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Open Access Research article

Intimal Hyperplasia in Balloon Dilated Coronary Arteries is Reduced by Local Delivery of the NO Donor, SIN-1 Via a cGMP-Dependent Pathway

Jan Harnek1*, Evita Zoucas2, Valéria Perez de Sá3, Eva Ekblad4, Anders Arner5 and Unne Stenram6

Author Affiliations

1 Department of Coronary Heart Disease. Skane University Hospital. Institute of Clinical Sciences. Lunds University, Getingev 4, SE-22185 Lund, Sweden

2 Department of Surgery. Skane University Hospital. Institute of Clinical Sciences. Lunds University. Getingev 4, SE-22185 Lund, Sweden

3 Department of Anaesthesiology. Skane University Hospital. Institute of Clinical Sciences. Lunds University, Getingev 4, SE-22185 Lund, Sweden

4 Department of Experimental Medical Science. Skane University Hospital. Institute of Clinical Sciences Lunds University, Getingev 4, SE-22185 Lund, Sweden

5 Department of Cellular Musclephysiology. Institute of Physiology and Pharmacology, Karolinska Institute, 171 77 Stockholm, Sweden

6 Department of Pathology. Skane University Hospital. Institute of Clinical Sciences. Lunds University. Getingev 4, SE-22185 Lund, Sweden

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BMC Cardiovascular Disorders 2011, 11:30  doi:10.1186/1471-2261-11-30

Published: 11 June 2011

Abstract

Background

To elucidate the mechanism by which local delivery of 3-morpholino-sydnonimine (SIN-1) affects intimal hyperplasia after percutaneous transluminal coronary angioplasty (PTCA).

Methods

Porcine 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.

Results

Luminal 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.

Conclusions

After 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.

Keywords:
Nitric oxide; Angioplasty; Endothelium-derived factors; Restenosis; Remodeling