Robert D. Harvey

In isolated heart cells, beta-adrenergic receptor stimulation induced a background current that was suppressed by simultaneous muscarinic receptor stimulation. Direct activation of adenylate cyclase with forskolin also elicited this current, suggesting regulation by adenosine 3',5'-monophosphate (cAMP). This current could be recorded when sodium, calcium, and potassium currents were eliminated by channel antagonists or by ion substitution. Alteration of the chloride equilibrium potential produced changes in the reversal potential expected for a chloride current. Activation of this chloride current modulated action potential duration and altered the resting membrane potential in a chloride gradient-dependent manner.

The parasympathetic component of the autonomic nervous system plays an important role in the physiological regulation of cardiac function by exerting significant influence over the initiation as well as propagation of electrical impulses, in addition to being able to regulate contractile force. These effects are mediated in whole or in part through changes in ion channel activity that occur in response to activation of M(2) muscarinic cholinergic receptors following release of the neurotransmitter acetylcholine. The coupling of M(2) receptor activation to most changes in cardiac ion channel function can be explained by one of two general paradigms. The first involves direct G protein-dependent regulation of ion channel activity. The second involves indirect regulation of ion channel activity through modulation of cAMP-dependent responses. This review focuses on recent advances in our understanding of the mechanisms by which M(2) muscarinic receptor activation both inhibits and facilitates cAMP-dependent ion channel responses in the heart.

The properties of the autonomically regulated chloride current (ICl) were studied in isolated guinea pig ventricular myocytes. This current was elicited upon exposure to isoproterenol (ISO) and reversed upon concurrent exposure to acetylcholine (ACh). ICl was time independent and exhibited outward rectification. The responses to ISO and ACh could be blocked by propranolol and atropine, respectively, and ICl was also elicited by forskolin, 8-bromoadenosine 3',5'-cyclic monophosphate, and 3-isobutyl-l-methylxanthine, indicating that the current is regulated through a cAMP-dependent pathway. The reversal potential of the ISO-induced current followed the predicted chloride equilibrium potential, consistent with it being carried predominantly by Cl-. Activation of ICl produced changes in the resting membrane potential and action potential duration, which were Cl- gradient dependent. These results indicate that under physiological conditions ICl may play an important role in regulating action potential duration and resting membrane potential in mammalian cardiac myocytes.

Nonelectrogenic movement of Cl- is believed to be responsible for the active accumulation of intracellular Cl- in cardiac muscle. The electro-neutral pathways underlying this nonpassive distribution of Cl- are believed to include Cl(-)-HCO3- exchange, Na(+)-dependent cotransport (operating as Na(+)-Cl- and Na(+)-K(+)-2Cl- cotransport), and K(+)-Cl- cotransport. The electrogenic movement of Cl- in cardiac muscle is particularly interesting from a historical perspective. Until recently, there was some doubt as to whether Cl- carried any current in the heart. Early microelectrode experiments indicated that a Cl- conductance probably played an important role in regulating action potential duration and resting membrane potential. Subsequent voltage-clamp experiments identified a repolarizing, transient outward current that was believed to be conducted by Cl-, yet further investigation suggested that this transient outward current was more likely a K+ current, not a Cl- current. This left some doubt as to whether Cl- played any role in regulating membrane potential in cardiac muscle. More recent studies, however, have identified a highly selective Cl- conductance that is regulated by intracellular adenosine 3',5'-cyclic monophosphate, and it appears that this Cl- current may play an important role in the regulation of action potential duration and resting membrane potential.