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.
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine