Role of Nitric Oxide in Cardiovascular Disorders - Applications of Biotechnology in Cardiovascular Therapeutics - page 81

postischemia and reperfusion. Current evidence suggests that HBO preconditioning
may partly attenuate IRI by stimulating the endogenous production NO, which has
the ability to reduce neutrophil sequestration, adhesion, and associated injury, and
improve blood flow (Yogaratnam et al. 2008 ). HBO preconditioning-induced NO
may play a role in providing myocardial protection during operations that involve
an inevitable episode of IRI and protection of the myocardium from the effects of
IRI during cardiac surgery.
Combined proteomic and metabolomic analyses provide direct evidence of the
effect of protein expression on cellular processes, and this approach has been used to
investigate the cardioprotective mechanisms following exposure to nitrate, which is
an important bioactive molecule, capable of conferring cardioprotection and a variety
of other benefits in the cardiovascular system (Perlman et al. 2009 ). Nitrate adminis-
tration resulted in a short-lived increase in cardiac nitrate levels, but substantial eleva-
tions in cardiac ascorbate oxidation. This was accompanied by significant
improvements in cardiac contractile recovery following ischemia-reperfusion after
preconditioning with low or high nitrate doses. There was significant nitrite-induced
protein modifications (including phosphorylation) revealed by MS-based proteomic
studies. Altered proteins included those involved in metabolism (e.g., aldehyde dehy-
drogenase 2), redox regulation (e.g., protein disulfide isomerase A3), contractile
function (e.g., filamin-C), and serine/threonine kinase signaling (e.g., protein kinase
A R1a). Thus, brief elevations in plasma nitrite trigger a concerted cardioprotective
response characterized by persistent changes in cardiac metabolism, redox stress, and
alterations in myocardial signaling. These findings help elucidate possible mecha-
nisms of nitrite-induced cardioprotection and have implications for nitrite dosing in
therapeutic regimens. A similar mechanism may underpin the cardioprotective value
of physical exercise and a diet containing nitrite/nitrate-rich foods.
Role of NO in the Management of Angina Pectoris
Three common categories of drugs used for chronic stable angina pectoris are
nitrates, beta-adrenoreceptor blockers and calcium channel blockers. Various forms
of nitrates used are sublingual nitroglycerine, isosorbide dinitrate (slow release
formulation), transdermal nitroglycerine, and oral isosorbide-5-monitrate. Other
NO-based therapies have been investigated.
A new once-a-day formulation of molsidomine (16 mg) for patients with stable
angina pectoris was evaluated in a pilot double-blind randomized placebo-controlled
study (Messin et al. 2003 ). The pharmacokinetics of molsidomine with this dose in
patients with stable angina pectoris was compatible with a once-daily dosage regimen.
This formulation was found to be effective and well tolerated, providing a 24 h
therapeutic control of myocardial ischemia. A positive and significant linear rela-
tionship between molsidomine plasma concentration and the increase in exercise
tolerance was observed. Nitorol ® (isosorbide dinitrate) Injection Syringe (Eisai Co
Ltd) is the first nitric acid syringe formulation approved for the treatment of acute
cardiac failure and unstable angina in Japan.