Role of Nitric Oxide in Cardiovascular Disorders - Applications of Biotechnology in Cardiovascular Therapeutics - page 85

enhancing vagal tone to the heart, and thereby suppressing atrioventricular nodal
conduction, have been clinically used to terminate tachycardia. Injectable formula-
tions of ATP have been approved in Europe for over 50 years as safe and efficacious
treatments for PSVT.
ATPace (intravenous ATP injection) is being developed by Cordex Pharma for
the acute treatment and diagnosis of certain cardiac arrhythmias including the ter-
mination of PSVT, and is in phase III clinical trials in the USA. ATPace is also
being developed to diagnose bradycardia, which is one of the main causes of
fainting.
Prophylaxis of Cardiovascular Disorders
Prevention is an important aspect of cardiovascular health. The value of physical
exercise is well recognized. The role of NO in maintaining the integrity of the car-
diovascular system is also established. Exercise increases the production of NO.
But even with a regular exercise regimen, the body may not produce sufficient
quantities of NO to maintain normal levels in unhealthy cells. This can be supple-
mented by natural sources of L-arginine including nuts, fruits, dairy, and meats as
well as natural sources of L-citrulline including melon rinds and cucumbers. A low-
fat diet also helps increase the body's production of NO. No also plays a role in
retarding atherosclerosis with aging, an important risk factor for cardiovascular
disease.
Prevention of Atherosclerosis with Aging
Aging may contribute to the pathogenesis of atherosclerosis. Bioavailability of NO
is limited in senescence, the effect of NO on senescence and its relationship to
cardiovascular risk factors have been studied by investigating senescence-associated
b-galactosidase (SA-b-gal) and human telomerase activity in human umbilical
venous endothelial cells (HUVECs). Treatment with a NO donor, DETA-NO, and
transfection with eNOS into HUVECs each decreased the number of SA-b-gal
positive cells and increased telomerase activity (Hayashi et al. 2006 ). The NOS
inhibitor L-NAME abolished the effect of eNOS transfection. The physiological
concentration of 17b-estradiol activated hTERT, decreased SA-b-gal-positive cells,
and caused cell proliferation. However, ICI 182780, an estrogen receptor-specific
antagonist, and L-NAME each inhibited these effects. Treatment with L-arginine or
L-citrulline of eNOS-transfected cells partially inhibited, and combination of
L-arginine and L-citrulline with antioxidants strongly prevented high glucose-
induced cellular senescence. These data demonstrate that NO can prevent endothe-
lial senescence, thereby contributing to the antiaging action of estrogen. The
ingestion of NO-boosting substances, including L-arginine, L-citrulline, and anti-
oxidants, can delay endothelial senescence under high glucose. Prevention of
endothelial senescence by NO and/or eNOS activation may have clinical utility in
the treatment of atherosclerosis in the elderly.