Nitric oxide synthase gene transfer

Abstract

Chronic liver diseases are often characterized by portal hypertension, an important component of which is increased intrahepatic vascular resistance. Portal hypertension in turn has profound clinical consequences, many of which are associated with substantial morbidity and mortality1. Nitric oxide (NO) modulates numerous physiological processes in the liver circulation2. The basal production of NO in the hepatic circulation is generated through the catalytic activity of the endothelial NO synthase (eNOS) isoform, localized within liver endothelial cells (LEC) and regulated through physiological stimuli including shear stress3, 4. Several recent studies suggest that the biological activity of hepatic eNOS is diminished in portal hypertension3, 5, 6. Thus, NO supplementation is a rational therapeutic approach in portal hypertension. While NO donor therapy in portal hypertension may be beneficial under specific clinical circumstances, its benefits are limited by several factors including short half-life, high reactivity, tolerance and, most importantly, the unwanted systemic delivery of these compounds that tends to exacerbate an existing hyperdynamic circulatory state and create untoward side-effects and limit effectiveness of clinical application 7, 8.