Adenosine triphosphate: a potential therapy for hypoxic pulmonary hypertension

In this study we investigated whether a low-dose infusion of ATP-MgCl2 could ameliorate the pulmonary hypertension resulting from hypoxic pulmonary vasoconstriction. Three-week-old piglets were anesthetized, intubated, ventilated with room air, and cannulated for the measurement of pulmonary and systemic arterial pressure and pulmonary artery flow (cardiac output). The ventilator inflow was then changed to a mixture containing 10% oxygen, 4% CO2, and balance nitrogen. Serial infusions of ATP-MgCl2 at 0.1, 0.5 and 1.0 mg/kg/min were compared to preinfusion hypoxia baselines. Hypoxia alone produced a significant elevation in pulmonary artery pressure. Although all dose rates of ATP-MgCl2 produced a significant decrease (30%) in mean pulmonary artery pressure, we observed a maximum decrease in MPAP at the lowest rate of ATP infusion. Pulmonary artery flow rose slightly during ATP infusion; therefore, it was the change in pulmonary vascular resistance that accounted for the decrease in pulmonary artery pressure. In contrast, the systemic pressure was significantly decreased only during the 1.0 mg/kg/min infusion. The predominant pulmonary effects are a result of the virtual clearance of ATP-MgCl2 in a single pass through the circulation. Adenosine in the presence or absence of MgCl2 produced only a 10% reduction in mean pulmonary artery pressure, and MgCl2 had no effect when infused alone. From these results, we conclude that a low-dose infusion of ATP-MgCl2 could ameliorate the vasoconstriction associated with hypoxic pulmonary hypertension without significant deleterious systemic side effects.     

The effect of adenosine triphosphate on the functional status of the ductus arteriosus

We investigated whether a low-dose infusion of ATP-MgCl2 could affect the functional status of the ductus arteriosus during hypoxia-induced pulmonary vasoconstriction. Three-day-old piglets were made hypoxic by ventilation with a mixture containing 10% oxygen, 4% CO2, and balance nitrogen. Serial infusions of ATP-MgCl2 at 0.1, 0.5, and 1.0 mg/kg/min were compared with preinfusion hypoxia baselines. The functional status of the ductus arteriosus was determined by change in transit time of a bolus of iced saline between thermistor probes in the pulmonary artery and aorta. The method was validated using a Blalock-Taussing shunt (subclavian to pulmonary artery) in 3-week-old piglets instrumented in a similar manner. In these three-day-old piglets, hypoxia alone produced a significant elevation in pulmonary artery pressure and reduction in PO2. All dose rates of ATP-MgCl2 produced a significant decrease in mean pulmonary artery pressure. Systemic pressure was significantly decreased only during the 1.0-mg/kg/min infusion. Transit times of a bolus of iced saline during the validation were definitive for characterizing a situation of "shunt open" or "shunt closed." Infusion of ATP-MgCl2 produced no change in the status of the ductus arteriosus in 45 (94%) of the determinations. In only three cases was the effect of ATP-MgCl2 sufficient to result in a functional change in the status of the ductus arteriosus. Pre- and postductal pulmonary artery PO2 were not altered during ATP-MgCl2 infusion, thus corroborating the transit time determinations. From these results, we conclude that an infusion of ATP-MgCl2 does not alter the functional status of the ductus arteriosus.     

Effects of prostacyclin (PGI2) on the hypoxic pulmonary vasoconstriction in dogs

Effects of exogenous PGI2 on the hypoxic pulmonary vasoconstriction (HPV) were investigated by measuring %QLLL and the ratio of the left lower lobe blood flow (QLLL) to the total pulmonary blood flow (QT), in separately ventilated canine in vivo model. With PGI2 infusion, %QLLL, that had decreased from 20.7 +/- 1.9% to 4.1 +/- 1.1% by the hypoxic gas ventilation, gradually increased to 16.4 +/- 3.2% at the maximum dose (1.0 micrograms kg-1. min-1). Simultaneously both pulmonary artery pressure and PaO2 decreased significantly. Systemic blood pressure dropped markedly but cardiac output remained at the initial level. These results suggest that exogenous PGI2 improves the pulmonary circulation by reducing pulmonary hypertension induced with HPV, while PGI2 induces hypoxia by inhibiting HPV response and systemic hypotension by dilating the peripheral resistance vessels. Therefore, we have to consider these two opposite effects of PGI2 on its clinical application.     

Reperfusion with ATP-MgCl2 following prolonged ischemia improves myocardial performance

This study was designed to test the hypothesis that infusion of ATP-MgCl2 during reperfusion following a prolonged period of hypothermic global ischemia would result in enhanced functional recovery of cardiac function. Two groups of dogs (n = 6 each) were placed on cardiopulmonary bypass (CP) with systemic hypothermia to 28 degrees C and subjected to 150 min of aortic cross-clamping. Crystalloid cardioplegia was infused every 20 min during ischemia. Reperfusion and rewarming were carried out for 20 min before discontinuation of CP bypass. During reperfusion, the experimental group received ATP-MgCl2(1.0 mg/kg/min ATP, 0.33 mg/kg/min magnesium). At 15 and 45 min following bypass, hemodynamic assessment was carried out for each animal by constructing Starling curves over a range of filling pressures at constant heart rate and comparing each animal to its own prebypass control level. The results indicated that ATP-treated animals exhibited complete functional recovery whereas control animals showed marked reduction in hemodynamic performance and myocardial compliance and had a higher myocardial water content (P less than 0.05). We conclude that infusion of ATP-MgCl2 during reperfusion following hypothermic ischemia may help ameliorate reperfusion injury.     

Mechanism of the beneficial effects of ATP-MgCl2 following trauma-hemorrhage and resuscitation: downregulation of inflammatory cytokine (TNF, IL-6) release.

Although ATP-MgCl2 improves hepatocellular function in a nonheparinized model of trauma-hemorrhage and crystalloid resuscitation, it remains unknown whether the beneficial effects of this agent are due to downregulation of the release of the inflammatory cytokines, tumor necrosis factor (TNF), and interleukin-6 (IL-6) under those conditions. To study this, rats underwent a 5-cm laparotomy (i.e., trauma induced) and were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of maximum bleedout volume was returned in the form of Ringer's lactate (RL). The animals were then resuscitated with four times the volume of shed blood with RL over 60 min. ATP-MgCl2 (50 mumoles/kg body weight each) or an equivalent volume of normal saline was infused intravenously for 95 min. This infusion was started during the last 15 min of RL resuscitation. Plasma levels of TNF and IL-6 were measured at 1.5 hr after the completion of resuscitation by cytokine-dependent cellular assays. Hepatic blood flow was determined by in vivo indocyanine green clearance (corrected by hepatic extraction ratio for indocyanine green), radioactive microspheres, and [3H]-galactose clearance techniques. The results indicate that the levels of circulating TNF and IL-6 increased significantly in the hemorrhaged-resuscitated animals. ATP-MgCl2 treatment, however, markedly decreased the synthesis and/or release of these cytokines to levels similar to the sham group. The markedly decreased hepatic blood flow (as determined by three different methods) and hepatic extraction ratio for indocyanine green were also restored by ATP-MgCl2 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypoxic Pulmonary Vasoconstriction in the Human Lung: the Effect of Prolonged Unilateral Hypoxic Challenge during Anaesthesia

The influence of time on the pulmonary vasoconstrictor response to hypoxia was studied in six subjects during general anaesthesia and artificial ventilation prior to elective surgery. The lungs were intubated separately with a double-lumen bronchial catheter. After preoxygenation of both lungs for 30 min, the test lung was rendered hypoxic for 60 min by ventilation with 5% O2 in N2, with the control lung still being ventilated with 100% O2. Cardiac output was determined by thermodilution, and the distribution of blood flow between the lungs was assessed from the excretion of a continuously infused poorly soluble gas (SF6). The fractional perfusion of the test lung decreased from 53% to 25% of cardiac output within the first 15 min of unilateral hypoxia. The pulmonary artery mean pressure increased by 14% and the pulmonary vascular resistance (PVR) of the test lung increased by 54%. Venous admixture increased from 21% to 39% of cardiac output, while the "true" shunt was maintained at about 15%. Arterial oxygen tension (Pao2) fell from 45 kPa to 12 kPa. Prolonging the unilateral hypoxic challenge caused no further change in the redistribution of the pulmonary blood flow, but cardiac output and pulmonary artery mean pressure continued to increase to 40%-50% above control values after 1 h of hypoxia. The PVR of the test lung remained unchanged. The findings suggest that there is an immediate vasoconstrictor response to hypoxia in the human lung and that there is no further potentiation or diminution, of the response during a 60-min period of hypoxia.     

Aqueous oxygen: the solution to relief hypoxic pulmonary hypertension.

OBJECTIVE: To evaluate the effects of hyperbaric oxygen solution on hypoxic pulmonary hypertension. METHODS: Eleven calves, 2-month-old, 71+/-6 kg, underwent general anaesthesia, mechanical ventilation and median sternotomy. Catheters for continuous pressure and blood gas measurements were inserted in carotid and femoral arteries, left atrium, right atrium and pulmonary artery (PA), and a flow-probe placed around the PA. After baseline measurements 30 min hypoxic ventilation reduced the mean arterial PO2 from 285+/-115 to 46+/-11 mmHg (P < 0.0001). At this point, without changes in hypoxic ventilation (mean arterial PO2 maintained at 50+/-5 mmHg), 3 ml/min of hyperbaric aqueous oxygen (AO, oxygen diluted in saline solution) was infused directly into the PA for 30 min, with continuous reading of the monitored parameters. RESULTS: Hypoxic ventilation raised significantly (P < 0.005) the values of systolic (36+/-7 vs 22+/-6 mmHg), diastolic (16+/-3 vs 9+/-4 mmHg) and mean (24+/-4 vs 14+/-4 mmHg) PA pressure, PA/systemic pressure ratio for systolic (0.47+/-0.09 vs 0.24+/-0.06) and mean (0.49+/-0.13 vs 0.23+/-0.08) pressures and Pulmonary Vascular Resistance (PVR) (6.89+/-0.87 vs 2.67+/-0.38 U), while the Pulmonary Blood Flow (PBF) decreased (2.7+/-0.4 vs 3.7+/-0.4 l/min). AO infusion reduced significantly (P < 0.005) the values obtained with hypoxic ventilation with systolic (26+/-6 vs 36+/-7 mmHg), diastolic (11+/-4 vs 16+/-3 mmHg) and mean (16+/-4 vs 24+/-4 mmHg) PA pressure, PA/systemic pressure ratio for systolic (0.27+/-0.07 vs 0.47+/-0.09) and mean (0.27+/-0.08 vs 0.49+/-0.13) pressures and PVR (3.42+/-0.31 vs 6.89+/-0.87 U), while the PBF increased (3.6+/-0.4 vs 2.7+/-0.4 l/min). CONCLUSIONS: Acute infusion of hyperbaric AO solution into the PA completely reverses the negative effects of acute hypoxia on pulmonary circulation.     

Adenosine and amrinone reverse felypressin-induced depression of myocardial tissue oxygen tension in dogs

PURPOSE: To determine whether continuous infusion of adenosine triphosphate (ATP), nitroglycerin (NTG) or amrinone (AM) would ameliorate the reductions in coronary blood flow (CBF) and myocardial oxygen tension (PmO2) induced by felypressin. METHODS: Seven open-chest dogs were studied under urethane and alpha-chloralose anesthesia. Hemodynamic variables including heart rate (HR), systolic blood pressure, diastolic blood pressure (DBP), mean pulmonary artery pressure, pulmonary capillary wedge pressure, CBF (ultrasound flowmetry), PmO2(polarography) and cardiac output (thermodilution method) were recorded. Felypressin was infused in a loading dose of 6 mIU x kg(-1) for five minutes and then continued at 0.2 mIU x kg(-1) x min(-1). After 30 min felypressin infusion, each agent was administered for 15 min to evaluate hemodynamic changes. Infusions were 100 and 200 microg x kg(-1) x min(-1) for ATP, 2.5 and 5 microg x kg(-1) x min(-1) for NTG, and 10 and 20 microg x kg(-1) x min(-1) for AM. RESULTS: After felypressin DBP increased by 17 +/- 5 (mean +/- SD) %; CBF decreased by 49 +/- 9%; CI decreased by 40 +/- 13%; HR decreased by 29 +/- 11%; PmO2 in the inner layer decreased by 21 +/- 7%. The Cl and CBF returned to baseline afterATP 100 and 200 microg x kg(-1) x min(-1), AM 10 and 20 microg x kg(-1) x min(-1), but not after NTG. The PmO2 in the inner layer returned to the baseline value by any infusion except for NTG 5 microg x kg(-1) min(-1) CONCLUSION: Adenosine and amrinone, but not nitroglycerin reverses the adverse cardiovascular effects of felypressin.     

Sensory neuropeptides and hypoxic pulmonary vasoconstriction in the rat.

BACKGROUND--Endogenous vasodilators such as endothelially derived relaxant factor have been shown to modulate hypoxic pulmonary vasoconstriction. Sensory peptides such as substance P (SP) and calcitonin gene related peptide (CGRP) are also potent pulmonary vasodilators in both animals and humans. Their possible role in the modulation of the normal hypoxic pressor response has been examined in an isolated, ventilated, and blood perfused rat lung preparation. METHODS--Animals (n = 7) were pretreated with 50 mg/kg capsaicin administered subcutaneously to deplete nerve endings of sensory neuropeptides. A control group (n = 7) received a subcutaneous dose of capsaicin vehicle. One week later the rats were killed and the rise in pulmonary artery pressure was measured during four successive periods of hypoxic ventilation (FIO2 0.03), and after four injections of angiotensin II (1.0 microgram). RESULTS--A 60% depletion of SP levels was measured in the sciatic nerves of animals treated with capsaicin. The hypoxic pressor response was not significantly altered in capsaicin treated animals compared with controls, except during the fourth hypoxic episode when it was augmented. The angiotensin II pressor response was the same in both groups during each of the injections. CONCLUSION--The sensory neuropeptide SP (and possibly CGRP) does not have a major role in modulating the pulmonary vascular response to hypoxia.     

Protamine-heparin-induced pulmonary hypertension in pigs: effects of treatment with a thromboxane receptor antagonist on hemodynamics and coagulation.

Adverse hemodynamic reactions after protamine neutralization of heparin are an infrequent but important clinical problem. Pre-treatment of swine with a thromboxane A2 receptor antagonist has been reported to prevent the pulmonary hypertensive response occasionally seen after protamine reversal of heparin anticoagulation. In the current study, a control group of pigs (n = 9) received intravenous heparin (300 IU/kg), followed after 10 min by a neutralizing dose of protamine (3 mg/kg). A treatment group of pigs (n = 11) was treated identically, except that the thromboxane A2 receptor antagonist L-670596 (2 mg/kg) was infused intravenously 2 min after the protamine infusion. Hemodynamic and coagulation profiles were monitored during these procedures. Pulmonary hypertension developed and reached a peak within 2 min of protamine administration, often at the same time that L-670596 was administered in the treatment group. There was no statistical difference between control and treatment groups' peak pulmonary arterial pressure and peak pulmonary vascular resistance. However, the interval for return of mean pulmonary artery pressure from peak to baseline values was 11.6 +/- 3.1 versus 5.5 +/- 1.9 min (mean +/- SD) for control and treatment groups, respectively (P less than 0.01). Thromboxane B2 plasma concentrations increased in both groups and were correlated with the pulmonary hypertensive response (r = 0.86, P less than 0.01). Platelet aggregation to collagen was inhibited by the thromboxane A2 receptor antagonist (P less than 0.05). Bleeding time was prolonged beyond normal range in 50% of L-670596-treated pigs. All other coagulation tests in both groups returned to baseline after reversal of heparin with protamine and were unaffected by L-670596.(ABSTRACT TRUNCATED AT 250 WORDS)     

Propofol does not inhibit hypoxic pulmonary vasoconstriction in humans

The influence of increasing doses of propofol (from 6 to 12 mg/kg/h by continuous infusion) on hypoxic pulmonary vasoconstriction was studied in 10 patients prior to thoracic surgery. All patients were intubated with a left-sided double-lumen endobronchial tube. Initial anesthesia and muscle relaxation were accomplished by administering fentanyl, droperidol, and pancuronium. After 100% oxygen ventilation of both lungs for 20 min in a lateral decubitus position, the nondependent lung was deflated and one-lung ventilation was started. The dependent lung was continuously ventilated with 100% oxygen. Twenty minutes after the start of one-lung ventilation, propofol at an IV infusion rate of 6 mg/kg/h was added to the anesthetic technique. Thirty minutes later it was increased to 10 mg/kg/h and another 15 min later to 12 mg/kg/h. Then the propofol infusion was stopped. Thirty minutes later, two-lung ventilation was restarted to compare initial values. No changes in venous admixture or PaO2 were observed during propofol infusion. There was no change in any respiratory or circulatory variables except systemic vascular resistance, which decreased significantly immediately after the propofol infusion commenced but returned to control values 15 min later for the rest of the observation period. After reestablishing two-lung ventilation, all variables did not differ from control values. In all patients, the hypoxic pulmonary vasoconstriction reflex was present after institution of one-lung ventilation and was not abolished after administration of propofol in doses from 6 to 12 mg/kg/h.     

Positive experimental demonstration of the negative brain "protective" effects of anesthetics following cardiac arrest

The cerebral metabolic effects of a massive dose of thiopental (177 mg/kg) were investigated in seven dogs. The systemic circulation was supported with an extracorporeal circuit. At an infusion rate of 2 mg/kg/min, cerebral oxygen consumption (CMR(O(2))) decreased progressively until cerebral electrical silence was produced. This occurred after a mean dose of 72 mg/kg, which caused a mean decrease in CMR(O(2)) to 58% of the control value (measured at 1.5% halothane inspired). Thereafter, despite continued at 4 mg/kg/min, CMR(O(2)) did not decrease further. The oxygen-glucose index never changed during the infusion period and, at the termination of the infusion, brain assays for ATP, phosphocreatine, lactate, and pyruvate revealed normal concentrations. It is concluded that there was no alteration in normal cerebral metabolic pathways, that cerebral metabolic effects of thiopental are secondary to functional effects, that thiopental would provide no cerebral protection during hypoxia sufficient to abolish cerebral function, and that thiopental does not uncouple oxidative phosphorylation.     

Sevoflurane has no inhibitory effect on hypoxic pulmonary vasoconstriction (HPV) in dogs

There is no general agreement on the effect of inhalation anesthetics on hypoxic pulmonary vasoconstriction (HPV). We have examined the effect of sevoflurane upon the pulmonary vascular response to a left lower lobe (LLL) hypoxia in dogs by continuously measuring the fractional distribution to the LLL of total pulmonary blood flow (Q_LLL/Q_T) employing an ultrasonic transit time rheometer with flow probes attached to the LLL artery and the main pulmonary artery.During regional hypoxia without sevoflurane, blood flow distribution to the LLL as a mean was 48.2% of that determined under hyperoxic conditions. When sevoflurane was administered at concentrations of 2% and 4%, the LLL blood flow distributions during hypoxia were as a mean 40.2% and 47.0%, respectively, of the values obtained during the first hyperoxic periods. No change occurred in the pulmonary vascular resistance of the LLL(PVR_LLL) and the shunt ratio(Qs/Qt) between the concentrations used.Thus there was no significant effect of sevoflurane upon HPV whatever concentration used.(Okutomi T, Ikeda K: Sevoflurane has no inhibitory effect on hypoxic pulmonary vasoconstriction (HPV) in dogs. J Anesth 4: 123–130, 1990)     

The effects of propofol on cerebral blood flow in correlation to cerebral blood flow velocity in dogs

This study correlates the effects of propofol on cerebral blood flow (CBF) and middle cerebral artery blood flow velocity in dogs. CBF was measured using radioactive microspheres. Cerebral oxygen consumption (CMRO2) was measured with each CBF determination. Blood flow velocity was measured through a transtemporal window using a pulsed 8 MHz transcranial Doppler ultrasound system (TCD). Electroencephalogram (EEG) was continuously recorded over both cerebral hemispheres. Cardiac output (CO) was measured using an electromagnetic flow probe placed on the pulmonary artery. Baseline measures were made in all dogs (n = 11) with 0.7% isoflurane end tidal and 50% N2O in O2. There were two treatment groups. In group 1 (n = 6), propofol (0.8 mg/kg/min) was infused and a second measurement made at induction of EEG burst suppression (12 +/- 2 min). CBF and CMRO2 decreased by 70% and mean blood flow velocity decreased by 60%. Blood pressure, heart rate, and CO did not change. Propofol infusion was discontinued and all parameters were measured following recovery of EEG to baseline activity (48 +/- 9 min). CBF and blood flow velocity increased 35 and 25%, respectively, and CMRO2 increased by 32% during this period. A second propofol infusion (0.8 mg/kg/min) was started and all cerebral and systemic hemodynamic parameters were again determined at induction of EEG burst suppression (12 +/- 2 min). CBF decreased 35% and blood flow velocity decreased 25% to levels seen during the first propofol infusion. Over the entire study, changes in CBF correlated with changes in blood flow velocity (r = 0.86, p < 0.05). In group 2 (n = 5), four control measures were made at the same time intervals as in group 1. Baseline CBF and blood flow velocity were lower in group 2 compared to group 1 but these measures did not change over time. Our results show that propofol produces marked decreases in CBF in dogs and that these changes are closely correlated with CBF velocity.     

Pulmonary artery pressure: flow relationships in hyperoxic and in hypoxic dogs

Methylprednisolone has been reported to impair hypoxic pulmonary vasoconstriction in isolated lungs, possibly by inhibiting the generation of vasoconstricting products of arachidonic acid metabolism. We investigated the effects of methylprednisolone on mean pulmonary artery pressure (PAP):cardiac index (Q) relationships in intact pentobarbital anaesthetized dogs ventilated alternatively in hyperoxia (fraction of inspired O2, FiO2 0.4) and in hypoxia (FiO2 0.1). Cardiac output was increased by opening an arterio-venous femoral fistula or reduced by stepwise inflations of a balloon in the inferior vena cava. Five point PAP:Q relationships were found to be rectilinear in all experimental conditions. Over the entire range of Q studied (2 to 5 l/min.m2), hypoxia increased PAP in seven dogs ("responders") and did not affect PAP in three other dogs ("non-responders"). A hypoxic pulmonary pressor response was restored in these three "non-responders" by administration of 1 g acetylsalicylic acid iv. Methylprednisolone 30 mg/kg iv had no effect on hyperoxic and on hypoxic pulmonary vascular tone in the "responders" and in the "non-responders" treated with acetylsalicylic acid. An additional dog pretreated with methylprednisolone 30 mg/kg iv 24 h before the experiment still had a marked hypoxia-induced increase in PAP over the entire range of Q studied. Thus a large dose of methylprednisolone does not affect hypoxic or hyperoxic pulmonary vascular tone in intact dogs. These data do not support the hypothesis that products of arachidonic acid metabolism mediate hypoxic pulmonary vasoconstriction.     

Intravenous PGF2 alpha infusion does not enhance hypoxic pulmonary vasoconstriction during canine one-lung hypoxia

The effect of prostaglandin F2 alpha (PGF2 alpha) on the hypoxic pulmonary vasoconstrictor (HPV) response was studied in 12 closed-chest dogs anesthetized with pentobarbital and paralyzed with pancuronium. The right lung was ventilated continuously with 100% O2, while the left lung was either ventilated with 100% O2 ("hyperoxia") or ventilated with an hypoxic gas mixture ("hypoxia:" end-tidal PO2 approximately equal to 50.0 +/- 0.1 mmHg). Cardiac output (CO) was altered from a "normal" value of 2.89 +/- 0.26 1.min-1 to a "high" value of 3.55 +/- 0.26 1.min-1 by opening arteriovenous fistulae which allowed measurements of two points along a pressure-flow line. These four phases of left lung hypoxia or hyperoxia with normal and high cardiac output were performed in the absence of, and in the presence of, PGF2 alpha administered as a constant peripheral intravenous infusion of 1.0 microgram.kg-1.min-1. During left lung hypoxia, mean pulmonary artery pressure (PAP) increased significantly when compared to hyperoxia. With PGF2 alpha administration, mean PAP increased significantly during both hyperoxia and hypoxia. The presence or absence of PGF2 alpha had no effect on cardiac output or PaO2 during hypoxia. Relative blood flow to each lung was measured with a differential CO2 excretion (VCO2) method corrected for the Haldane effect. With both lungs hyperoxic, the percent left lung blood flow (%QL-VCO2) was 45 +/- 1%. When the left lung was exposed to hypoxia, the %QL-VCO2 decreased significantly to 29 +/- 3%. However, with the administration of PGF2 alpha, the %QL-VCO2 during left lung hypoxia did not change significantly 26 +/- 3%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clonidine Modulation of Hemodynamic and Catecholamine Responses Associated with Hypoxia or Hypercapnia in Dogs

Background: Hypoxia or hypercapnia elicits cardiovascular responses associated with increased plasma catecholamine concentrations, whereas clonidine, an alpha2 -adrenergic agonist, decreases plasma catecholamine concentrations. The authors examined whether systemic clonidine administration would alter the hemodynamic and catecholamine responses to hypoxia or hypercapnia in anesthetized dogs.

Methods: Pentobarbital-anesthetized dogs whose lungs were mechanically ventilated were instrumented for measurement of mean arterial pressure, heart rate, mean pulmonary artery pressure, right atrial pressure, cardiac output, left ventricular end-diastolic pressure, and the peak of first derivative of left ventricular pressure. The dogs were randomly assigned to receive an intravenous bolus injection of 10 micro gram/kg clonidine followed by continuous infusion at a rate of 1 micro gram *symbol* kg sup -1 *symbol* min sup -1 (clonidine-10 group, n = 7), an intravenous bolus injection of 5 micro gram/kg clonidine followed by continuous infusion at a rate of 0.5 micro gram *symbol* kg sup -1 *symbol* min sup -1 (clonidine-5 group, n = 7), or an equivalent volume of 0.9% saline (control group, n = 7). Each dog underwent random challenges of hypoxia (PaO2 30, 40, and 50 mmHg) and hypercapnia (PaCO sub 2 60, 80, and 120 mmHg). Measurements of hemodynamic and plasma norepinephrine and epinephrine concentrations were made during each period of hypoxia or hypercapnia, and measurements of plasma clonidine concentrations were made after the loading dose of clonidine and the first and the second exposure of hypoxia or hypercapnia.

Results: Although significant increases from prehypoxic values in mean arterial pressure (39+/-10 mmHg) and plasma norepinephrine (291+/-66 pg/ml) and epinephrine (45+/-22 pg/ml) concentrations were noted during hypoxia of PaO2 30 mmHg in the control group (P < 0.05), such changes were absent in both clonidine groups. During hypercapnia of PaCO2, 120 mmHg, changes from prehypercapnic values in mean arterial pressure, mean pulmonary artery pressure, the peak of first derivative of left ventricular pressure, and plasma norepinephrine and epinephrine concentrations in the clonidine-10 and clonidine-5 groups were significantly less than those in the control group. Plasma clonidine concentrations in the clonidine-10 and clonidine-5 groups were 16.8+/-1.7 and 8.9+/-1.0, 42.5+/- 2.9 and 21.5+/-1.5, and 51.1+/-3.2 and 26.7+/- 1.0 ng/ml after the loading dose of clonidine and the first and the second exposure of hypoxia or hypercapnia, respectively.     

Enhancement of hypoxic pulmonary vasoconstriction by metabolic acidosis in dogs

The effects of HCl infusion on multipoint mean pulmonary arterial pressure (PAP)/cardiac index (CI) plots in pentobarbital-anesthetized dogs whose lungs were ventilated alternately in hyperoxia (fraction of inspired O2 [FIO2], 0.4) and hypoxia (FIO2, 0.1) were investigated. Over the range of CI studied (1 to 5 l.min-1.m-2), hypoxia increased PAP in 22 dogs (responders) and did not affect PAP in 16 other dogs (nonresponders). In eight nonresponders, two repetitions of alternated 0.4 and 0.1 FIO2 exposures did not restore hypoxic pulmonary vasoconstriction (HPV), defined as a hypoxia-induced increase in PAP at a given flow. Intravenous infusion of 2 M HCl (2 mmol.kg-1.h-1) decreased arterial pH from normal to around 7.20 in eight responders and eight nonresponders. This metabolic acidosis increased PAP at all levels of CI in hyperoxia and in hypoxia in all the dogs, enhanced HPV in the responders, and restored HPV in the nonresponders. In eight responders, 2 M HCl infusion (2 mmol.kg-1.h-1) together with a 7% sodium bicarbonate infusion (adjusted to maintain arterial pH unchanged) did not affect hyperoxic or hypoxic PAP/CI plots. Pretreatment with 1 g acetylsalicylic acid iv (6 dogs) did not affect the pulmonary vasoreactivity to HCl-induced (2 M HCl, 2 mmol.kg-1.h-1) metabolic acidosis. It was concluded that in intact dogs: 1) metabolic acidosis enhances HPV; 2) at the given dose, HCl does not produce pulmonary vascular effects unrelated to the circulating blood pH; and 3) it is unlikely that the pulmonary vasoreactivity to metabolic acidosis is mediated by products of the cyclooxygenase pathway.     

The longitudinal distribution of pulmonary vascular resistance during unilateral hypoxia

Pulmonary capillary hydrostatic pressure and the longitudinal distribution of pulmonary vascular resistance (arterial and venous components) can be determined by analysis of pressure decay curves following pulmonary artery occlusion. To validate this technique in intact animals, pulmonary artery occlusion pressure decay curves were obtained from both lungs in six anesthetized sheep during control conditions (100% O2) and during unilateral hypoxic ventilation (100% O2 versus 100% N2). Analysis of pulmonary artery occlusion pressure curves indicated the following: 1) in the hypoxic lung, unilateral hypoxia increased the precapillary portion of pulmonary vascular resistance from 72% of the total resistance to 89% of the total resistance in that lung; 2) in the nonhypoxic lung, unilateral hypoxia did not significantly affect the distribution of pulmonary vascular resistance; and 3) unilateral hypoxia produced no significant change in pulmonary capillary pressure in the hypoxic lung compared with control; however, pulmonary capillary pressure was significantly greater in the nonhypoxic lung. These results are consistent with other evidence that hypoxic pulmonary vasoconstriction acts locally and primarily affects resistance at the arteriolar level. Pulmonary artery occlusion pressure decay curve analysis appears to be a valid technique for the measurement of pulmonary capillary pressure and the longitudinal distribution of pulmonary vascular resistance in intact anesthetized animals. These measurements pertain only to the vasculature distal to the site of pulmonary artery occlusion with the catheter, and, thus, caution must be used when applying this technique in a setting of nonhomogenous lung injury.