Pulmonary vasoregulation by endothelin in conscious dogs after left lung transplantation.

We tested the hypothesis that regulation of the pulmonary circulation by endogenous endothelin (ET) during normoxia and hypoxia was altered in conscious dogs 1 mo after left lung autotransplantation (LLA). Sham-operated control and post-LLA dogs were chronically instrumented to measure the left pulmonary vascular pressure-flow (LP-Q) relationship. LP-Q plots were generated on separate days during normoxia and hypoxia (arterial PO(2) approximately 50 Torr) in the intact condition, after selective ET(A)-receptor inhibition (BQ-485), and after combined ET(A+B)-receptor inhibition (bosentan). Although LLA resulted in a chronic increase in pulmonary vascular resistance, the ET-receptor antagonists had no effect on the LP-Q relationship during normoxia in either group. The magnitude of hypoxic pulmonary vasoconstriction (HPV) was flow dependent in both groups, and the HPV response was potentiated post-LLA compared with control. ET(A)-receptor inhibition attenuated the HPV response to the same extent in both groups. ET(A+B)-receptor inhibition attenuated the HPV response to a greater extent than did ET(A)-receptor inhibition alone, and this effect was greater post-LLA compared with control. Plasma ET-1 concentration only increased during hypoxia in the LLA group. These results indicate that ET does not regulate the baseline LP-Q relationship in either group. Both ET(A)- and ET(B)-receptor activation mediate a component of HPV in conscious dogs, and the vasoconstrictor influence of ET(B)-receptor activation is enhanced post-LLA.     

Pulmonary hypertension and increased vasoreactivity caused by repeated indomethacin in sheep

Six chronically catheterized awake sheep were given the cyclooxygenase inhibitor indomethacin (5 mg/kg) twice a day over a 3-wk period. Three sheep receiving vehicle alone served as controls. Pulmonary arterial, left atrial, and systemic arterial pressures, cardiac output, blood gases, and pH were measured biweekly. Pulmonary vasoreactivity to 12% O2 and an analogue of prostaglandin H2 (PGH2-A) was also assessed. As a percent of base line, indomethacin caused a doubling in pulmonary vascular resistance (3 wk = 190 +/- 26%, mean +/- SE) and a 50% increase in pulmonary arterial pressure (3 wk = 151 +/- 9%). Vasoreactivity to 12% O2 increased approximately fourfold during the 1st wk of treatment and then declined. Vasoreactivity to PGH2-A increased steadily, nearly doubling by 3 wk. Light-microscopic counts of peripheral lung biopsy tissue revealed marked sequestration of granulocytes. Morphometric techniques applied to lungs removed at autopsy and fixed with the pulmonary arteries distended with barium gelatin mixture showed a significant reduction in number of barium-filled peripheral arteries and reduction in their external diameter. We conclude that repeated administration of indomethacin alters pulmonary vasoreactivity and causes sustained pulmonary hypertension. Structural studies reveal peripheral lung inflammation and changes in the arterial circulation that are perhaps more consistent with maintained vasoconstriction than chronic pulmonary hypertension.     

A model of embolic chronic pulmonary hypertension in the dog

Despite numerous efforts, a reliable model of chronic embolic pulmonary hypertension has not been established. To develop such a model five conscious mongrel dogs were embolized repeatedly over 16-30 wk with Sephadex microspheres 286 +/- 70 micron in diameter. Hemodynamic and respiratory measurements were obtained just prior to each embolization. Chronic pulmonary hypertension developed in all dogs. Pulmonary hypertension was not accounted for by increased cardiac output, wedge pressure, right atrial pressure, or systemic arterial pressure. Gas exchange was little altered. Lung histological study revealed microspheres clustered within vessels. In three dogs increased pulmonary arterial pressure was sustained despite cessation of embolization for up to 5 mo. Reembolization in one of these caused further pulmonary hypertension. In two dogs acute pulmonary vasodilation by O2 breathing and administration of prostaglandin E1 reduced, but did not abolish, the increased pulmonary vascular resistance, suggesting some vascular tone was present. An embolic model of chronic pulmonary hypertension in awake dogs allows further investigation into the evolution of pulmonary hypertension.     

Anesthesia alters pulmonary vasoregulation by angiotensin II and captopril.

We investigated the effects of an intravenous (pentobarbital sodium) and inhalational (halothane) general anesthetic on the pulmonary vascular responses to angiotensin II and angiotensin-converting enzyme inhibition (CEI). Multipoint pulmonary vascular pressure-flow (P/Q) plots were generated in conscious pentobarbital- (30 mg/kg iv) and halothane-anesthetized (approximately 1.2% end-tidal) dogs in the intact (no drug) condition, during angiotensin II administration (60 ng.kg-1.min-1 iv), and during CEI (captopril 1 mg/kg plus 1 mg.kg-1.h-1 iv). In conscious dogs, angiotensin II increased (P less than 0.001) the pulmonary vascular pressure gradient [pulmonary arterial pressure--pulmonary arterial wedge pressure (PAP-PAWP)] over the empirically measured range of Q; i.e., angiotensin II caused pulmonary vasoconstriction. Pulmonary vasoconstriction (P less than 0.01) in response to angiotensin II was also observed during pentobarbital sodium anesthesia. In contrast, angiotensin II had no effect on the P/Q relationship during halothane anesthesia. In conscious dogs, CEI decreased (P less than 0.001) PAP-PAWP over the empirically measured range of Q; i.e., CEI caused pulmonary vasodilation. However, CEI caused pulmonary vasoconstriction (P less than 0.02) during pentobarbital sodium and had no effect on the P/Q relationship during halothane. Thus, compared with the conscious state, the pulmonary vasoconstrictor response to angiotensin II is unchanged or abolished, and the pulmonary vasodilator response to CEI is reversed to vasoconstriction or abolished during pentobarbital sodium and halothane anesthesia, respectively.     

Sinoaortic deafferentation reduces intrapulmonary shunt in dogs with oleic acid lung injury

Hypoxic stimulation of the peripheral chemoreceptors has been reported to inhibit hypoxic pulmonary vasoconstriction. To evaluate the pathophysiological importance of this observation, we investigated the effects of surgical peripheral chemoreceptor denervation on pulmonary vascular tone and gas exchange in 17 pentobarbital-anesthetized dogs with oleic acid pulmonary edema. Pulmonary arterial pressure-cardiac index (Ppa/Q) plots, blood gases, and intrapulmonary shunt measured by the SF6 method were obtained at base line, after peripheral chemodenervation (n = 9) or after sham operation (n = 8), and again after 0.09 ml.kg-1 intravenous oleic acid. Over the range of Q studied (2-5 l.min-1.m-2), Ppa/Q plots were best fitted as first-order polynomials in most dogs in all experimental conditions. Chemoreceptor denervation increased Ppa at the lowest Q, while sham operation did not affect the Ppa/Q plots. Oleic acid increased Ppa over the entire range of Q and increased intrapulmonary shunt. This latter was measured at identical Q during the construction of the Ppa/Q plots. Chemoreceptor-denervated dogs, compared with sham-operated dogs, had the same pulmonary hypertension but lower intrapulmonary shunt (36 +/- 4 vs. 48 +/- 5%, means +/- SE, P less than 0.04) and venous admixture (43 +/- 4 vs. 54 +/- 3%, P less than 0.02). We conclude that in intact dogs chemoreceptor denervation attenuates the rise in intrapulmonary shunt after oleic acid lung injury. Whether this improvement in gas exchange is related to an enhanced hypoxic pulmonary vasoconstriction is uncertain.     

Bradykinin actively modulates pulmonary vascular pressure-cardiac index relationships

Our objectives were to investigate the pulmonary vascular effects of exogenously administered bradykinin at normal and reduced levels of cardiac index in intact conscious dogs and to assess the extent to which the pulmonary vascular response to bradykinin is the result of either cyclooxygenase pathway activation or reflex activation of sympathetic beta-adrenergic and -cholinergic receptors. Multipoint pulmonary vascular pressure-cardiac index (P/Q) plots were constructed during normoxia in conscious dogs by step-wise constriction of the thoracic inferior vena cava to reduce Q. In intact dogs, bradykinin (2 micrograms X kg-1 X min-1 iv) caused systemic vasodilation, i.e., systemic arterial pressure was slightly decreased (P less than 0.05), Q was markedly increased (P less than 0.01), and mixed venous PO2 and oxygen saturation (SO2) were increased (P less than 0.01). Bradykinin decreased (P less than 0.01) the pulmonary vascular pressure gradient (pulmonary arterial pressure-pulmonary capillary wedge pressure) over the entire range of Q studied (140-60 ml X min-1 X kg-1) in intact dogs. During cyclooxygenase pathway inhibition with indomethacin, bradykinin again decreased (P less than 0.05) pulmonary arterial pressure-pulmonary capillary wedge pressure at every level of Q, although the magnitude of the vasodilator response was diminished at lower levels of Q (60 ml X min-1 X kg-1). Following combined administration of sympathetic beta-adrenergic and -cholinergic receptor antagonists, bradykinin still decreased (P less than 0.01) pulmonary arterial pressure-pulmonary capillary wedge pressure over the range of Q from 160 to 60 ml X min-1 X kg-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

The ischemic lung: Role of the bronchial arteries in lung function

A patient with a dissecting aortic aneurysm, Type 1, developed acute pulmonary edema unexplained by the usual etiologic factors. Pathologic evidence that bronchial arterial circulation was interrupted led us to hypothesize that pulmonary edema could be due to ischemia of the bronchial circulation. To test this hypothesis, two chronic studies were done in dogs. The first study consisted of selective ligation of the right posterior bronchial artery at its origin at the fifth or sixth intercostal artery. After recovery from surgery, biopsies were taken from the ipsilateral and contralateral lung at time periods from 5 hours to 11 days. Ischemic damage was found in seven of eight dogs (87.5%), and was confined to the right lung. Histological examination revealed initial congestion within 8 hours, followed by pulmonary edema within 72 hours, and finally, disruption of alveolar septa with small emphysematous bullae on the eleventh postoperative day. The left lung remained normal in histological appearance. The second study consisted of transplanting the bronchial artery to the pulmonary artery to create a low pressure system and low O(2) content, and to simulate a regional shock situation. In five of six dogs (83.3%), the anastomosis was occluded within 72 hours, probably due to pressure competition from small collateral bronchial circulation. However, in these five dogs, pulmonary vascular resistance increased by 53%, intrapulmonary shunting increased by 83%, and the alveolar-to-arterial oxygen gradient increased by 150 mm Hg. Pulmonary edema was again confined to the right lung. Bronchial arteriograms demonstrated the extensive and variable distribution of the bronchial circulation in dogs. In the sixth dog, the anastomosis remained patent with a left-to-right shunt, due to a larger bronchial arterial collateral circulation. In this animal, the pulmonary arterial resistance, intrapulmonary shunting, and alveolar-arterial O(2) gradient were normal. Pulmonary edema was absent in lung biopsies. Bronchial circulation is discussed with respect to its clinical implications for lung transplants, shock, thoracic aneurysms, and mediastinal surgery. The results of this study suggest that the systemic bronchial circulation is important for normal lung function.     

Umbilical cord compression produces pulmonary hypertension in newborn lambs: a model to study the pathophysiology of persistent pulmonary hypertension in the newborn

We investigated the effects of chronic intrauterine hypoxaemia produced by prolonged partial umbilical cord compression on the circulation shortly after birth in lambs. Vascular catheters were inserted in 10 fetal sheep at 120 to 130 days gestation to measure descending aortic blood gases, arterial pH, and arterial O2 saturation. An inflatable silicone rubber balloon cuff was also placed around the umbilical cord. After recovery and the return of descending aortic blood gases to the normal range, the balloon was gradually inflated, decreasing the PaO2 from 21.2 +/- 3.6 to 17.5 +/- 1.3 mm Hg and the arterial O2 saturation from 57.1 +/- 9.2% to 37.2% +/- 5.2. After 14.3 +/- 3.7 days of partial umbilical cord compression, the lambs were delivered by Caesarean section, instrumented to measure systemic and pulmonary arterial, right atrial and pulmonary arterial wedge pressures, pulmonary and systemic blood flows, and mechanically ventilated. Five normal lambs were also studied. From 60 to 120 min after delivery, when compared to normal lambs, the umbilical compression lambs had an increased pulmonary arterial pressure (P less than 0.05) pulmonary vascular resistance (P less than 0.05), and right atrial pressure (P less than 0.05) with similar arterial blood gases. In both groups, hypoxic ventilation produced an increase in pulmonary arterial pressure (P less than 0.05) which on return to room air ventilation decreased to baseline in the normal lambs but not in the umbilical cord compression lambs (P less than 0.05). Prolonged partial umbilical cord compression produces chronic fetal hypoxaemia and pulmonary arterial hypertension after birth. This may represent a model to study the pathophysiology of persistent pulmonary hypertension syndrome.     

Acute increases in anastomotic bronchial systemic to pulmonary blood flow due to generalized lung injury

Since pulmonary blood flow to regions involved in adult respiratory disease syndrome (ARDS) is reduced by hypoxic vasoconstriction, compression by cuffs of edema, and local thromboses, we postulated that the bronchial circulation must enlarge to provide for the inflammatory response. We measured anastomotic bronchial systemic to pulmonary blood flow [QBr(s-p)] serially in a lung lobe in 31 open-chest dogs following a generalized lobar injury simulating ARDS. The pulmonary circulation of the weighed left lower lobe (LLL) was isolated and perfused (zone 2) with autologous blood in anesthetized dogs. QBr(s-p) was measured from the amount of blood which overflowed from this closed vascular circuit corrected by any changes in the lobe weight. The LLL was ventilated with 5% CO2 in air. The systemic blood pressure (volume infusion), gases, and acid-base status (right lung ventilation) were kept constant. We injured the LLL via the airway by instilling either 0.1 N HCl or a mixture of glucose and glucose oxidase or via the pulmonary vessels by injecting either alpha-naphthylthiourea or oleic acid into the LLL pulmonary artery. In both types of injury, there was a prompt rise in QBr(s-p) (mean rise = 247% compared with control), which was sustained for the 2 h of observation. The cause of this increase in flow was studied. Control instillation of normal saline into the airways or into the pulmonary vessels did not change QBr(s-p) nor did a similar increase in lobar fluid (weight) due to hydrostatic edema. Neither cardiac output nor systemic blood pressure increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of vasoconstricting prostanoids on the coronary and hindlimb vascular beds of the conscious sheep

Vasoconstricting prostaglandins were injected, in bolus doses, into the lower abdominal aorta on the left circumflex coronary artery (LCCA) of conscious sheep. Local blood flow, mean arterial pressure (MAP), heart rate (HR) and ECG were continuously monitored. Thromboxane B2 had no effect on either vascular bed in doses up to 100 micrograms. PGF2 alpha produced mild vasoconstriction in both vascular beds with no systemic response. The endoperoxide analogues, U-44069 and U-46619, produced complex responses in both vascular beds. Initial vasodilation was followed rapidly by prolonged vasoconstriction. In the coronary circulation, vasoconstriction was temporarily masked by a hyperaemic phase. The U-compounds also affected MAP, possibly as a result of pulmonary and systemic vasoconstriction.     

Circulatory effects of prolonged hypoxia before and during antihistamine.

Five chronically instrumented healthy dogs were exposed to a 5-day period of breathing 10% oxygen in a chamber. The response to hypoxia was found to be time dependent. During the first 24 h of hypoxia the circulatory response was characterized by increases in cardiac output, heart rate, pulmonary and systemic arterial blood pressures, and pulmonary vascular resistance. Systemic vascular resistance increased; left atrial pressure decreased. During the early part of hypoxia the animals became hypocapnic; the arterial blood pH rose significantly. During the rest of the hypoxic period cardiac output, heart rate, and arterial blood pH returned to the control values; pulmonary and systemic arterial pressures and pulmonary vascular resistance remained significantly elevated. Systemic vascular resistance rose; left atrial pressure remained below control. This response to hypoxia was not substantially modified when the experiment was repeated during the administration of the antihistamine promethazine, an H1-receptor blocking agent, in a dose which blocked the pulmonary vasoconstrictor response to small doses of exogenous histamine. The circulatory response to acute hypoxia in five anesthetized dogs was not modified by intravenous administration of metiamide, an H2-receptor blocking agent.     

Increased vasoreactivity and chronic pulmonary hypertension following thoracic irradiation in sheep

Six chronically catheterized sheep were exposed to 1,500-rad whole-lung irradiation and followed for a four-week period. Pulmonary arterial, left atrial and systemic arterial pressures, cardiac output, arterial blood gases, and pH were measured at base line and biweekly following radiation. Pulmonary vasoreactivity to 12% O2, 100% O2, and an analogue of prostaglandin H2 (PGH2-A) was also assessed. Five nonirradiated sheep served as controls. By the 2nd wk following irradiation, pulmonary vascular resistance had doubled. Final pulmonary arterial pressure was increased 50% over the base-line value (base line = 14 +/- 1 cm H2O; final 22 +/- 2; mean +/- SE; P less than 0.05). Arterial PO2 was decreased to approximately 70 Torr throughout the study. In addition, pulmonary vasoreactivity to PGH2-A, but not to breathing 12 or 100% O2, was significantly increased above base line in the irradiated animals (P less than 0.05). Morphometric techniques applied to the lungs in which the pulmonary arterial circulation was distended with barium gelatin mixture, showed extension of muscle into the distal intra-acinar arteries, and a reduction in both the external diameter and the number of barium-filled peripheral arteries in the irradiated animals. Thus thoracic irradiation results in functional and structural changes of chronic pulmonary hypertension and increased pulmonary vasoreactivity to PGH2-A. The structural changes in the peripheral pulmonary arterial bed may contribute to the increased pulmonary vascular reactivity following thoracic irradiation.     

Pulmonary pressure-flow relationships in the fetal lamb during in utero ventilation

Pressure-flow relationships in the ventilated lung have not been previously determined in undelivered fetal sheep. Therefore we studied 11 late-gestation chronically prepared fetal sheep during positive-pressure ventilation with different gas mixtures to determine the roles of mechanical distension and blood gas tensions on pressure-flow relationships in the lung. Ventilation with 3% O2-7% CO2 produced a substantial fall in pulmonary vascular resistance even though arterial blood gases were not changed. Increases in pulmonary arterial PO2 during ventilation were associated with falls in pulmonary vascular resistance beyond that measured during mechanical distension. Decreases in pulmonary arterial PCO2 and associated increases in pH were also associated with falls in pulmonary vascular resistance. Pulmonary blood flow ceased at a pulmonary arterial pressure that exceeded left atrial pressure, indicating that left atrial pressure does not represent the true downstream component of driving pressure through the pulmonary vascular bed. The slope of the driving pressure-flow relationship in the normal mature fetal lamb was therefore different from the ratio of pulmonary arterial pressure to pulmonary arterial flow. We conclude that mechanical ventilation, increased PO2 and decreased PCO2, and/or increased pH has an important influence on the fall in pulmonary vascular resistance elicited by positive pressure in utero ventilation of the fetal lamb and that the downstream driving pressure for pulmonary blood flow exceeds left atrial pressure.     

Coronary arteriolar vasoconstriction to angiotensin II is augmented in prediabetic metabolic syndrome via activation of AT1 receptors

The metabolic syndrome is associated with activation of the renin-angiotensin system. However, whether the coronary vascular response to ANG II is altered under this condition is unknown. Experiments were conducted in control and chronically high-fat-fed dogs with the prediabetic metabolic syndrome both in vitro (isolated coronary arterioles, 60-110 microm) and in vivo (anesthetized and conscious). We found that plasma renin activity and ANG II levels are elevated in high-fat-fed dogs and that this increase in ANG II is associated with a significant increase in ANG II-mediated coronary vasoconstriction in isolated coronary arterioles and in anesthetized open-chest dogs. The vasoconstriction to ANG II is abolished by ANG II type 1 (AT1) receptor blockade. In conscious chronically instrumented dogs, AT1 receptor blockade with telmisartan improved the balance between coronary blood flow and myocardial oxygen consumption in the high-fat-fed dogs but not in normal control dogs, i.e., the relationship between coronary venous Po2 and myocardial oxygen consumption was shifted upward, toward normal control values. Quantitative assessment of coronary arteriolar AT1 and ANG II type 2 (AT2) receptor mRNA levels by real-time PCR revealed no significant difference between normal control and high-fat-fed dogs; however, Western blot analysis showed a significant increase in AT1 receptor protein level with no change in AT2 receptor protein density. These findings indicate that AT1 receptor-mediated coronary constriction is augmented in the prediabetic metabolic syndrome and contributes to impaired control of coronary blood flow via increases in circulating ANG II and/or coronary arteriolar AT1 receptor density.     

Reference cardiopulmonary values in normal dogs

The purpose of this project was to collate canine cardiopulmonary measurements from published and unpublished studies in our laboratory in 97 instrumented, unsedated, normovolemic dogs. Body weight; arterial and mixed-venous pH and blood gases; mean arterial, pulmonary arterial, pulmonary artery occlusion, and central venous blood pressures; cardiac output; heart rate; hemoglobin; and core temperature were measured. Body surface area; bicarbonate concentration; base deficit; cardiac index; stroke volume index, systemic and pulmonary vascular resistance indices; left and right cardiac work indices; alveolar partial pressure of oxygen (pO2) ; alveolar-arterial pO2 gradient (A-apO2); arterial, mixed-venous, and pulmonary capillary oxygen content; oxygen delivery; oxygen consumption; oxygen extraction; venous admixture; arterial and mixed-venous blood CO2 contents; and CO2 production were calculated. In the 97 normal, resting dogs, mean arterial and mixed-venous pH were 7.38 and 7.36, respectively; partial pressure of carbon dioxide (pCO2), 40.2 and 44.1 mm Hg, respectively; base-deficit, -2.1 and -1.9 mEq/liter, respectively; pO2, 99.5 and 49.3 mm Hg, respectively; oxygen content, 17.8 and 14.2 ml/dl, respectively; A-a pO2 was 6.3 mm Hg; and venous admixture was 3.6%. The mean arterial blood pressure (ABPm), mean pulmonary arterial blood pressure (PAPm), pulmonary artery occlusion pressure (PAOP) were 103, 14, and 5.5 mm Hg, respectively; heart rate was 87 beats/min; cardiac index (CI) was 4.42 liters/min/m2; systemic and pulmonary vascular resistances were 1931 and 194 dynes.sec.cm-5, respectively; oxygen delivery, consumption and extraction were 790 and 164 ml/min/m2 and 20.5%, respectively. This study represents a collation of cardiopulmonary values obtained from a large number of dogs (97) from a single laboratory using the same measurement techniques.     

Pulmonary hemodynamics and tissue damage after one lung infusion of Pseudomonas aeruginosa in sheep.

The relative roles of hematogenous mediators and direct bacterial toxicity due to phagocytosis by pulmonary intravascular macrophages were determined by selective bacterial infusion into the left pulmonary artery and comparison of right and left lungs at 24 h. Chronically instrumented sheep received 15-min pulmonary arterial infusions of live Pseudomonas aeruginosa (0.35-2.9 x 10(9), n = 6) or saline (n = 5). The saline group demonstrated stable cardiopulmonary function over time. Left lung blood flow, measured by Doppler flow probe, decreased 15 min into the bacterial infusion, with a concomitant sevenfold increase in left lung pulmonary vascular resistance index. The right lung pulmonary vascular resistance index doubled at 1 h, in association with increased plasma thromboxane B2 levels. An increase in cardiac index and decrease in systemic vascular resistance occurred at 12 h. The wet-to-dry weight ratio of the Pseudomonas-infused left lung was increased compared with that of the sham-infused lung. The tissue count of neutrophils in the lungs was doubled in both sides, but neutrophils on the left were more degranulated. The left lung tissue damage was caused by direct bacterial toxicity, including activation of phagocytic cells. Hematogenous mediators induced pulmonary and systemic hemodynamic changes and right lung neutrophil sequestration, but they did not damage the noninfused lung.     

Neural antagonists modulate pulmonary vascular pressure-flow plots in conscious dogs

Multipoint pulmonary vascular pressure-cardiac index (P/Q) plots were constructed in conscious dogs during normoxia by graded constriction of the thoracic inferior vena cava to reduce Q. P/Q plots were generated with the autonomic nervous system (ANS) intact and following total autonomic ganglionic block, cholinergic block, and sympathetic alpha- and beta-adrenergic block alone and in combination. With the ANS intact, the relationship between the pulmonary vascular pressure gradient [pulmonary arterial pressure (PAP)--pulmonary capillary wedge pressure (PCWP)] and Q was linear with an extrapolated pressure intercept of 0 mmHg. Total autonomic ganglionic block increased PAP-PCWP over the entire range of Q studied (60-140 ml . min-1 . kg-1). Cholinergic block resulted in a small increase in PAP-PCWP at a Q of 60 ml . min-1 . kg-1, a small decrease in PAP-PCWP at a Q of 140 ml . min-1 . kg-1, but no change in PAP-PCWP over the midrange of Q. Sympathetic beta-adrenergic block increased, and sympathetic alpha-adrenergic block decreased PAP-PCWP over the entire range of Q studied. Combined sympathetic alpha- and beta-adrenergic block also increased PAP-PCWP at each level of Q. Thus the ANS, either directly or via circulating catecholamines, exerts an active regulatory influence on the pulmonary vascular P/Q relationship of intact conscious dogs during normoxia over a wide range of Q. Activation of sympathetic beta-adrenergic receptors results in pulmonary vasodilatation, whereas, alpha-receptor activation results in vasoconstriction. Surprisingly, based on the effects of total autonomic ganglionic block and combined sympathetic alpha- and beta-adrenergic block, the net effect of the ANS on PAP-PCWP/Q during normoxia appears to be pulmonary vasodilatation.     

Acute and chronic cardiovascular effects of intermittent hypoxia in C57BL/6J mice.

We investigated the effects of 1) acute hypoxia and 2) 5 wk of chronic intermittent hypoxia (IH) on the systemic and pulmonary circulations of C57BL/6J mice. Mice were chronically instrumented with either femoral artery or right ventricular catheters. In response to acute hypoxia (4 min of 10% O2; n = 6), systemic arterial blood pressure fell (P < 0.005) from 107.7 +/- 2.5 to 84.7 +/- 6.5 mmHg, whereas right ventricular pressure increased (P < 0.005) from 11.7 +/- 0.8 to 14.9 +/- 1.3 mmHg. Another cohort of mice was then exposed to IH for 5 wk (O2 nadir = 5%, 60-s cycles, 12 h/day) and then implanted with catheters. In response to 5 wk of chronic IH, mice (n = 8) increased systemic blood pressure by 7.5 mmHg, left ventricle + septum weight by 32.2 +/- 7.5 x 10(-2) g/100 g body wt (P < 0.015), and right ventricle weight by 19.3 +/- 3.2 x 10(-2) g/100 g body wt (P < 0.001), resulting in a 14% increase in the right ventricle/left ventricle + septum weight (P < 0.005). We conclude that in C57BL/6J mice 1) acute hypoxia causes opposite effects on the pulmonary and systemic circulations, leading to preferential loading of the right heart; and 2) chronic IH in mice results in mild to moderate systemic and pulmonary hypertension, with resultant left- and right-sided ventricular hypertrophy.     

Effect of a local disorder of bronchial patency on the circulation and gas exchange in the lungs

Acute and chronic experiments on dogs have demonstrated the onset of local alveolar hypoxia in disturbed bronchial patency. Alveolar hypoxia caused a rise in the pulmonary vascular resistance. Pulmonary hypertension is predetermined by an increased number of pulmonary zones of hypoxic vasoconstriction due to higher incidence and degree of bronchial obstruction. Despite pulmonary circulation redistribution confirmed by radioactive indicator 99mTc distribution, the perfusion of hypoventilated pulmonary regions is retained leading to venous shunt generation and the reduction of oxygen tension in the arterial animal blood.     

A fetal-instrumented model to study age-specific responses to leukotriene D4 and prostaglandin D2 in unsedated newborn lambs

Sequential studies of the pulmonary vascular response to leukotriene D4 (LTD4) and prostaglandin D2 (PGD2) in the immediate newborn period were performed in lambs, instrumented in utero and delivered vaginally. Compounds were tested in fully conscious 1.5-day-old lambs and the study was repeated 1 week later. Bolus injections of PGD2 (0.05-2.0 micrograms/kg) or LTD4 (0.01-1.0 micrograms/kg) were made into the main pulmonary artery or aorta while pulmonary blood flow and aortic, pulmonary artery, and left and right atrial pressures were monitored continuously. PGD2 was a systemic constrictor regardless of age. In lambs 1.5 days of age, it decreased pulmonary vascular pressure and resistance by 6% (p less than 0.05) and 15% (p less than 0.05), respectively, while 1 week later it increased pulmonary vascular resistance by 18% (p less than 0.05). In contrast, LTD4 was a pulmonary and systemic vasoconstrictor in both the early and late newborn, the threshold dose being between 0.01 and 0.05 micrograms/kg at either age. The decrease in pulmonary blood flow and the increase in pressure and resistance were greater in older animals. In lambs 1.5 days of age, LTD4 (1 micrograms/kg) increased pulmonary vascular resistance by 66.1% (p less than 0.05) and 1 week later by 210% (p less than 0.001). These sequential observations in the same animal indicate that unlike PGD2, LTD4 is a pulmonary vasoconstrictor regardless of age, and its effectiveness increases significantly with age. These results support previous reports that PGD2 action in the pulmonary circulation changes shortly after birth from dilation to constriction.