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Differential acetylcholine release mechanisms in the ischemic and non-ischemic myocardium
T Kawada1, T Yamazaki, T Akiyama
1Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka, 565-8565, Japan.
Insights
Myocardial ischemia triggers acetylcholine release via local mechanisms, not vagal nerves. This release depends on intracellular calcium, not specific calcium channels, offering insights into heart disease pathophysiology.
Area of Science:
- Cardiovascular Physiology
- Neuropharmacology
- Ischemic Heart Disease Research
Background:
- The vagal efferent system plays a role in ischemic heart diseases.
- Understanding endogenous acetylcholine (ACh) release in the myocardium is crucial for elucidating these pathophysiological mechanisms.
Purpose of the Study:
- To investigate the source and mechanism of endogenous acetylcholine release in the myocardium during acute myocardial ischemia.
- To differentiate between vagal and local mechanisms of ACh release in ischemic and non-ischemic heart regions.
Main Methods:
- Acute myocardial ischemia was induced in anesthetized cats by occluding the left anterior descending coronary artery (LAD).
- Dialysis probes were implanted in the left ventricular free wall to measure dialysate ACh concentration using liquid chromatography.
- Pharmacological interventions included bilateral vagotomy and administration of N-type Ca(2+) channel blockers and intracellular Ca(2+) mobilization inhibitors.
Main Results:
- LAD occlusion significantly increased ACh levels in the ischemic region (0.68 to 12.3 nM), independent of vagotomy or N-type Ca(2+) channel blockade.
- Local administration of an intracellular Ca(2+) mobilization inhibitor suppressed ischemia-induced ACh release in the ischemic region.
- ACh levels increased in the non-ischemic region (1.9 to 6.0 nM) following LAD occlusion, an effect completely abolished by vagotomy.
Conclusions:
- Acetylcholine release in the ischemic myocardium is primarily mediated by a local mechanism dependent on intracellular Ca(2+) mobilization, not N-type Ca(2+) channels.
- In contrast, ACh release in the non-ischemic region during ischemia relies on intact vagal nerve activity.
- These findings highlight distinct mechanisms of ACh release in different myocardial regions during ischemic events.
Abstract:
To understand better the pathophysiological roles of the vagal efferent system in ischemic heart diseases, we examined endogenous acetylcholine (ACh) release in the myocardium in vivo. Acute myocardial ischemia was induced in anesthetized cats by a 60-min occlusion of the left anterior descending coronary artery (LAD). We implanted dialysis probes in the left ventricular free wall and measured the dialysate ACh concentration using liquid chromatography. In the ischemic region, the ACh level increased from 0.68+/-0.12 to 12.3+/-3.3 n M (mean+/-S.E., P<0.01) by LAD occlusion. Bilateral vagotomy did not inhibit ischemia-induced ACh release (20.3+/-6.4 n M). In vagotomized animals, inhibition of the N-type Ca(2+)channel by intravenous administration of omega-conotoxin GVIA (10microg/kg) also failed to suppress ACh release (15.9+/-2.0 n M). However, the inhibition of intracellular Ca(2+)mobilization by local administration of 3,4,5-trimethoxybenzoic acid 8-(dietyl amino)-octyl ester (1 m M) suppressed ACh release (4.4+/-0.8 n M, P<0.05 compared with no pharmacological intervention). In the non-ischemic region, the ACh level increased from 1.9+/-0.4 to 6. 0+/-1.0 n M (P<0.05) by LAD occlusion, which was completely abolished by vagotomy. We concluded that ACh release in the ischemic region was mainly attributed to a local release mechanism, whereas that in the non-ischemic region depended on the presence of intact vagal activity. The local release mechanism would depend on intracellular Ca(2+)mobilization but not on N-type Ca(2+)channel opening.