In passage through the pulmonary circulation, a variety of blood-borne substances are subject to metabolism by enzymes associated with the pulmonary endothelium (Table 3). The metabolic processes appear to be very selective, as exemplified by the ability of the lung to metabolize norepinephrine but not other catecholamines, such as epinephrine and dopamine. For many of the compounds, uptake into the endothelial cell is required before enzymatic degradation occurs, and it is the substrate selectivity of these processes that appear to govern metabolic selectivity. Substances that are taken up into the endothelial cells include 5-hydroxytryptamine, norepinephrine, and prostaglandins E2 and F2a. The external surface of the endothelium bears several enzymes that serve to inactivate or biotransform blood-borne substances. These include phosphate esterases, which metabolize the adenosine phosphate compounds, and angiotensin-converting enzyme, which cleaves bradykinin to inactive fragments. The latter enzyme has been extensively studied, primarily because it is responsible for the bioactivation of angiotensin I to angiotensin II (a potent vasoconstrictor) and because the lungs represent the principal site of this conversion. Other peptidases have been identified on the pulmonary endothelium, but their physiological relevance remains to be established [48]. A fair amount is known about the metabolic properties of the pulmonary endothelium, in large part because of the relative ease of studying the pulmonary circulation, and the ability to study endothelium grown in cell culture. Considerably less is known about the metabolic properties of the airway epithelium, save that related to neutral endopeptidase or endothelin-converting enzyme activity [49-51]. In both areas, more research is needed to allow a more comprehensive understanding about how the lung metabolizes substances perfused through or depositing in it. In the context of aerosol administration to

Table 3 Fate of Substances Passing Through the Pulmonary Circulation

Removal 5-Hydroxytryptamine Norepinephrine Prostaglandins E2, F2a Leukotrienes C4, D4

Adenosine monophosphate, diphosphate, triphosphate Bradykinin Tachykinins Endothelin Unaffected Epinephrine Dopamine Isoproterenol Histamine Prostaglandin A2 Prostacyclin Oxytocin Vasopressin Angiotensin II Activation Angiotensin I

the peripheral airways, it should be evident from the foregoing that compounds delivered to the alveoli and absorbed into the pulmonary circulation will be subject to endothelial metabolic processes.

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