What is the role of Nitric Oxide (NO) in regulating blood flow?

From the Guidelines

Nitric oxide (NO) plays a crucial role in regulating blood flow by relaxing smooth muscle cells in blood vessel walls, causing them to widen and increase blood flow while decreasing blood pressure. This is achieved through the production of nitric oxide synthase (eNOS) by endothelial cells, which converts L-arginine to nitric oxide 1. The released NO then diffuses into nearby smooth muscle cells and activates guanylate cyclase, increasing cyclic guanosine monophosphate (cGMP) levels, leading to relaxation and vasodilation.

Some key points about the role of NO in regulating blood flow include:

• NO is generated by three isoforms of NO synthase (NOS), which are present in multiple and diverse cell types and continuously active in endothelium, or “inducible” in other cells, such as macrophages, bronchial epithelium, and vascular smooth muscle 1.
• Regulation of NOS is complex, and includes growth factors, hormones, oxygen tension, hemodynamics, and other factors 1.
• NO has antiplatelet activity, anti-inflammatory and anti-oxidant properties, modulatory effects on angiogenesis, and can alter the expression and activity of several vascular growth factors and vasoactive products 1.
• Inhaled nitric oxide (iNO) has been shown to acutely decrease pulmonary vascular resistance (PVR) and improve cardiac output (CO) in patients with pulmonary hypertension (PH), especially in those who are post-coronary bypass surgery or valve replacement 1.

The use of iNO has become an accepted standard therapy for postoperative PH, due to its selective pulmonary vasodilator effects, ease of administration, and rapid onset of effect 1. The administration of iNO at low doses can improve ventilation-perfusion matching, decrease intrapulmonary shunt fraction, and often improve systemic arterial oxygenation, especially in the setting of lung disease. However, it is essential to carefully consider the potential disadvantages of iNO, including its significant cost, potential to cause methemoglobinemia, and potential for tachyphylaxis 1.

From the FDA Drug Label

Mechanism of Action: Nitroglycerin forms free radical nitric oxide (NO) which activates guanylate cyclase, resulting in an increase of guanosine 3'5' monophosphate (cyclic GMP) in smooth muscle and other tissues. These events lead to dephosphorylation of myosin light chains, which regulate the contractile state in smooth muscle, and result in vasodilatation

The role of Nitric Oxide (NO) in regulating blood flow is to cause vasodilatation by activating guanylate cyclase, leading to an increase in cyclic GMP in smooth muscle and other tissues, resulting in the relaxation of vascular smooth muscle and dilation of both arterial and venous beds 2.

• Key effects of NO include:
  • Dilation of postcapillary vessels
  • Decrease in venous return to the heart
  • Reduction in left ventricular end-diastolic pressure (preload)
  • Reduction in peripheral vascular resistance and arterial pressure (afterload)

From the Research

Role of Nitric Oxide in Regulating Blood Flow

• Nitric oxide (NO) plays a crucial role in regulating blood flow, particularly in response to hypoxia, by mediating vasodilation and modulating energetic metabolism 3.
• NO is a powerful mediator with biological activities such as vasodilation and prevention of vascular smooth muscle cell proliferation, and its impaired production or reduced bioavailability can predispose to the onset of different cardiovascular diseases 4.
• The role of NO in hypoxic vasodilation is complex and involves the S-nitrosothiol-based (SNO-based) vasoactivity, which is conveyed substantially by the βCys93 residue in hemoglobin, highlighting the importance of red blood cells in cardioprotection 5.

Mechanisms of NO Regulation

• Hemoglobin and the erythrocyte regulate the bioavailability of NO in the vascular compartment, with hemoglobin scavenging NO under normoxic conditions and producing a vasopressor effect 6.
• The red blood cell contains arginase, which when released into plasma, further dysregulates arginine metabolism, supporting the existence of a novel mechanism of human disease, hemolysis-associated endothelial dysfunction 6.
• Deoxygenated hemoglobin can deliver NO through two mechanisms: oxygen-linked allosteric delivery of S-nitrosothiols from S-nitrosated hemoglobin (SNO-Hb) and a nitrite reductase activity that reduces nitrite to NO 6.

Influence of Red Blood Cells on NO Bioavailability

• Red blood cells (RBCs) can affect the bioavailability of NO in blood vessels, acting as NO scavengers, and their concentration can significantly influence NO bioavailability 7.
• The distribution of RBCs, particularly in strongly confined channels, can significantly influence NO bioavailability, and two phases of NO bioavailability are observed in different regions of the blood vessels 7.
• The study of RBC flow, ATP release from RBCs and ECs, and NO dynamics can provide valuable insights into the mechanisms of NO-dependent vasodilation and the transport of oxygen by RBCs within microvascular networks 7.