inotropic action in humans. Recent controversial data have suggested that histamine2 (H2) receptor blockade depresses overall left ventricular systolic performance in healthy volunteers. To explore the possibility that H2 receptors positively influence basal left ventricular contractile tone, 10 normal subjects were studied by using imaging and Doppler echocardiography and calibrated subclavian pulse data in a blinded, randomized, two-period crossover trial with measurements obtained at the end of each 7-day period. Oral drug administration consisted of either the potent H2 antagonist famotidine (40 mg/day) or placebo. Left ventricular circumferential end-systolic wall stress-rate-corrected velocity of fiber shortening (Vcfc) relations were generated over a range of loads with methoxamine. Contractility was assessed by using Vcfc at a common end-systolic wall stress. During each study, data were obtained before and during high dose intravenous esmolol administration to determine the contributions, if any, of sympathetic reflex responses. Famotidine did not alter blood pressure, left ventricular percent fractional shortening, circumferential end-systolic wall stress, stroke volume index, cardiac index, total vascular resistance or ventricular contractile state in comparison with placebo but did decrease heart rate by 3 beats/min (p less than 0.05). With beta-adrenergic blockade, no differences in contractility were evident between esmolol alone and famotidine plus esmolol. Thus, H2 receptor blockade with famotidine does not alter myocardial mechanics or cardiac sympathetic tone, suggesting that in humans basal left ventricular contractile state is not physiologically dependent on the H2-mediated effects of histamine.

Identification and characterization of surface receptors for histamine in the human promyelocytic leukemia cell line HL-60. Comparison with human peripheral neutrophils.

The magnitude, the potency, the duration, and the specificity of histamine-induced cyclic AMP formation has been compared in human promyelocytic leukemic HL-60 cells and in human peripheral neutrophils. In HL-60 cells incubated at 37 degrees in the absence of phosphodiesterase inhibitor, histamine caused a 20-fold stimulation of basal cyclic AMP levels, with an EC50 of 5 X 10(-6) M. Typical H2 receptors were involved as shown by the relative potencies of the H1-selective agonists, 2-(2-pyridyl)ethylamine (PEA) and 2-(2-amino-ethyl)thiazole (AET), and the H2-selective agonists, impromidine and 4-methyl)histamine(4-MH): impromidine greater than histamine greater than 4-MH greater than AET greater than PEA. In this system, impromidine had mixed agonist-antagonist properties as shown by the rightward shift of the concentration-response curve of histamine (EC50 = 2 X 10(-3) M histamine in the presence of 10(-4) M impromidine). Histamine stimulation was competitively inhibited by the furane derivative ranitidine (Ki = 0.16 X 10(-6) M) as well as by the imidazole analogues oxmetidine (Ki = 0.48 X 10(-6) M) and cimetidine (Ki = 0.65 X 10(-6) M), whereas the H1 antagonist diphenhydramine inhibited histamine action at about 100-300 times higher concentrations (Ki = 51 X 10(-6) M). Prostaglandin E1 (PGE1) also stimulated cyclic AMP levels (50-fold increase) in HL-60 cells; half-maximal activation by PGE1 occurred at 3.2 X 10(-6) M. Our results indicate, first, that prostaglandin and histamine H2 receptors are present and functional at an early stage during myeloid differentiation; second, that there is no substantial difference between the pharmacological properties of the histamine H2 receptors in HL-60 cells and in mature human peripheral neutrophils; third, that the remarkable capacity for cyclic AMP formation noted in HL-60 leukemic cells after cell surface interaction by histamine or prostaglandin suggests that cyclic AMP and agents which increase its formation may have a role in the regulation of proliferation and/or differentiation of human myeloid progenitor cells.