Abstract
BackgroundTo elucidate the mechanism by which local delivery of 3-morpholino-sydnonimine (SIN-1) affects intimal hyperplasia after percutaneous transluminal coronary angioplasty (PTCA).MethodsPorcine coronary arteries were treated with PTCA and immediately afterwards locally treated for 5 minutes, with a selective cytosolic guanylate cyclase inhibitor, 1 H-(1,2,4)oxadiazole(4,3-alpha)quinoxaline-1-one (ODQ) + SIN-1 or only SIN-1 using a drug delivery-balloon. Arteries were angiographically depicted, morphologically evaluated and analyzed after one and eight weeks for actin, myosin and intermediate filaments (IF) and nitric oxide synthase (NOS) contents.ResultsLuminal diameter after PCI in arteries treated with SIN-1 alone and corrected for age-growth was significantly larger as compared to ODQ + SIN-1 or to controls (p < 0.01). IF/actin ratio after one week in SIN-1 treated segments was not different compared to untreated segments, but was significantly reduced compared to ODQ + SIN-1 treated vessels (p < 0.05). Expression of endothelial NADPH diaphorase activity was significantly lower in untreated segments and in SIN-1 treated segments compared to controls and SIN-1 + ODQ treated arteries (p < 0.01). Restenosis index (p < 0.01) and intimal hyperplasia (p < 0.01) were significantly reduced while the residual lumen was increased (p < 0.01) in SIN-1 segments compared to controls and ODQ + SIN-1 treated vessels.ConclusionsAfter PTCA local delivery of high concentrations of the NO donor SIN-1 for 5 minutes inhibited injury induced neointimal hyperplasia. This favorable effect was abolished by inhibition of guanylyl cyclase indicating mediation of a cyclic guanosine 3',5'-monophosphate (cGMP)-dependent pathway. The momentary events at the time of injury play crucial role in the ensuring development of intimal hyperplasia.
Highlights
To elucidate the mechanism by which local delivery of 3-morpholino-sydnonimine (SIN-1) affects intimal hyperplasia after percutaneous transluminal coronary angioplasty (PTCA)
This study shows that delivery of the NO donor SIN-1 at the site of a PTCA injury for 5 minutes decreases significantly intimal hyperplasia/restenosis
In the present study we examined whether the beneficial effect of an externally applied NO donor in a high concentration could be modified by a guanylyl cyclase inhibitor, as an indication for the implication of a cGMP dependent pathway in the development of intimal hyperplasia/restenosis
Summary
To elucidate the mechanism by which local delivery of 3-morpholino-sydnonimine (SIN-1) affects intimal hyperplasia after percutaneous transluminal coronary angioplasty (PTCA). The. Orally or intravenously administered NO precursors and donors have been shown to moderately affect intimal hyperplasia after arterial injury in animal and human studies [9,10,11,12]. Or intravenously administered NO precursors and donors have been shown to moderately affect intimal hyperplasia after arterial injury in animal and human studies [9,10,11,12] These studies have been hampered by the fast degradation rate of NO in blood, which allows only minimal amounts of NO, if any, to reach the injured area. The NO donor SIN-1 has recently been shown to reduce intimal hyperplasia after PTCA, and may be advantageous as it releases NO by fast and spontaneous degradation[14]
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