REGIONAL DIFFERENCES IN THE NEGATIVE INOTROPIC EFFECT OF ACETYLCHOLINE WITHIN THE CANINE VENTRICLE

1 Regional differences in the effects of ACh on sub-epicardial, mid-wa ll and sub-endocardial cells of the dog left ventricle have been studi ed. 2. ACh produced a dose-dependent, atropine-sensitive negative inot ropic effect that was greatest in sub-epicardial cells and small or ab sent in sub-endocardial cells. 3. In sub-epicardial (but not sub-endoc ardial) cells, ACh also resulted in a dose-dependent decrease in actio n potential duration. The inotropic effect of ACh on sub-epicardial ce lls was primarily the result of the decrease of action potential durat ion, because during trains of voltage clamp pulses the inotropic effec t of ACh was reduced or abolished. At a holding potential of -80 mV, 1 0(-5) M ACh decreased L-type Ca2+ current by similar to 8% and this is thought to be responsible for the small inotropic effect during train s of pulses. 4. Although 4-AP, a blocker of the transient outward curr ent (I-to), abolished the 'spike and dome' morphology of the sub-epica rdial action potential, it had little or no effect on the actions of A Ch on sub-epicardial cells. ACh had no effect on I-to in sub-epicardia l cells in voltage clamp experiments. 5. ACh activated a Ba2+-sensitiv e outward current (I-K,I-ACh) in sub-epicardial cells, but little or n o such current in subendocardial cells. In sub-epicardial cells, ACh a lso inhibited the inward rectifier current, I-K,I-1. 6. It is conclude d that in left ventricular sub-epicardial cells, ACh activates I-K,I-A Ch. This results in a shortening of the action potential and, therefor e, a negative inotropic effect. Ln subendocardial cells, ACh activates little or no I-K,I-ACh and, therefore, it has little or no negative i notropic effect. This may result from a regional variation in the expr ession of the muscarinic K+ channel.