Positive and negative effects of nitric oxide on Ca(2+) sparks: influence of beta-adrenergic stimulation

Nitric oxide (NO) can have a positive or negative effect on cardiac contractility and the ryanodine receptor (RyR). This dual effect has been explained as being dependent on the concentration of NO. We find that cellular RyR response to NO is also dependent on the degree of beta-adrenergic stimulation, and thus the state of protein kinase A activation. Ca(2+) spark frequency (CaSpF) in rat ventricular myocytes was used as an index of resting RyR activity. CaSpF response to beta-adrenergic stimulation was used as an index of protein kinase A activation. High concentration of isoproterenol, a beta-adrenergic agonist, caused a large increase in CaSpF; addition of NO (spermine NONOate, 300 microM) then caused a decrease in CaSpF. Low concentration of isoproterenol produced only a slight increase in CaSpF, but the same NO concentration now caused a large increase in CaSpF. A dual effect was also observed in twitch. Thus the net direction of the effects of NO on RyR activity and Ca(2+) transients (directly or by alteration of sarcoplasmic reticulum Ca(2+) load) can be reversed, depending on the ambient level of beta-adrenergic activation.