Restoration of myocardial bioenergetic metabolism in swine after periods of ischemic ventricular fibrillation.

Myocardial mitochondrial function and high energy phosphate levels were measured in normal swine, in swine after either 5 or 10 minutes of ischemic ventricular fibrillation (IVF) while on cardiopulmonary bypass, and in swine defibrillated after either 5 or 10 minutes of IVE. The damage to myocardial mitochondria induced by IVF, such as partial uncoupling, decreased oxygen uptake, and loss of cytochrome oxidase activity, was completely reversed almost instantly by coronary artery perfusion and the restoration of sinus rhythm. After either 5 or 10 minutes of IVF followed by coronary artery reperfusion and defibrillation, myocardial creatine phosphate (CP), adenosine monophosphate (AMP) and adenosine diphosphate (ADP) return to normal levels very rapidly. However, adenosine triphosphate (ATP) levels remain significantly lower than control levels. If the bioenergetic mechanisms of swine and human myocardium are similar, it appears that IVF at least for a 10 minute period produces no damage to myocardial mitochondria that is not corrected by perfusion of the coronary arteries and re-establishment of sinus rhythm. Furthermore, sinus rhythm can be re-established and maintained despite signficantly lower levels of myocardial ATP.

Chemoreflex blunting of hypoxic pulmonary vasoconstriction is vagally mediated.

We investigated the role of the autonomic nervous system in the arterial chemoreceptor attenuation of hypoxic pulmonary vasoconstriction (HPV) using anesthetized dogs. Total pulmonary blood flow (Qt) and left pulmonary blood flow (Ql) were determined using electromagnetic flow probes. Carotid body chemoreceptors were perfused using blood pumped from an extracorporeal circuit containing an oxygenator. Four groups were used: 1) prevagotomy (control), 2) bilateral vagotomy, 3) post-atropine, and 4) post-propranolol. Left lung hypoxia decreased Ql/Qt from 42.9 +/- 2.9 to 28.1 +/- 3.0%, from 41.1 +/- 5.3 to 26.7 +/- 4.2%, from 38.6 +/- 1.3 to 22.2 +/- 2.4%, and from 48.2 +/- 4.2 to 28.5 +/- 3.7% in the four groups, respectively. Chemoreceptor stimulation during unilateral hypoxia increased Ql/Qt from 28.1 +/- 3.0 to 39.1 +/- 4.9% and from 28.5 +/- 3.7 to 40.6 +/- 3.7% in the control and propranolol groups. However, chemoreceptor stimulation had no effect on Ql/Qt during left lung hypoxia after vagotomy or atropine, as Ql/Qt went from 26.7 +/- 4.2 to 29.3 +/- 5.2% and from 22.2 +/- 2.4 to 24.1 +/- 1.5% in groups 2 and 3, respectively. Because chemoreceptor stimulation did not affect HPV in groups 2 and 3, we conclude that the chemoreceptor attenuation of HPV is mediated by the parasympathetic nervous system.

Endothelin produces systemic vasodilation independent of the state of consciousness.

The effects of endothelin, ET-1, on pulmonary and systemic hemodynamics were studied in the open chest dog and changes in systemic arterial pressure in dogs under conscious and anesthetized states were compared. Rapid intravenous (IV) bolus injections of ET-1, 100-1,000 nanograms/kg, significantly decreased systemic arterial pressure, and significantly decreased systemic vascular resistance whereas left atrial pressure and pulmonary vascular resistance were not altered. Reductions in systemic arterial pressure in response to bolus injection of ET-1, 100 and 300 nanograms/kg IV, during conscious state and during anesthesia were similar, respectively. The present data suggest that ET-1 dilates the systemic vascular bed independent of the animal's state of consciousness. The present data also suggest that when compared to the systemic vascular bed, the pulmonary vascular bed is less responsive to bolus administration of ET-1.

Regional hypoxic pulmonary vasoconstriction in dogs with asymptomatic dirofilariasis.

The pulmonary hemodynamic response to unilateral alveolar hypoxia was investigated in pentobarbital-anesthetized dogs with mild heartworm (HW) disease and in dogs free of HW (HWF). Left lung nitrogen ventilation in HWF dogs resulted in a decrease in the fraction of the cardiac output (QT) perfusing the left lung (QL) from 0.37 +/- 0.03 (SEM) to 0.20 +/- 0.02 (P less than 0.01). In contrast, dogs with mild HW disease did not develop a significant decrease in QL/QT which decreased from 0.38 +/- 0.02 to 0.33 +/- 0.02. This attenuated pulmonary vascular response to regional alveolar hypoxia in dogs with HW disease was associated with a normal pulmonary arterial pressure (14.8 +/- 1.5 mm of Hg) that was not different from that seen in HWF dogs (15.8 +/- 1.7 mm of Hg). These results indicate that mild HW disease interferes with the ability of hypoxic pulmonary vasoconstriction to redistribute pulmonary blood flow away from hypoxic regions of the lung.

Chemoreceptor stimulation and hypoxic pulmonary vasoconstriction in conscious dogs.

Dogs with electromagnetic flow probes implanted on their left (QL) and main (QT) pulmonary arteries, catheters in their left atria and external jugular veins, and chronic tracheostomies were trained to accept Carlens dual-lumen endotracheal tubes into their tracheostomies, thus allowing separate ventilation of the two lungs. Swan-Ganz catheters were inserted through the jugular vein catheters. Pneumotachographs measured air flow to each lung. During bilateral ventilation with room air or O2, QL was about 36% of QT. When the left lung was ventilated with N2 while the right remained on O2, PAO2 was above 90 mmHg and QL fell to about 25% of QT. When the left lung was ventilated with N2 and the right with room air, PAO2 fell below 40 mm Hg and QL increased to control levels. This increase in perfusion of the hypoxic lung during systemic hypoxemia was not seen in dogs after surgical deafferentation of the systemic arterial chemoreceptors, indicating that stimulation of the arterial chemoreceptors may interfere with the hypoxic pulmonary vasoconstriction.

Hypoxemia and hypoxic pulmonary vasoconstriction: autonomic nervous system versus mixed venous PO2.

Hypoxemia interferes with hypoxic pulmonary vasoconstriction (HPV). We investigated the respective roles of the autonomic nervous system and the mixed venous PO2 (PVO2) in the attenuation of HPV by hypoxemia. Pentobarbital-anesthetized dogs had their lungs separately ventilated with a dual-lumen endotracheal tube. Left (Ql) and total (Qt) pulmonary blood flows were determined using electromagnetic flow probes. HPV was initiated by ventilating the left lung with nitrogen for 5-10 min while the right lung received 100% oxygen. The animals were subsequently made hypoxemic by switching the right lung to room air ventilation (5-10 min). Two different protocol groups received either intravenous atropine during hypoxemia (group I) or intravenous propranolol prior to protocol initiation (group II). A third group of dogs (group III) had their mixed venous PO2S maintained above 30 torr during hypoxemia. In response to left lung hypoxia, Ql/Qt decreased from 44 +/- 5, 48 +/- 3 and 46 +/- 2% to 25 +/- 4, 28 +/- 2 and 26 +/- 3% in the three groups, respectively. During hypoxemia Ql/Qt increased to 50 +/- 7 and 47 +/- 3% in groups I and II. In group III dogs, Ql/Qt remained significantly decreased at 31 +/- 3%. Subsequent administration of atropine in group I had no effect on Ql/Qt. We conclude that the loss of flow diversion from a hypoxic lung during hypoxemia may be mediated primarily by a decreased in mixed venous PO2 when PVO2 is allowed to decrease to 15-20 torr.

Effect of high-frequency oscillation on blood flow to an atelectatic lung in closed-chest dogs.

Seven dogs with electromagnetic flow probes implanted on their main (QT) and left (QL) pulmonary arteries, had catheters placed in their left atria and pulmonary artery, and were ventilated via Carlen's double-lumen endotracheal tubes. The effect of high-frequency oscillation (HFO) on the redistribution of pulmonary blood flow away from unilaterally atelectatic lungs was determined. During bilateral ventilation with 100% O2, using either a Harvard respirator (PPV) or an Emerson airway vibrator (HFO), the fraction of cardiac output perfusing the left lung (QL/QT) was 0.45 +/- .01 and 0.43 +/- .01, respectively, whereas PaO2 was 465 +/- 40 and 334 +/- 34 torr, respectively. With left lung atelectasis during right lung ventilation with PPV at 10 to 15 cycle/min, QL/QT fell to 0.37 +/- .01 and PaO2 was 56 +/- 5 torr. During HFO at 100 cycle/min, QL/QT fell to 0.32 +/- .02 whereas PaO2 rose to 102 +/- 23 torr. Mean transpulmonary pressure was 10.0 +/- 1.5 torr with PPV and 7.3 +/- 1.2 torr during HFO; intrapleural pressures were -3.2 +/- 1.6 and -5.7 +/- 1.4 mm Hg, respectively. Thus, the diversion of blood away from unilaterally atelectatic lungs was better maintained during HFO.

Effect of baroreceptor reflex stimulation on blood flow to an atelectatic lung.

The effect of baroreceptor reflex stimulation by carotid sinus hypotension on the pulmonary vascular response to atelectasis was studied in eight dogs anesthetized with chloralose. Closed-chest dogs with electromagnetic flow probes previously implanted on their left (QL) and main (QT) pulmonary arteries had their left and right lungs ventilated separately. Their carotid sinuses were isolated bilaterally and perfused by a pulsatile pump with a physiological salt solution. After an initial period of bilateral 100% O2 ventilation with carotid sinus perfusion pressures (CSPP) set at each animal's initial mean arterial pressure (98 +/- 19 Torr), the left airway was occluded, QL/QT fell from 0.33 +/- 0.01 to 0.24 +/- 0.02 and PO2 fell from 323 +/- 35 Torr to 74 + 7 Torr. When CSPP was lowered to 21 +/- 3 Torr, there were no changes in QL/QT and PO2. These results suggest that stimulation of the baroreceptor reflex by carotid sinus hypotension does not interfere with the diversion of pulmonary blood flow away from a unilaterally atelectatic lung.

Effect of chemoreceptor denervation on the pulmonary vascular response to atelectasis.

Six dogs anesthetized with 30 mg/kg pentobarbital were ventilated after differential cannulation of the main stem bronchi. Following sternotomy, blood flow was monitored by electromagnetic flow probes on the left pulmonary artery (QL) and on the pulmonary trunk or aorta (QT). Following 10 min of bilateral 100% O2, QL was 37.4 +/- 5.8% of QT. When left lung atelectasis was induced while the right lung remained on 100% O2, PaO2 remained above 75 mm Hg and QL fell to 26.1 +/- 5.0% of QT. However, when the right lung was ventilated with room air while the left lung remained atelectatic, PaO2 fell to 50.0 +/- 2.6 mm Hg and QL rose to 36.7 +/- 6.2% of QT. Six dogs which had undergone peripheral chemoreceptor denervation prior to these experiments showed a similar decrease in perfusion of the atelectatic left lung when the right lung was ventilated with 100% O2, but did not increase blood flow to the atelectatic lung during systemic hypoxemia. Thus, the increased blood flow to the atelectatic lung which occurs during systemic hypoxemia appears to be mediated by the arterial chemoreceptors.

Chemoreceptor stimulation interferes with regional hypoxic pulmonary vasoconstriction.

Hypoxemia interferes with the diversion of blood flow away from hypoxic regions of the lung, possibly through activation of the arterial chemoreceptor reflex. The purpose of this study was to determine if selective stimulation of carotid chemoreceptors reduces the diversion of flow (hypoxic vasoconstriction) when normal systemic oxygen levels are present. Chloralose anesthetized dogs were paralyzed and each lung was separately ventilated via a dual-lumen endobronchial tube. Left pulmonary artery (QL) and main pulmonary artery (QT) blood flows were measured with electromagnetic flow probes. Chemoreceptors were stimulated by perfusion of the carotid sinuses with hypoxic, hypercapnic blood. QL/QT averaged 46 +/- 4, 29 +/- 2, and 36 +/- 4% during bilateral O2 ventilation (control), left lung N2 ventilation, and left lung N2 plus chemoreceptor stimulation in dogs treated with the cyclo-oxygenase inhibitor meclofenamate. After vagotomy, QL/QT averaged 45 +/- 4, 27 +/- 3, and 28 +/- 2% during the same conditions. QL/QT decreased significantly from control (P less than 0.05) during left lung N2 alone but did not decrease during left lung N2 plus chemoreceptor stimulation in dogs with intact vagi. In contrast, QL/QT decreased significantly both before and during chemoreceptor stimulation in vagotomized dogs. The same responses were observed in dogs not treated with meclofenamate. These results indicate that selective stimulation of arterial chemoreceptors can interfere with regional hypoxic vasoconstriction and suggest that the vagus nerves may mediate this effect.

Attenuation of hypoxic pulmonary vasoconstriction by pulsatile flow in dog lungs.

We measured pulmonary arterial pressure in isolated lower lobes of dog lungs perfused in situ at several flows during ventilation with 95% O2-5% CO2 and with 3% O2-5% CO2. Pulsatile perfusion was provided by a piston pump, and steady perfusion was provided by a roller pump. The slope of the pressure-flow curve was 16.1 +/- 1.6 Torr X 1(-1) X min at all flows between 200 and 800 ml/min during 95-5 ventilation and increased to 19.4 +/- 3.7 in hypoxia. When flow was 600 ml/min, with 95-5 ventilation, mean arterial pressure was 16.2 +/- 1.2 Torr in steady flow and was unchanged at 15.0 +/- 1.0 Torr in pulsatile flow. At the same flow during hypoxic ventilation, mean arterial pressure increased to 27.9 +/- 2.4 Torr (P less than 0.01) when flow was steady but only to 19.3 +/- 1.6 Torr (P less than 0.01) when flow was made pulsatile. Thus hypoxia increased perfusion pressure by a nearly parallel shift of the pressure-flow curve to higher pressures, and this change was smaller in pulsatile than in steady flow.

Phasic reflux of pulmonary blood flow in atelectasis: influence of systemic PO2.

In 16 dogs ventilated with 100% O2, control blood flow to the left lung was 35 +/- 2% of aortic flow. When left lung atelectasis was induced, left pulmonary artery flow fell to 19 +/- 2% of aortic flow. A large retrograde component of flow developed in this pulmonary artery, suggesting that blood flows into the pulmonary arteries of both lungs during systole, but flows back out of the collapsed lung and into the uncollapsed lung during diastole. Systemic PaO2 remained above 78 mmHg. Subsequently, when the ventilation of the right lung was changed from oxygen to room air, systemic PaO2 fell to 64 +/- 3 mmHg and atelectatic left lung flow rose from 19 +/- 2% to 28 +/- 2% f aortic flow. This was associated with a reduction in reflux from the atelectatic lung. These results suggest that the attenuation of flow to an atelectatic lung is more pronounced if systemic normoxemia is maintained by adequate oxygenation of the normal lung.

Chemoreceptor influence on pulmonary blood flow during unilateral hypoxia in dogs.

Dogs anesthetized with 30 mg/kg pentobarbital were artificially respired after differential cannulation of the main stem bronchi. Following median sternotomy, blood flow was monitored by electromagnetic flow probes on the left pulmonary artery (QL) and on the pulmonary trunk or aorta, QT. Following 10 min of bilateral 100% O2, QL was 42.5 +/- 7% of QT. When 6% O2, was substituted as the gas mixture inspired by the left lung while the right lung remained on 100% O2, PaO2 was above 70 mm Hg and QL fell to 24.5 +/- 5% of QT. Room air was then used to ventilate the right lung while the left lung remained on 6% O2. This caused PaO2 to fall to 42.3 +/- 3 MM Hg and QL to rise to 38.3 +/- 6% QT. This increase in blood flow to the unilaterally hypoxic lung during systemic hypoxemia did not occur in dogs after peripheral chemoreceptor denervation. Therefore, interference with the local response to alveolar hypoxia during systemic hypoxemia appears to be mediated by the arterial chemoreceptors.

Effect of high-frequency positive-pressure ventilation on halothane ablation of hypoxic pulmonary vasoconstriction.

High-frequency positive-pressure ventilation (HFPPV) was compared to intermittent positive-pressure ventilation (IPPV) during unilateral atelectasis with and without halothane anesthesia. Dogs with electromagnetic flow probes chronically implanted on their main (Qt) and left (Ql) pulmonary arteries were ventilated via Carlen's dual-lumen endotracheal tubes. In eight closed-chest dogs, about 43% of the cardiac output perfused the left lung during bilateral ventilation by either a Harvard animal respirator (IPPV) or a Health-dyne model 300 high-frequency ventilator (HFPPV). Unilateral atelectasis decreased blood flow (Ql/Qt) to that lung. Ql/Qt was 19 +/- 1% with HFPPV during left-lung atelectasis and right-lung ventilation, compared to 32 +/- 1% with unilateral IPPV. This suggests that HFPPV permits stronger hypoxic pulmonary vasoconstriction. Addition of 1% halothane increased blood flow to the atelectatic left lung during unilateral ventilation with IPPV but not with HFPPV. This suggests that halothane decreases the effects of hypoxic pulmonary vasoconstriction during conventional ventilation but not during HFPPV.

A comparison of pulmonary arterial occlusion algorithms for estimation of pulmonary capillary pressure.

Using the arterial occlusion method, we compared five literature-based estimates of pulmonary capillary pressure (Ppc) with the corresponding double occlusion pressures (Pdo) in anesthetized dogs whose chests had been closed after sternotomy for instrumentation. Arterial occlusions were performed with a balloon-tipped pulmonary artery catheter that housed pressure transducers immediately proximal and distal to the balloon. Separation of the proximal and distal pressure waveforms during balloon inflation allowed us to precisely define the moment of occlusion. We fit a monoexponential curve to pressure data beginning 200 ms after the onset of occlusion and a biexponential curve to data beginning at the instant of occlusion, with data obtained over a range of vascular states (control, serotonin infusion, histamine infusion). In addition, we investigated the use of sampling of the raw data to estimate capillary pressure. Three of the five literature-based estimates of Ppc yielded values similar to Pdo. The optimal (least average difference from Pdo) interpolation/extrapolation time points of the curve fits varied, depending on the type of curve fitting and the state of the pulmonary vasculature. We also determined that a close approximation of Pdo may be derived from the raw data, as an alternative to exponential curve fitting.