Role of nitric oxide in regulation of coronary blood flow during myocardial ischemia in dogs

Ischemic heart disease (IHD) has several risk factors, among which diabetes mellitus represents one of the most important. In diabetic patients, the pathophysiology of myocardial ischemia remains unclear yet: some have atherosclerotic plaque which obstructs coronary blood flow, others show myocardial ischemia due to coronary microvascular dysfunction in the absence of plaques in epicardial vessels. In the cross-talk between myocardial metabolism and coronary blood flow (CBF), ion channels have a main role, and, in diabetic patients, they are involved in the pathophysiology of IHD. The exposition to the different cardiovascular risk factors and the ischemic condition determine an imbalance of the redox state, defined as oxidative stress, which shows itself with oxidant accumulation and antioxidant deficiency. In particular, several products of myocardial metabolism, belonging to oxidative stress, may influence ion channel function, altering their capacity to modulate CBF, in response to myocardial metabolism, and predisposing to myocardial ischemia. For this reason, considering the role of oxidative and ion channels in the pathophysiology of myocardial ischemia, it is allowed to consider new therapeutic perspectives in the treatment of IHD.

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Differential role of endothelial versus neuronal nitric oxide synthase in the regulation of coronary blood flow during pacing-induced increases in cardiac workload

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00927.2012 ◽

2013 ◽

Vol 304 (9) ◽

pp. H1277-H1282 ◽

Cited By ~ 10

Author(s):

Husain Shabeeh ◽

Narbeh Melikian ◽

Rafal Dworakowski ◽

Barbara Casadei ◽

Phil Chowienczyk ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Flow ◽

Nitric Oxide Synthase ◽

Coronary Blood Flow ◽

Human Study ◽

Right Atrial ◽

Atrial Pacing ◽

Relative Contribution ◽

Oxide Synthase

Endothelial nitric oxide synthase (eNOS) was assumed to be the only source of nitric oxide (NO) involved in the regulation of human coronary blood flow (CBF). However, our recent first-in-human study using the neuronal NOS (nNOS)-selective inhibitor S-methyl-L-thiocitrulline (SMTC) showed that nNOS-derived NO also plays a role. In this study, we investigated the relative contribution of nNOS and eNOS to the CBF response to a pacing-induced increase in cardiac workload. Incremental right atrial pacing was undertaken in patients with angiographically normal coronary arteries during intracoronary infusion of saline vehicle and then either SMTC or NG-monomethyl-l-arginine (l-NMMA; which inhibits both eNOS and nNOS). Intracoronary SMTC (0.625 μmol/min) and l-NMMA (25 μmol/min) reduced basal CBF to a similar extent (−19.2 ± 3.2% and 25.0 ± 2.7%, respectively; n = 10 per group). Pacing-induced increases in CBF were significantly blunted by l-NMMA (maximum CBF: 83.5 ± 14.2 ml/min during saline vs. 61.6 ± 9.5 ml/min during l-NMMA; P < 0.01). By contrast, intracoronary SMTC had no effect on the maximum CBF during pacing (98.5 ± 12.9 ml/min during saline vs. 102.1 ± 16.6 ml/min during SMTC; P = not significant). l-NMMA also blunted the pacing-induced increase in coronary artery diameter ( P < 0.001 vs. saline), whereas SMTC had no effect. Our results confirm a role of nNOS in the regulation of basal CBF in humans but show that coronary vasodilation in response to a pacing-induced increase in cardiac workload is exclusively mediated by eNOS-derived NO.

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