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1 Department of Integrative Physiology and The Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth, Texas, USA
* To whom correspondence should be addressed. E-mail: jcaffrey{at}hsc.unt.edu.
Endogenous opioids and nitric oxide are recognized modulators of cardiac function. Enkephalins and inhibitors of nitric oxide synthase (NOS) both produce similar interruptions in the vagal control of heart rate. This study was conducted to test the hypothesis that nitric oxide systems within the canine sinoatrial (SA) node facilitate local vagal transmission and that the endogenous enkephalin, methionine-enkephalin-arginine-phenylalanine (MEAP) attenuates vagal bradycardia by interrupting the NOS-cyclicGMP pathway. Microdialysis probes were inserted into the SA node and they were perfused with non-selective (L-NAME) and neuronal (7-nitroindazole) NOS inhibitors. The right vagus nerve was stimulated and both inhibitors gradually attenuated the resulting vagal bradycardia. The specificity of these inhibitions was verified by an equally gradual reversal of the inhibition with an excess of the NOS substrate, L-Arginine. Introducing MEAP into the nodal interstitium produced a quickly developing but quantitatively similar interruption of vagal bradycardia that was also slowly reversed by the addition of L-arginine and not by D-arginine. Additional support for convergence of opioid and NO pathways was provided when the vagolytic effects of MEAP were also reversed by the addition of the NO donor, SNAP, the protein kinase G activator, 8-bromocyclic-GMP, or the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine. MEAP and 7-nitroindazole were individually combined with the direct acting muscarinic agonist, methacholine to evaluate potential interactions with muscarinic receptors within the SA node. MEAP and 7-nitroindazole were unable to overcome the bradycardia produced by methacholine. These data suggest that NO and enkephalins moderate the vagal control of heart rate via interaction with converging systems that involve the regulation of cAMP within nodal parasympathetic nerve terminals.
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