Endothelium-independent and -dependent vasodilation in alkalotic and acidotic piglet lungs

Abstract

Although significant pulmonary hypertension can occur in patients treated with either hypocapnic alkalosis or “permissive” hypercapnic acidosis, the effects of sustained alkalosis or acidosis on subsequent vasodilator responses have not been established. This study measured the effects of 60–100 min of sustained alkalosis or acidosis on endothelium‐independent and ‐dependent vasodilation with inhaled nitric oxide (iNO) and acetylcholine (ACh) in isolated lungs from 1‐week‐old piglets. After stabilization, lungs were divided into control (pH 7.40, PaCO2 40 torr, n = 5), alkalotic (pH 7.60, PaCO2 25 torr, n = 6), or acidotic (pH 7.25, PaCO2 65 torr, n = 5) groups and ventilated with 21% O2 for 40 min. Acute hypoxic pulmonary vasoconstriction (HPV) was then induced with 4–6% O2. After a stable pressor response had occurred (≊mF20 min), pulmonary artery dose‐response relationships to increasing concentrations of iNO were measured. The iNO was then stopped and after a stable hypoxic pressure had again been reestablished (≊mF20 min), dose‐responses to increasing concentrations of ACh were measured. Hypoxic pulmonary vascular resistance (PVR) was similar in all groups. Pulmonary artery pressure dose‐response relationships to iNO and ACh were blunted in the alkalosis group, suggesting that both endothelium‐independent and ‐dependent vasodilation were reduced during sustained hypocapnic alkalosis. In contrast, sustained acidosis did not alter subsequent vasodilator responses. Future studies must elucidate the mechanisms underlying blunted pulmonary vasodilation during sustained alkalosis and examine the consequences of sustained alkalosis therapy on subsequent vasodilator responses in clinical practice. Pediatr Pulmonol. 2000; 30:241–248. © 2000 Wiley‐Liss, Inc.

Hypercapnic acidosis and compensated hypercapnia in control and pulmonary hypertensive piglets

“…28 Our observation that acute hypercapnic acidosis increased normoxic and hypoxic PAP and PVRI in control piglets (Fig. 3A) was consistent with many previous studies showing that metabolic and hypercapnic acidosis increased pulmonary vasomotor tone in normal newborn [14][15][16]29 and mature [17][18][19] animals. The mechanism underlying increased vascular responsiveness has not been fully elucidated, but likely includes an acute increase in vascular smooth muscle cytosolic Ca 2þ 30 and increased sympathetic activity.…”

“…8 Despite these limitations, our study suggests that acute hypercapnia may have deleterious effects on pulmonary hemodynamics during hypoxia in normal and pulmonary hypertensive subjects, and these pressor effects may not be reversed by buffering the pH. Previous studies showing that inhaled nitric oxide (iNO) effectively reduced pulmonary vasoconstriction during hypercapnic acidosis 15,44 led us to speculate that iNO therapy may improve the outcome of children who develop pulmonary hypertension when treated with ventilator strategies leading to permissive hypercapnia.…”

Hypercapnic acidosis and compensated hypercapnia in control and pulmonary hypertensive piglets

“…28 Our observation that acute hypercapnic acidosis increased normoxic and hypoxic PAP and PVRI in control piglets (Fig. 3A) was consistent with many previous studies showing that metabolic and hypercapnic acidosis increased pulmonary vasomotor tone in normal newborn [14][15][16]29 and mature [17][18][19] animals. The mechanism underlying increased vascular responsiveness has not been fully elucidated, but likely includes an acute increase in vascular smooth muscle cytosolic Ca 2þ 30 and increased sympathetic activity.…”

“…8 Despite these limitations, our study suggests that acute hypercapnia may have deleterious effects on pulmonary hemodynamics during hypoxia in normal and pulmonary hypertensive subjects, and these pressor effects may not be reversed by buffering the pH. Previous studies showing that inhaled nitric oxide (iNO) effectively reduced pulmonary vasoconstriction during hypercapnic acidosis 15,44 led us to speculate that iNO therapy may improve the outcome of children who develop pulmonary hypertension when treated with ventilator strategies leading to permissive hypercapnia.…”

pH and nitric oxide synthase activity and expression in bovine aortic endothelial cells

“…In our study, the pH was maintained for only about 16 h, which may not be enough time for the changes to take effect. Moreover, in several previous studies hypoxia appeared to be a more important factor in producing vasoconstriction and/or decreased eNOS production 2829 then pH itself, and our cells were maintained in normoxic environment.…”

Effect of voluntary hypocapnic hyperventilation on the relationship between core temperature and heat loss responses in exercising humans

“…Esophageal temperature, cutaneous vascular conductance, and sweat rate. Although there was a main effect of time on esophageal temperature [F (4,36) ϭ84.2, P Ͻ 0.001] and forehead cutaneous vascular conductance [F (4,36) ϭ22.4, P Ͻ 0.001], no interactions [both F (8,72) Ͻ1.74, P Ͼ 0.104] and no main effect of ventilatory condition [both F (2,18) Ͻ2.07, P Ͼ 0.156] on esophageal temperature or forehead cutaneous vascular conductance were seen, indicating that esophageal temperature and forehead cutaneous vascular conductance did not differ between trials at any time point (Fig. 2, A and C).…”

“…An interaction was observed between the effects of ventilatory condition and time on mean skin temperature, heart rate, and middle cerebral artery vascular conductance index [all F (8,72) Ͼ2.27, P Ͻ 0.032], while main effects of ventilatory condition on forearm skin temperature [F (2,18) ϭ 4.02, P ϭ 0.036] and of time on forearm and forehead skin temperature and mean arterial pressure were detected [all F (4,36) Ͼ 4.11, P Ͻ 0.008]. During voluntary hyperventilation at rest or during exercise, mean skin temperature, forearm skin temperature, heart rate, and middle cerebral artery vascular conductance index were all lower in the hypocapnic hyperventilation trial than in the spontaneous ventilation or normocapnic hyperventilation trial (Table 1).…”

Hypercapnic acidosis and compensated hypercapnia in control and pulmonary hypertensive piglets

“…28 Our observation that acute hypercapnic acidosis increased normoxic and hypoxic PAP and PVRI in control piglets (Fig. 3A) was consistent with many previous studies showing that metabolic and hypercapnic acidosis increased pulmonary vasomotor tone in normal newborn [14][15][16]29 and mature [17][18][19] animals. The mechanism underlying increased vascular responsiveness has not been fully elucidated, but likely includes an acute increase in vascular smooth muscle cytosolic Ca 2þ 30 and increased sympathetic activity.…”

“…8 Despite these limitations, our study suggests that acute hypercapnia may have deleterious effects on pulmonary hemodynamics during hypoxia in normal and pulmonary hypertensive subjects, and these pressor effects may not be reversed by buffering the pH. Previous studies showing that inhaled nitric oxide (iNO) effectively reduced pulmonary vasoconstriction during hypercapnic acidosis 15,44 led us to speculate that iNO therapy may improve the outcome of children who develop pulmonary hypertension when treated with ventilator strategies leading to permissive hypercapnia.…”

pH and nitric oxide synthase activity and expression in bovine aortic endothelial cells

“…In our study, the pH was maintained for only about 16 h, which may not be enough time for the changes to take effect. Moreover, in several previous studies hypoxia appeared to be a more important factor in producing vasoconstriction and/or decreased eNOS production 2829 then pH itself, and our cells were maintained in normoxic environment.…”

Effect of voluntary hypocapnic hyperventilation on the relationship between core temperature and heat loss responses in exercising humans

“…Esophageal temperature, cutaneous vascular conductance, and sweat rate. Although there was a main effect of time on esophageal temperature [F (4,36) ϭ84.2, P Ͻ 0.001] and forehead cutaneous vascular conductance [F (4,36) ϭ22.4, P Ͻ 0.001], no interactions [both F (8,72) Ͻ1.74, P Ͼ 0.104] and no main effect of ventilatory condition [both F (2,18) Ͻ2.07, P Ͼ 0.156] on esophageal temperature or forehead cutaneous vascular conductance were seen, indicating that esophageal temperature and forehead cutaneous vascular conductance did not differ between trials at any time point (Fig. 2, A and C).…”

“…An interaction was observed between the effects of ventilatory condition and time on mean skin temperature, heart rate, and middle cerebral artery vascular conductance index [all F (8,72) Ͼ2.27, P Ͻ 0.032], while main effects of ventilatory condition on forearm skin temperature [F (2,18) ϭ 4.02, P ϭ 0.036] and of time on forearm and forehead skin temperature and mean arterial pressure were detected [all F (4,36) Ͼ 4.11, P Ͻ 0.008]. During voluntary hyperventilation at rest or during exercise, mean skin temperature, forearm skin temperature, heart rate, and middle cerebral artery vascular conductance index were all lower in the hypocapnic hyperventilation trial than in the spontaneous ventilation or normocapnic hyperventilation trial (Table 1).…”

Hypercapnic acidosis and compensated hypercapnia in control and pulmonary hypertensive piglets

“…28 Our observation that acute hypercapnic acidosis increased normoxic and hypoxic PAP and PVRI in control piglets (Fig. 3A) was consistent with many previous studies showing that metabolic and hypercapnic acidosis increased pulmonary vasomotor tone in normal newborn [14][15][16]29 and mature [17][18][19] animals. The mechanism underlying increased vascular responsiveness has not been fully elucidated, but likely includes an acute increase in vascular smooth muscle cytosolic Ca 2þ 30 and increased sympathetic activity.…”

“…8 Despite these limitations, our study suggests that acute hypercapnia may have deleterious effects on pulmonary hemodynamics during hypoxia in normal and pulmonary hypertensive subjects, and these pressor effects may not be reversed by buffering the pH. Previous studies showing that inhaled nitric oxide (iNO) effectively reduced pulmonary vasoconstriction during hypercapnic acidosis 15,44 led us to speculate that iNO therapy may improve the outcome of children who develop pulmonary hypertension when treated with ventilator strategies leading to permissive hypercapnia.…”

pH and nitric oxide synthase activity and expression in bovine aortic endothelial cells

“…In our study, the pH was maintained for only about 16 h, which may not be enough time for the changes to take effect. Moreover, in several previous studies hypoxia appeared to be a more important factor in producing vasoconstriction and/or decreased eNOS production 2829 then pH itself, and our cells were maintained in normoxic environment.…”

Effect of voluntary hypocapnic hyperventilation on the relationship between core temperature and heat loss responses in exercising humans

“…Esophageal temperature, cutaneous vascular conductance, and sweat rate. Although there was a main effect of time on esophageal temperature [F (4,36) ϭ84.2, P Ͻ 0.001] and forehead cutaneous vascular conductance [F (4,36) ϭ22.4, P Ͻ 0.001], no interactions [both F (8,72) Ͻ1.74, P Ͼ 0.104] and no main effect of ventilatory condition [both F (2,18) Ͻ2.07, P Ͼ 0.156] on esophageal temperature or forehead cutaneous vascular conductance were seen, indicating that esophageal temperature and forehead cutaneous vascular conductance did not differ between trials at any time point (Fig. 2, A and C).…”

“…An interaction was observed between the effects of ventilatory condition and time on mean skin temperature, heart rate, and middle cerebral artery vascular conductance index [all F (8,72) Ͼ2.27, P Ͻ 0.032], while main effects of ventilatory condition on forearm skin temperature [F (2,18) ϭ 4.02, P ϭ 0.036] and of time on forearm and forehead skin temperature and mean arterial pressure were detected [all F (4,36) Ͼ 4.11, P Ͻ 0.008]. During voluntary hyperventilation at rest or during exercise, mean skin temperature, forearm skin temperature, heart rate, and middle cerebral artery vascular conductance index were all lower in the hypocapnic hyperventilation trial than in the spontaneous ventilation or normocapnic hyperventilation trial (Table 1).…”