Failure of Hypoxic Pulmonary Vasoconstriction in the Canine Asthma Model

Abstract

A B S T R A C T Measurements of respiratory mechanics, arterial blood gases, and pulmonary vascular resistance were made before and 15 min after inhalation challenge with Ascaris suum extract in dogs with natural sensitivity to this antigen. 25 of 47 dogs were treated before inhalation challenge with a prostaglandin inhibitor (90 mg/kg of aspirin or 2 mg/kg of indomethacin by intravenous infusion). In response to the challenge, bronchospasm developed in approximately half (responders) of each group reflected by decreases in mean specific respiratory system conductance and arterial oxygen tenision. While the dogs were breathing room air, pulmonary vaseular resistance remained unchanged after antigen challenge in the responders not given aspirin or indomethacin, but increased significantly and was associated with a lesser degree of arterial hypoxemia in the responders pretreated with either of the prostaglandin inhibitors. Prevention of arterial hypoxemia by oxygen breathing blocked an increase in pulmoinary vascular resistance in four pretreated responiders. No changes in respiratory mechanies, pulmonary hemodyiianaies, or arterial blood gases were noted in the 21 dogs who did not develop bronchospasmi regardless of whether or not they wvere pretreated. 12 additional dogs in whom arterial hypoxemia was produiced by 10% oxygen breathing, showed an increase in pulmonary vaseular resistance that was not potentiated by pretreatment with aspirin in 6. We conclude that in acuite experimental canine asthma, vasodilator prostaglandins appear to blunt the hypoxic pulmonary vasoconstrictor response, thereby further compromising gas exchange btut preventing the development of pulmonary hypertension.

Does Slow-reacting Substance of Anaphylaxis Mediate Hypoxic Pulmonary Vasoconstriction?1–3

“…The results of the present investigation suggest that in sheep with a typical hypoxic vasoconstrictor response, during hypoxia the predominant pathway is the lipoxygenase pathway, whereas in those with a blunted response, cyclooxygenase is the predominant pathway (31). Similarly, the endotoxic and allergic states might shift the arachidonic acid metabolism toward the cyclooxygenase pathway (28)(29)(30). Thus, in situations with blunted hypoxic vascular response, the mediators of prevailing cyclooxygenase pathways would mask the effects of SRS-A, and vasoconstrictor response is only observed after pretreating the animals with cyclooxygenase inhibitors.…”

“…The pattern of various mediators released from mast cells would perhaps vary, depending upon the type of challenge, i.e., hypoxic versus antigen. During antigen-induced hypoxemia, pulmonary vasoconstriction is only observed after prostaglandin synthetase inhibition (28,29), whereas during equivalent levels of exogenous hypoxia (low Fio 2 ), pulmonary vasoconstriction is observed and generally not influenced by prostaglandin synthetase inhibitors (11). This suggests that release of vasodilator prostaglandins is variable, depending upon the specific challenge to mast cells.…”

“…This suggests that release of vasodilator prostaglandins is variable, depending upon the specific challenge to mast cells. In addition to canine and ovine models of allergic asthma (28,29), prostaglandins and other products of the cyclooxygenase pathway have been implicated in the blunting of hypoxic pulmonary vasoconstriction by endotoxin infusion in dogs (30). Similarly, the hypoxic pulmonary vasoconstrictor response is naturally blunted in a minority of sheep and can be unmasked by pretreatment with indomethacin (31).…”

Restoration of Hypoxic Pulmonary Vasoconstriction following Normoxia in Isolated Dog Lungs Occurs in the Presence but Not in the Absence of Prostaglandin Synthesis Inhibitors

“…3, 4) [3] but also can occur in vivo in the dog [5,[12][13][14], Such in vivo reductions can occur after an attack of asthma [12], with an infusion of arachidonic acid (a precursor of PGs) [5], or for undefined reasons [13,14], Our results ( fig. 3, 4) in conjunction with the previous in vivo findings [5,[12][13][14] suggest that studies of the pulmonary vascular effects of PG syn thesis in the isolated dog lung may be ap plicable to the intact animal.…”

Variability of Hypoxic Pulmonary Vasoconstriction in Sheep

“…In dogs and sheep with airway hyperreactivity to Ascaris suum antigen, Cohn and colleagues (16) and Kung and coworkers (17) have shown that the pulmonary vascular response to hypoxia associated with allergic bronchospasm was blunted when compared with equivalent levels of exogenous hypoxia. In both investigations, the blunted response was reversed with prostaglandin synthetase inhibitor pretreatment.…”