Hypoxic Pulmonary Vasoconstriction: Mechanism
Mechanism
Two main hypotheses underlie most investigations of the mechanism of the AHPR. The first is that the response is dependent on the release of a vasoactive mediator from some site within the lung. The opposing view states that acute hypoxia elicits vasoconstriction via a direct effect on pulmonary vascular smooth muscle without the involvement of a mediator.
Mediator Hypothesis
The mediator hypothesis is derived from work with isolated pulmonary artery segments in which the AHPR appeared to be dependent upon the presence of parenchyma attached to the vessels, since the response could not be elicited with isolated vessels alone. Data gathered in pursuit of this question occupied a central position in research involving the pulmonary circulation for many years.
The status of this field can be summarized very succinctly. Despite a lengthy list of candidates (Table 2), no single agent satisfies all the necessary requirements of a mediator. Fishman summarized the essential criteria for an ideal mediator as follows: 1) the agent or its precursors must exist within the lung; 2) the agent must be shown to be present in close proximity to its anatomic site of action; 3) an activation mechanism for release of the agent must be present within the lung; 4) the agent must simulate the AHPR when applied to the pulmonary vasculature under the appropriate conditions; and 5) inhibition or depletion of the agent should appropriately modify the AHPR in the intact lung or animal. levitra plus
The candidates for mediator of acute hypoxic vasoconstriction included the catecholamines, histamine, serotonin, and the peptide, angiotensin II. Although none of these agents now qualifies as a mediator of the AHPR, we have learned a great deal about the pharmacologic regulation of pulmonary vascular reactivity from investigations involving these agents, notably, that the pulmonary vasculature, like its systemic counterpart, is responsive to a wide array of physical and chemical stimuli, and contains many different types of vascular receptor systems. Many questions still remain about the role of these agents in the regulation of pulmonary vascular reactivity in the normal and diseased lung.
Table 2—Agents Investigated as Potential Mediators of the AHPR
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Reference
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The pulmonary vessels of many species are well endowed with autonomic nervous connections. The pulmonary vasculature has important links with the stellate ganglia, hypothalamus, and efferent connections with systemic chemoreceptors. Therefore, it was a logical step to speculate that neural input might mediate the AHPR. In support of this concept are studies demonstrating that alpha adrenergic antagonists and beta adrenergic agonists blunt the AHPR, while beta receptor antagonists augment the response. Nevertheless, the current view is that neural input does not have a primary role in the mechanism of the AHPR. Proof that sympathetic innervation is not essential for the AHPR is demonstrated by the following findings: 1) the response has been elicited in isolated perfused lungs in numerous studies; and 2) the response can still be observed in sympathecto- mized animals and after adrenergic transmitter depletion, although this has not been a universal finding.
The sympathetic nervous system does exert a modifying influence in the adult animal. The mediator released from sympathetic nerve endings, norepinephrine, has a biphasic tone-dependent effect. When pulmonary vascular resistance is low, the catecholamine has a vasoconstrictor effect, but when tone is elevated, norepinephrine produces a vasodilator response. In addition, systemic hypoxia, but not alveolar hypoxia alone, elicits a chemoreflexive stiffening or decrease in distensibility of the large pulmonary arteries with no change in pulmonary vascular resistance which is abolished by sympathectomy or vagotomy. The cholinergic and the noncholinergic/non- adrenergic (purinergic) systems are also thought to function as modifying vasodilator influences in response to vasoconstrictor stimuli, with no role as primary vasoconstrictive systems, although much less information is available on the influence of these components of the nervous system on pulmonary vascular reactivity.
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Prostaglandins attracted attention as potential mediators because of the appeal of the concept that a mediator might originate from the release of a substrate from the cell membrane. Arachidonic acid (AA), an essential fatty acid and a normal constituent of many cell membranes, is the endogenous source of all prostaglandins. Its release from the cell membrane is an early step in the formation of a number of vasoconstrictor and vasodilator compounds. The lung has a large capacity for prostaglandin production which led to the hypothesis that during acute hypoxia there might be a shift in metabolic pathways with increased production of vasoconstrictor metabolites. Thus, one or more prostanoid compounds could qualify as mediators) of the AHPR.
There are two major AA metabolic pathways: the cyclooxygenase and the lipoxygenase pathways. Inhibition of the cyclooxygenase pathway potentiates the AHPR in the isolated perfused lung, suggesting that products of this pathway modulate, but do not mediate, the AHPR. The vasodilator prostaglandin, PGI2, is continuously produced under basal conditions in the isolated perfused rat lung. During acute hypoxia, PGI2 output is significantly increased. Recent emphasis has shifted to the leukotrienes, the products of the other major AA metabolic pathway. Morganroth et al demonstrated that blockade of leukotriene synthesis inhibited hypoxic vasoconstriction in isolated perfused lungs, suggesting that leukotrienes mediate the AHPR. However, initial enthusiasm has been tempered by conflicting results with pharmacologic blockade of leukotriene synthesis and action. For example, Lonigro et al demonstrated that blockade of leukotriene synthesis inhibited the increase of vasoconstrictor leukotrienes C4, D4 in bronchoalveolar lavage during alveolar hypoxia, but did not abolish the AHPR. These data suggest that arachidonic acid metabolites are not the primary mediators of the response.
The most recent addition to the mediator controversy derives from the discovery that the vascular endothelium is an important regulator of vascular reactivity. For example, the uptake of serotinin by the pulmonary vasculature is regulated by proteins produced by endothelial cells. Pulmonary vessels, along with many systemic vessels, release a labile endothelial-derived relaxing factor (EDRF) which modifies vasopressor activity to different pharmacologic stimuli and acute hypoxia. Inhibitors of EDRF potentiate hypoxic vasoconstriction in isolated perfused lungs. Recent evidence suggests that this factor is nitric oxide. Systemic and pulmonary endothelial cells also release another peptide, endothe- lin, which is an endothelial cell-derived constricting factor. Since the endothelium is necessary for hypoxia-induced contractions of isolated pulmonary arteries, but not cerebral vessels, a similar factor could play a role in mediation of the AHPR. This area of research promises to contribute significantly to our understanding of the regulation of pulmonary vascular response in the normal or injured lung.
Category: Health
Tags: clinical relevance, Hypoxic Pulmonary, Vasoconstriction