Extrauterine Hypoxic Vasoconstriction

Nitroglycerin is a pulmonary artery vasodilator. We wondered if it would inhibit HPV, letting us demonstrate whether HPV was important in improving gas exchange in humans. In a dog model similar to that shown with the double lumen endotracheal tube in Figure 1A, we found a mean decrease in perfusion to the hypoxic lung of 28% in 8 animals (12). An infusion of 20 ng/min of nitroglycerin reduced the HPV so that only 9% of blood flow was diverted from the hypoxic lung resulting in a fall in Pa02 in the dogs from 89 to 59 mmHg. Knowing that HPV was inhibited by nitroglycerin, we then gave 0.6 mg sublingual nitroglycerin to a supine 53-year old man admitted to the hospital with suspected coronary artery disease but found to have gastritis with no coronary artery disease. He was a former smoker with an FEV, of 99% predicted but a flow at low lung volumes of only 44% predicted, consistent with small airways dysfunction and susceptibility to increased airway collapse (Fig. 3). The arterial Po2 fell from 80 to 65 mmHg six minutes after the nitroglycerin tablet was taken with no significant change in PaC02, pH, shunt or cardiac output (Fig. 4). Thus, the nitroglycerin tablet disturbed ventilation-perfusion (V/Q) balance since neither shunt nor ventilation was changed, consistent with a loss of HPV allowing increased blood flow to hypoxic areas of lung (12).

We then looked at a series of individuals studied supine as it minimized any change in cardiac output by nitroglycerin, and maximized airway narrowing or closure since functional residual capacity falls by 15% in the supine position. Eight of the subjects had reduced airflow at low lung volumes (V25) consistent with small airways dysfunction and six were completely normal. Normal subjects decreased their Pa02 by 9 mmHg and those with small airways dysfunction by 14 mmHg after nitroglycerin (Fig. 5). Shunt fraction was assessed in 13 of these individuals and it changed by less than 1%, thus not being responsible for the fall in Pa02. Subjects with advanced emphysema or pulmonary fibrosis were in generally much less responsive to nitroglycerin (Fig. 5). The DLC0 in these subjects was very low reflecting a likely significant loss ofvascular bed. Perhaps in this state there is insufficient compliant vasculature anywhere in the lung for HPV to effectively divert blood. This display of the importance of HPV in humans with minimal or no lung disease has subsequently been shown by nitroprusside infusions in patients with congestive heart failure where Pa02 fell in spite of an increase in cardiac output and a small rise in mixed venous Po2 from 31 to 33 mmHg (30).

Figure 4. Sequential changes in arterial blood gases in one supine subject with small airways dysfunction given 0.6 mg of nitroglycerin sublingually at the arrow. Alveolar-arterial (A-a) gradient during 02 breathing was obtained in the control period and at 16 mins after nitroglycerin administration (02 given from 9 to 16 mins). Twenty-two mins after the nitroglycerin was given, the Po2 was still reduced at 67 mmHg (Reprinted from Ref. 12).

Figure 4. Sequential changes in arterial blood gases in one supine subject with small airways dysfunction given 0.6 mg of nitroglycerin sublingually at the arrow. Alveolar-arterial (A-a) gradient during 02 breathing was obtained in the control period and at 16 mins after nitroglycerin administration (02 given from 9 to 16 mins). Twenty-two mins after the nitroglycerin was given, the Po2 was still reduced at 67 mmHg (Reprinted from Ref. 12).

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