Sodium Nitroprusside—Sodium nitroprusside, which dilates arterioles and venules, is used for rapid pressure reduction in arterial hypertension. In response to light as well as chemical or enzymatic mechanisms in cell membranes, sodium nitroprusside breaks down to generate five cyanide molecules and a single NO. See Chapter 11 for additional details.
4.
NO Gas Inhalation—NO itself can be used therapeutically. Inhalation of NO results in reduced pulmonary artery pressure and improved perfusion of ventilated areas of the lung. Inhaled NO is used for pulmonary hypertension, acute hypoxemia, and cardiopulmonary resuscitation, and there is evidence of short-term improvements in pulmonary function. NO for inhalation is stored as a compressed gas mixture with nitrogen, which does not readily react with NO, and further diluted to the desired concentration upon administration. NO can react with O2 to form nitrogen dioxide, a pulmonary irritant that can cause deterioration of lung function (see Chapter 56). Additionally, NO can induce the formation of methemoglobin, a form of hemoglobin containing Fe3+ rather than Fe2+, which does not bind O2 (see also Chapter 12). Therefore, nitrogen dioxide and methemoglobin levels are monitored during inhaled NO treatment.
5.
Alternate Strategies—Another mechanism to potentiate the actions of NO is to inhibit the phosphodiesterase enzymes that degrade cGMP. Inhibitors of type 5 phosphodiesterase such as sildenafil allow NO-induced cGMP elevations to achieve higher cytosolic levels and result in prolongation of the duration of the cGMP elevations in a variety of tissues (see Chapter 12). This can allow otherwise insufficient NO production to have more pronounced physiologic effects.
NO has a significant effect on vascular smooth muscle tone and blood pressure. Numerous endothelium-dependent vasodilators, such as acetylcholine and bradykinin, act by increasing intracellular calcium levels in endothelial cells, leading to the synthesis of NO. NO diffuses to vascular smooth muscle, leading to vasorelaxation (Figure 19–2). Mice with a knockout mutation in the eNOS gene display increased vascular tone and elevated mean arterial pressure, indicating that eNOS is a fundamental regulator of blood pressure.
Apart from being a vasodilator and regulating blood pressure, NO also has antithrombotic effects. Both endothelial cells and platelets contain eNOS, which acts via an NO-cGMP pathway to inhibit platelet activation, an initiator of thrombus formation. In diseases such as diabetes, endothelial cells are dysfunctional and produce reduced levels of NO, resulting in an increased propensity for abnormal platelet function and thrombosis. NO may have an additional inhibitory effect on blood coagulation by enhancing fibrinolysis via an effect on plasminogen.
NO also protects against atherogenesis. A major antiatherogenic mechanism of NO involves the inhibition of proliferation and migration of vascular smooth muscle cells. In animal models, myointimal proliferation following angioplasty can be blocked by NO donors, by NOS gene transfer, and by NO inhalation. NO reduces the ability of monocytes and leukocytes to adhere to endothelial cells, which is an early step in the development of
Acetylcholine,bradykininEndothelial cellEndoplasmicreticulumArginineNOeNOSCa2+Ca2+Ca2+•CaMCaMPKGcGMPGTPGMPPhosphodiesteraseVascular smooth muscle cell ContractionLumen of blood vessel Solubleguanylylcyclase--