MUSCARINIC INHIBITION OF CARDIAC NOREPINEPHRINE AND NEUROPEPTIDE-Y RELEASE DURING ISCHEMIA AND REPERFUSION

It was the aim of the present study to characterize the modulatory eff ect of muscarinic agonists on the overflow of norepinephrine and neuro peptide Y (NPY) from the in situ perfused guinea pig heart, induced by electrical stimulation of the left stellate ganglion (6 Hz, 5 V, 1 mi n). The muscarinic agonists oxotremorine (0.01-1 mu M) and carbachol ( 0.1-10 mu M) reduced norepinephrine and NPY overflow in a concentratio n-dependent manner to similar to 30% of control. The inhibitory effect of carbachol was antagonized by the unspecific muscarinic antagonist atropine (1 mu M) but not by the nicotinic antagonist hexamethonium (1 00 mu M). The M(2)-specific antagonist AF-DX-116BS was 25 times more p otent than the M(1)-specific antagonist pirenzepine in antagonizing th e inhibitory effect of carbachol [50% inhibitory concentration (IC50) = 0.2 mu M for AF-DX-116BS; IC50 = 5.0 mu M for pirenzepine]. These fi ndings indicate that presynaptic muscarinic inhibition of stimulated n orepinephrine and NPY release from the guinea pig heart is mediated ma inly by activation of M(2) receptors. As early as 2 min after stop-flo w ischemia, the inhibitory effect of carbachol (10 mu M) on the stimul ation-evoked overflow of norepinephrine and NPY was lost. On reperfusi on with oxygenated buffer after 10 min of stop-flow ischemia the inhib itory effect of carbachol (10 mu M) on stimulation-induced norepinephr ine and NPY overflow recovered within 3 min.