Abstract
BackgroundIn the presence of a coronary occlusion, pre-existing small collateral vessels (arterioles) develop into much larger arteries (biological bypasses) that have the potential to allow a certain level of perfusion distal to the blockage. Termed arteriogenesis, this phenomenon proceeds via a complex combination of events, with nitric oxide (NO) playing an essential role. The aim of this study was to investigate the effects of supplemental administration of NO donors, i.e., short-acting nitroglycerin (NTG) or slow-release pelleted isosorbide dinitrate (ISDN), on collateral development in a repetitive coronary artery occlusion model in rats.MethodsCoronary collateral growth was induced via a repetitive occlusion protocol (ROP) of the left anterior descending coronary artery (LAD) in rats. The primary endpoints were the histological evaluation of rat heart infarct size and ST-segment elevation (ECG-analysis) upon final permanent occlusion of the LAD (experimentally induced myocardial infarction). The effects of NTG or ISDN were also evaluated by administration during 5 days of ROP. We additionally investigated whether concomitant application of NTG can compensate for the anti-arteriogenic effect of acetylsalicylic acid (ASA).ResultsAfter 5 days of ROP, the mean infarct size and degree of ST-elevation were only slightly lower than those of the SHAM group; however, after 10 days of the protocol, the ROP group displayed significantly less severe infarct damage, indicating enhanced arteriogenesis. Intermittent NTG application greatly decreased the ST-elevation and infarct size. The ISDN also had a positive effect on arteriogenesis, but not to the same extent as the NTG. Administration of ASA increased the infarct severity; however, concomitant dosing with NTG somewhat attenuated this effect.ConclusionIntermittent treatment with the short-acting NTG decreased the size of an experimentally induced myocardial infarct by promoting coronary collateral development. These new insights are of great relevance for future clinical strategies for the treatment of occlusive vascular diseases.
Highlights
It is many years since the first definitive evidence of the presence of coronary collateral vessels in humans was published [1]
The isosorbide dinitrate (ISDN) had a positive effect on arteriogenesis, but not to the same extent as the NTG
The resulting increase in shear stress activates the intimal endothelial cells in the collateral vessel, which produce nitric oxide (NO) as well as a variety of growth factors and cytokines. This leads to the recruitment of mononuclear cells, which form an inflammatory pro-arteriogenic environment that results in increased NO secretion, smooth muscle cells (SMCs) proliferation and extracellular matrix (ECM) production and remodelling [6,7,8], with NO playing a crucial role: Eitenmuller et al demonstrated that inhibition of endogenous NO synthesis with N(G)-nitro-L-arginine methyl ester (L-NAME) abrogated shear-stress induced arteriogenesis [9]
Summary
It is many years since the first definitive evidence of the presence of coronary collateral vessels in humans was published [1] Found in both healthy and diseased hearts, the presence of a coronary occlusion results in larger diameter collateral vessels, with multiple layers of smooth muscle cells (SMCs) within an elastin-containing extracellular matrix (ECM) [2]. In the presence of a coronary occlusion, pre-existing small collateral vessels (arterioles) develop into much larger arteries (biological bypasses) that have the potential to allow a certain level of perfusion distal to the blockage. Termed arteriogenesis, this phenomenon proceeds via a complex combination of events, with nitric oxide (NO) playing an essential role. The aim of this study was to investigate the effects of supplemental administration of NO donors, i.e., short-acting nitroglycerin (NTG) or slow-release pelleted isosorbide dinitrate (ISDN), on collateral development in a repetitive coronary artery occlusion model in rats.
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