The adrenergic and cholinergic components of the autonomic nervous system serve an important modulatory role in the cardiovascular system. Norepinephrine is the primary physiologic agonist in the adrenergic arm of the autonomic system. In the heart, norepinephrine is known to activate three types of receptors: alpha 1, alpha 2, and beta 1. The increase in cell calcium by norepinephrine both augments action potential triggered sarcoplasmic reticulum (SR) calcium release to cause an enhanced contractility and increased the likelihood for arrhythmogenic diastolic SR calcium release, seen in myocytes as spontaneous contractile waves. While the positive inotropic effect of alpha 1-adrenergic agonists on myocardial contractility is thought to be mediated via an increase in cell inositol 1,4,5-tris phosphate (IP3), alpha1-adrenergic agonists also increase 1,2- diacylglycerol which activates protein kinase C. We examined the relative potency of alpha and beta mechanisms and the effect of phorbol ester, an activator of protein kinase C, on these neuro- transmitter effects in single adult rat myocytes. Contractility was measured as the velocity of shortening during stimulation at 1 Hz. Waves were measured in a 30 sec window following 2 min of stimulation. In absence of drugs average velocity of shortening was 70 plus/minus 32 um/sec (xSEM, n=6) and no waves occurred. Norepinephrine (1x10-5M) increased velocity of shortening to 300 plus/minus 70% control (n=6), and caused 3.6 plus/minus 1.55 waves to occur (n=6). Beta (norepinephrine plus prazocin (1x10- 5M) had a similar effect: velocity of shortening increased to 310 plus/minus 93% control and 1.8 plus/minus 0.95 waves occurred (n=6). In contrast alpha (norepinephrine plus propranolol (1x10- 6M) increased velocity of shortening by 37 plus/minus 28% (n=6) and no waves occurred. Thus, the increased contractility and enhanced probability for spontaneous diastolic calcium release to occur in response to neurotransmitter release in situ are essentially beta rather than alpha in nature.
