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Published on: May 14, 2013
Inhibiting the NO pathway with intracoronary L-NAME infusion increases endothelial dysfunction and intimal
Louis P Perrault1, Olivier Malo, Jean-Pierre Bidouard
1Department of Surgery, Montreal Heart Institute, Montréal, Québec, Canada.
Insights
Inhibiting nitric oxide (NO) synthesis worsens endothelial dysfunction and accelerates graft coronary vasculopathy after heart transplantation. Preserving the NO pathway is crucial for preventing transplant complications.
Area of Science:
- Cardiovascular Research
- Transplantation Immunology
- Vascular Biology
Background:
- The endothelium regulates vascular health via nitric oxide (NO) release.
- Coronary endothelial dysfunction is an early complication post-heart transplant, predicting graft coronary vasculopathy.
- Graft coronary vasculopathy is characterized by intimal thickening.
Purpose of the Study:
- To investigate the impact of endothelial NO synthase (eNOS) inhibition on rejection-induced endothelial dysfunction.
- To assess the effect of eNOS inhibition on accelerated atherosclerosis post-heart transplantation.
Main Methods:
- A porcine heterotopic heart transplant model was utilized.
- Immunologic typing enabled slow rejection without immunosuppression.
- Intracoronary L-nitro arginine methyl ester (L-NAME) was infused for 30 days to inhibit eNOS.
- Endothelium-dependent relaxations and intimal thickening were evaluated in coronary arteries.
Main Results:
- L-NAME infusion significantly reduced serotonin-induced relaxations in allografted arteries.
- Intimal thickening was significantly increased in L-NAME-infused allografts compared to non-infused allografts and native arteries.
- No significant differences in bradykinin-induced relaxations were observed among groups.
Conclusions:
- Inhibition of the NO pathway exacerbates endothelial dysfunction and intimal thickening post-heart transplant.
- These findings highlight the role of NO in preventing graft coronary vasculopathy.
- Strategies to maintain endothelial NO pathway function are vital for preventing transplant vasculopathy.
Background:
The endothelium protects the vascular wall through the nitric oxide (NO) release. Coronary endothelial dysfunction occurs early after heart transplantation and predicts the development of intimal thickening typical of graft coronary vasculopathy.
Objective:
We designed this study to examine the effect of endothelial NO synthase (eNOS) inhibition on the endothelial dysfunction caused by rejection and on the development of accelerated atherosclerosis after heart transplantation.
Methods:
To study the effect on these 2 end-points of inhibiting eNOS with intracoronary L-nitro arginine methyl ester (L-NAME; 1 mg/kg/day), infused with an osmotic pump for 30 days, we used a porcine model of heterotopic heart transplantation with pre-operative immunologic typing, to permit slow rejection without the need for immunosuppression. The endothelium-dependent relaxations of allografted coronary arteries, allografted arteries infused with L-NAME, allografted arteries mounted with the pump, and vehicle and native coronary arteries were compared 30 days after graft implantation using standard organ chamber experiments. We evaluated intimal thickening using a semi-quantitative scale (0-4+ grading).
Results:
A significant decrease in relaxations to serotonin (5-HT) occurred in allografted arteries infused directly with L-NAME compared with allografted arteries from swine receiving 5-HT, and relaxations in the latter were decreased compared with those of swine receiving the vehicle and native coronary arteries (p < 0.05). We found no significant differences in endothelium-dependent relaxations to bradykinin among coronary rings from all groups. We observed a significant increase in the prevalence and severity of intimal thickening in allografted coronary arteries infused with L-NAME compared with allografts not infused (p < 0.05), which had significantly more intimal thickening compared with native coronary arteries (p < 0.05).
Conclusion:
These results demonstrate that inhibiting the NO pathway worsens the endothelial dysfunction caused by rejection after heart transplantation and accelerates the intimal thickening process, leading to graft coronary vasculopathy. Strategies designed to preserve endothelial integrity and function of the endothelial NO pathway should be used to prevent graft coronary vasculopathy.
