DOI: 10.1097/01.CCM.0000163241.13478.88

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PMID: 15891361

Issn Print: 0090-3493

Publication Date: 2005/05/01


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Going on and on with NO?*

Paul Steendijk

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Excerpt

Pulmonary artery vascular tone is mainly determined by the smooth muscle cell calcium balance (1). The most important vasoactive substances that regulate pulmonary vascular tone are derived from the endothelium. Key players in this process are endothelin-1 (ET-1), prostacyclin (PGI2), and nitric oxide (NO). The effects of ET-1 on pulmonary vascular resistance are mediated by two distinct receptor subtypes: the ETA receptor on the vascular smooth muscle cell is responsible for vasoconstriction (2), whereas the ETB receptor on the endothelial cell is responsible for vasodilation (3). There are clear developmental alterations in ET-1 receptor densities: In the fetal and newborn pulmonary circulations, exogenous ET-1 predominantly vasodilates (via the ETB receptor and subsequent NO release), whereas in the juvenile and adult pulmonary circulations, the predominant effect is vasoconstriction (via ETA receptor activation) (4). Arachidonic acid metabolites (eicosanoids) are among the most potent vasoactive substances. Arachidonic acid is degraded via the cyclooxygenase pathway to produce the primary prostaglandins, including PGI2 that is synthesized in endothelial cells. PGI2 subsequently activates adenylate cyclase in the adjacent smooth muscle cell. This process increases adenosine 3′,5′-cyclic monophosphate (cAMP), which in turn initiates a cascade resulting in calcium efflux and subsequent smooth muscle relaxation (5). The biological action of PGI2 may be balanced by thromboxane, a vasoconstrictor that is synthesized in platelets and macrophages (6). NO, an inorganic, gaseous free radical, is a potent vascular smooth muscle relaxant with an important regulatory function for the pulmonary vascular bed (7). NO is synthesized from L-arginine catalyzed by nitric oxide synthase (NOS). In mammals, three isoforms of NOS are known: neuronal and endothelial NOS (nNOS and eNOS, respectively), whose activities are regulated by calcium and calmodulin, and inducible NOS (iNOS), which is largely calcium independent. Whereas expression of iNOS is induced by cytokines and other agents, eNOS may be activated in response to endothelial shear stress and, for example, bradykinin. NO, produced in the endothelial cell, diffuses into adjacent vascular smooth muscle cells and activates soluble guanylate cyclase, which catalyzes the production of guanosine 3′,5′-cyclic monophosphate (cGMP). Finally, this cGMP initiates a cascade leading to smooth muscle relaxation. The intracellular levels of the cyclic nucleotide second messengers cAMP and cGMP, which play a central role in pulmonary vascular smooth muscle cell relaxation, are regulated by phosphodiesterases (PDE) (8). These enzymes, of which a large number of specific isoforms have been identified, are able to degrade the nucleotides. This underlies the vascular relaxation obtained by pharmacologic PDE inhibitors. Of note is that NO may also lead to smooth muscle relaxation by directly activating calcium-dependent potassium channels without requiring cGMP (9). Other important substances relevant for regulation of the pulmonary vascular tone include angiotensin II and atrial natriuretic peptide. The former has vasoconstrictive properties, and the latter causes pulmonary vasodilation (10). Important interactions are present: NO, for example, is involved in the regulation of vascular tone by the angiotensin II system by down-regulating the number and binding activity of angiotensin II receptors (11).
The therapeutic potential of exogenous, inhaled NO was recognized in the early 1990s. After inhalation, NO diffuses across the alveolar-capillary membrane into the smooth muscle of the pulmonary vessels and produces vasodilation via the same pathways as described for endogenous NO. Inhaled NO specifically increases blood flow to well-ventilated lung areas and thus improves ventilation-perfusion matching. This effect is in contrast to intravenously administered vasodilators that produce diffuse dilation of the pulmonary vasculature including the nonventilated areas and thereby may increase intrapulmonary shunting.
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