The effects of histamine on contraction frequency, sodium influx, and cyclic AMP in cultured rat heart cells

Histamine has been shown to have both positive inotropic and chronotropic effects. To evaluate the chronotropic effects, spontaneously contracting monolayers of cultured rat myocardial cells were treated with histamine, 10^-7 M-10^-4 M. This resulted in a dose-dependent increase in contraction frequency reaching a maximum in 10^-5 M histamine. Contraction frequency (mean ± SEM) increased from a control of 121 ± 5 contractions per minute to 153 ± 4.5, 181 ± 9, 212 ± 4, and 216 ± 1 in 10^-7 M, 10^-6 M, 10^-5 M, and 10^-4 M histamine, respectively (for each n = 10, p < 0.001). The effect was time-dependent, taking 30 minutes to develop fully. Changes in contraction frequency were accompanied by parallel dose- and time-dependent increases in the verapamil-sensitive sodium influx. Verapamil-sensitive sodium influx (pmol/cm²/sec) increased from a control of 10.45 ± 1.44 (mean ± SEM) to 24.34 ± 2.41 and 32.57 ± 2.35 at 10- and 30-minute treatment with 10^-6 M histamine (n = 5, p < 0.001). These data fit the previously described relation between verapamil-sensitive sodium influx and contraction frequency in these cells. Cimetidine (10^-4 M) but not diphenhydramine (10^-4 M) abolished both the contraction frequency and sodium influx response to histamine. Subsequent studies showed a dose- and time-dependent elevation of cyclic adenosine monophosphate (cAMP) with histamine treatment. Cell cAMP (control = 5.25 pmol/mg protein) increased by 30%, 57%, 94%, and 224% in 10^-7 M, 10^-6 M, 10^-5 M, and 10^-4 M histamine, respectively, the changes between 10^-7 M and 10^-5 M closely paralleled the changes in beating rate and sodium influx. The histamine effect on cAMP was competitively inhibited by cimetidine. The results suggest histamine increases beating rate by increasing verapamil-sensitive sodium influx and that the effects are mediated by H₂ receptors coupled to adenylate cyclase.