FAILURE OF THE CHOLINERGIC MODULATION OF NOREPINEPHRINE RELEASE DURING ACUTE MYOCARDIAL-ISCHEMIA IN THE RAT

The effect of ischemia on cholinergic presynaptic inhibition of exocytotic norepinephrine release was studied in the innervated perfused rat heart. In normoxic hearts, vagal nerve stimulation significantly reduced exocytotic norepinephrine overflow to 75% of control values. This inhibitory effect was not affected by 3 minutes of low-flow ischemia (67% of control overflow values), but was attenuated or abolished by 10-minute low-flow ischemia or by 1-, 3-, and 5-minute stop-flow ischemia (107%, 85%, 101%, and 120% of control overflow values, respectively). The α-adrenergic antagonist phentolamine could completely or partly restore the failure of vagally induced inhibition of norepinephrine overflow in hearts with 1-, 3-, and 5-minute stop-flow ischemia (72%, 73%, and 85% of control overflow values, respectively). The muscarinic agonist methacholine substantially inhibited norepinephrine overflow to 18% of control overflow values in normoxic hearts. This effect was also significantly attenuated by 10-minute low-flow ischemia or by 1-, 3-, and 5-minute stop-flow ischemia (46%, 38%, 53%, and 55% of control overflow values, respectively). The cholinesterase inhibitor physostigmine did not restore the methacholine-induced inhibition of norepinephrine overflow after 3-minute stop-flow ischemia to normoxic level (55% vs. 17%). These results indicate that myocardial ischemia interferes with endogenous and exogenous cholinergic presynaptic inhibition of norepinephrine overflow in the rat heart. The extent of this attenuation depends on the severity and duration of ischemia. Reduced exocytotic acetylcholine release, which is at least in part due to an enhanced adrenergic presynaptic modulation, and dysfunction of presynaptic muscarinic receptors are suggested as two possible mechanisms.