Effects of endotoxemia on pulmonary vascular resistances in unanesthetized sheep

Ten experiments were conducted on nine sheep to determine the effects of endotoxemia (1.0 microgram/kg iv over 15 min) on the vascular resistances of two segments of the pulmonary circulation. The first segment (S1) was from the main pulmonary artery to the site in the pulmonary veins corresponding to the pressure measured with a deflated and wedged 7-Fr Swan-Ganz catheter. The second segment (S2) was from the wedge pressure measurement site to the left atrium. Endotoxemia caused both pulmonary arterial pressure and pulmonary arterial wedge pressure to increase significantly during early (phase 1) and late (phase 2) periods of response; left atrial pressure was significantly decreased during both phases. Normalized cardiac output decreased significantly at 35 and 180 min but not at 240 min after starting endotoxin infusion. The calculated resistance of S1 significantly increased from a base-line value of 3.03 +/- 0.31 (cmH2O.1-1.min) to 7.60 +/- 0.71, 6.34 +/- 1.22, and 6.66 +/- 1.35 at 35, 180, and 240 min, respectively. Calculated resistance of S2 was 1.32 +/- 0.14 at base line and increased significantly to 11.43 +/- 1.66 at 35 min, 4.45 +/- 0.47 at 180 min, and 3.32 +/- 0.61 at 240 min. The calculated percent of total pulmonary resistance in S2 increased significantly from approximately 31 to 59% during phase 1 and remained significantly increased at 41% from 90 to 180 min after endotoxin. Hematocrit increased by 40% at 35 min, whereas plasma total protein concentration increased by only 8% at 35 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Atrial natriuretic peptide decreases cardiac output independent of coronary vasoconstriction

Studies were performed in isolated, Langendorff-perfused rat hearts and anesthetized dogs to determine the effects of synthetic atrial natriuretic peptide (ANP 8-33) on the coronary circulation. In vitro studies in the rat examined coronary flow dynamics to ANP 8-33 over a defined range from physiologic to pharmacologic concentrations. No changes in coronary flow or chronotropic and inotropic function of the isolated Langendorff-perfused heart were observed in response to increasing concentrations of ANP 8-33 (10(2) to 10(6) pg/ml). In the dog, a low, nonhypotensive dose of ANP 8-33 (0.05 microgram/kg/min) decreased cardiac output with no change in coronary blood flow or coronary vascular resistance. At a high, hypotensive dose (0.3 microgram/kg/min) ANP 8-33 decreased cardiac output in association with transient coronary vasodilation. Continued infusion resulted in a decrease in coronary blood flow and arterial pressure with no change in coronary vascular resistance. Thus, in vitro physiologic and pharmacologic concentrations of ANP, or in vivo low concentrations of ANP, do not result in an alteration in coronary flow. In vivo ANP 8-33, at both nonhypotensive and hypotensive concentrations, decreased cardiac output in the absence of coronary vasoconstriction.     

The effects of a prostacyclin analog OP-41483 on pulmonary oxygen toxicity in an isolated heart-lung autoperfusion model

Using an isolated canine heart-lung autoperfusion model, the effect of prostacyclin analog (OP-41483) on pulmonary oxygen toxicity was investigated. Twenty-four mongrel dogs were divided into four groups. Groups 1 and 2 inspired oxygen at concentrations (FiO2) of 0.95 and 0.6, respectively, while groups 3 and 4 received OP-41483 (0.1 micrograms/kg/min) in addition to FiO2 of 0.95 and 0.6. Autoperfusion was performed for five hours, and during the experiments the systolic blood pressure was maintained at 100 mmHg and the cardiac output at 40 ml/kg/min. After five hours of perfusion, PaO2 decreased significantly (P less than 0.01) from 410 +/- 49 mmHg to 237 +/- 38 mmHg in group 1, and also decreased significantly (P less than 0.01) from 368 +/- 44 mmHg to 243 +/- 26 mmHg in group 2. However, no significant changes in PaO2 were observed in groups 3 and 4. The pathological examinations clearly revealed perivascular edema and vascular dilation in groups 1 and 2, whereas no abnormal pathological findings were seen in groups 3 and 4. The above results indicate that OP-41483, when administered at the low dose of 0.1 micrograms/kg/min, induces no circulatory changes and exerts an effective action with respect to the prevention of pulmonary edema.     

Atrial natriuretic peptide ameliorates hypoxic pulmonary vasoconstriction without influencing systemic circulation.

Hypoxic pulmonary vasoconstriction (HPV) is encountered during ascent to high altitude. Atrial natriuretic peptide (ANP) could be an option to treat HPV because of its natriuretic, diuretic, and vasodilatory properties. Data on effects of ANP on pulmonary and systemic circulation during HVP are conflicting, partly owing to anesthesia, surgical stress or uncontrolled dietary conditions. Therefore, ten conscious, chronically tracheotomized dogs were studied under standardized dietary conditions. The dogs were trained to breathe spontaneously at a ventilator circuit. Protocol: 30min of normoxia [inspiratory oxygen fraction (F(i)O(2))=0.21] were followed by 30min of hypoxia without ANP infusion (Hypoxia I, F(i)O(2)=0.1). While maintaining hypoxia an intravenous infusion of atrial natriuretic peptide was started with 50ng x kg body wt(-1) x min(-1) for 30min (Hypoxia+ANP1=low dose), followed by 1000ng x kg body wt(-1) x min(-1) for 30min (Hypoxia+ANP2=high dose). Thereafter, ANP infusion was stopped and hypoxia maintained for a final 30min (Hypoxia II). Compared to normoxia, mean pulmonary arterial pressure (MPAP) (16+/-0.7 vs. 26+/-1.3mmHg) and pulmonary vascular resistance (PVR) (448+/-28 vs. 764+/-89dyn x s(-1) x cm(-5)) increased during Hypoxia I and decreased during Hypoxia+ANP 1 (MPAP 20+/-1mmHg, PVR 542+/-55dyn x s(-1) x cm(-5)) (P<0.05). The higher dose of ANP did not further decrease MPAP or PVR, but started to have a tendency to decrease mean arterial pressure and cardiac output. We conclude that low dose ANP is able to reduce HPV without affecting systemic circulation during acute hypoxia.     

Influence of vasoactive intestinal polypeptide (VIP) on splanchnic and central hemodynamics in healthy subjects

The influence of VIP, a potent vasodilator, on central hemodynamics, splanchnic blood flow and glucose metabolism was studied in six healthy subjects. Teflon catheters were inserted into an artery, a femoral vein and a right-sided hepatic vein. A Swan-Ganz catheter was introduced percutaneously and its tip placed in the pulmonary artery. Determinations of cardiac output, systemic, pulmonary arterial and hepatic venous pressures as well as splanchnic blood flow were made in the basal state and at the end of two consecutive 45 min periods of VIP infusion at 5 and 10 ng/kg/min, respectively. Arterial blood samples for analysis of glucose, FFA, insulin and glucagon were drawn at timed intervals. VIP infusion at 5 ng/kg/min resulted in an increase in cardiac output (55%) and heart rate (25%) as well as a reduction in mean systemic arterial pressure (15%) and vascular resistance (45%). With the higher rate of VIP infusion heart rate tended to rise further while cardiac output and arterial pressure remained unchanged. At 15 min after the end of VIP infusion the above variables had returned to basal levels. Splanchnic blood flow and free hepatic venous pressure did not change significantly. Arterial concentrations of glucose, FFA, insulin and glucagon increased during VIP infusion. At 15 min after the end of infusion the glucose levels were still significantly higher than basal (20%). Net splanchnic glucose output did not change in response to VIP infusion. It is concluded that VIP exerts a potent vasodilatory effect resulting in augmented cardiac output and lowered systemic blood pressure and vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary fibrin microembolism with Echis carinatus venom in dogs: effects of a synthetic thrombin inhibitor

We produced pulmonary fibrin microembolism using an infusion of a prothrombin activator (Echis carinatus venom, 30 min, 0.5 NIH thrombin equivalent units/kg) in open-chest mongrel dogs. To determine the nonclotting effects of this venom on edemagenesis we infused an irreversible thrombin inhibitor, D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK, 57 nmol X kg-1 X min-1 for 120 min), alone (n = 5) or with venom (Echis + PPACK, n = 5). The control group (n = 5) was given 1 ml of 0.9% NaCl. A decline in left atrial pressure (means +/- SE, 5.3 +/- 0.4 to 4.0 +/- 0.5 mmHg, P less than 0.05) and cardiac index (149 +/- 10 to 82 +/- 13 ml X min-1 X kg-1, P less than 0.01) in association with a marked increase in pulmonary arterial pressure (14.5 +/- 0.6 to 26.6 +/- 2.5 mmHg, P less than 0.001) and pulmonary vascular resistance (64 +/- 5 to 304 +/- 42 mmHg X ml-1 X min-1 X kg-1, P less than 0.001) was observed after 20 min of venom infusion. During this interval, pulmonary artery wedge pressure increased (4 +/- 1 to 12 +/- 4 mmHg, P less than 0.01) in four of eight animals. Fibrinogen declined below measurable levels and fibrin microemboli were seen in many pulmonary arterioles. These changes were not observed in the Echis + PPACK, PPACK, or control groups. Leukopenia and thrombocytopenia were observed in the Echis and Echis + PPACK groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary vascular response to leukotriene D4 in unanesthetized sheep: role of thromboxane

We examined the pulmonary vascular response to an intravenous leukotriene D4 (LTD4) injection of (1 microgram X kg-1 X min-1 for 2 min) immediately followed by infusion of 0.133 microgram X kg-1 X min-1 for 15 min in awake sheep prepared with lung lymph fistulas. LTD4 resulted in rapid generation of thromboxane A2 as measured by an increase in plasma thromboxane B2 concentration. The thromboxane B2 generation was associated with increases in pulmonary arterial and pulmonary arterial wedge pressures while left atrial pressure did not change significantly. Pulmonary lymph flow (Qlym) increased (P less than 0.05) transiently from base line 6.87 +/- 1.88 (SE) ml/h to maximum value of 9.77 +/- 1.27 at 15 min following the LTD4 infusion. The maximum increase in Qlym was associated with an increase in the estimated pulmonary capillary pressure. The increase in Qlym was not associated with a change in the lymph-to-plasma protein concentration (L/P) ratio. Thromboxane synthetase inhibition with dazoxiben (an imidazole derivative) prevented thromboxane B2 generation after LTD4 and also prevented the increases in pulmonary vascular pressures and Qlym. We conclude that LTD4 in awake sheep increases resistance of large pulmonary veins. The small transient increase in Qlym can be explained by the increase in pulmonary capillary pressure. Thromboxane appears to mediate both the pulmonary hemodynamic and lymph responses to LTD4 in sheep.     

Comparison of haemodynamic responses to dopamine and salbutamol in severe cardiogenic shock complicating acute myocardial infarction.

Twelve patients with severe persistent cardiogenic shock complicating acute myocardial infarction underwent single crossover treatment with intravenous dopamine and salbutamol to determine the more beneficial therapy. Salbutamol (10 to 40 microgram/min) reduced systemic vascular resistance and progressively increased both cardiac index and stroke index. Heart rate increased from 95 to 104 beats/min. Changes in mean arterial pressure and pulmonary artery end-diastolic pressure were small and insignificant. Dopamine infusion at rates of 200 and 400 micrograms/min also increased cardiac index and stroke index. Systemic vascular resistance fell slightly but mean arterial pressure rose from 57 to 65 mm Hg. Heart rate increased from 95 to 105 beats/min. Changes in pulmonary artery end-diastolic pressure were again small and insignificant. Dopamine infusion at 800 micrograms/min caused an appreciable increase in systemic vascular resistance; a further increment in mean arterial pressure was observed, though cardiac index fell slightly. Heart rate and pulmonary artery end-diastolic pressure rose steeply. Salbutamol, a vasodilator, increased cardiac output in patients with cardiogenic shock complicating acute myocardial infarction but did not influence blood pressure. If correction of hypotension is essential dopamine in low doses may be the preferred agent. Doses of 800 microgram/min, which is within the therapeutic range, worsen other manifestations of left ventricular dysfunction.     

Opposing hemodynamic effects of substance P on pulmonary vasculature in rabbits

Substance P is a peptide implicated in the control of a variety of physiological processes. Although substance P-containing neurons impinge on the pulmonary vasculature, the effects of substance P on the pulmonary circulation have not been systematically investigated. Rabbits were anesthetized with methohexital sodium and paralyzed with pancuronium bromide. Injection of substance P (0.002-0.10 microgram/kg) in the vena cava produced dose-dependent pulmonary vasoconstriction and systemic vasodilation. Pulmonary arterial pressure reached a peak within 15-20 s and declined toward base line over 10 min. Aortic pressure fell rapidly, reaching minimum at 5-10 s. At higher doses cardiac output fell transiently, resulting in a 65% fall in pulmonary vascular conductance. If repeat substance P dosages were administered 15 min apart, there was no tachyphylaxis. Pulmonary vasoconstriction was inhibited by the cyclooxygenase blocker meclofenamate (10 mg/kg) and the thromboxane synthase inhibitor Dazmegrel (UK-38,485) (2 mg/kg). In contrast, vasoconstriction was enhanced by atropine (2 mg/kg). In Dazmegrel-treated animals in whom pulmonary vasoconstriction was established by epinephrine infusion, low doses of substance P produced vasodilation. Our findings indicate that substance P produces pulmonary vasoconstriction via prostaglandin (particularly thromboxane) generation and pulmonary vasodilation via activation of cholinergic pathways.     

Increased pulmonary vascular capacitance with beta-adrenergic receptor stimulation: an experimental study of the effect of isoproterenol on the pulmonary vascular volume-pressure relationship

The present study is an investigation of the effect of beta-adrenergic receptor stimulation by isoproterenol on pulmonary vascular capacitance. The experiments were done in six intact-chest, anaesthetized dogs in which pulmonary and cardiac blood volumes were assessed by blood pool scintigraphy. Isoproterenol (0.150 microgram.kg-1.min-1) significantly (p less than 0.005) lowered pulmonary capillary wedge pressure (PPCW) and pulmonary artery pressure (PPA) but did not significantly change pulmonary blood volume (PBV). Left ventricular end-diastolic pressure and total cardiac volume both significantly (p less than 0.005) decreased. Pulmonary vascular volume-pressure (V-P) relationships before and during isoproterenol were described by means of blood transfusions and hemorrhage. In individual dogs the PBV-PPCW and the PBV-(PPCW + PPA)/2 relationships were significantly shifted upward by isoproterenol (p less than 0.05 or less); slope changes were variable. Pooled data from all dogs also showed a significant (p less than 0.001) upward shift in the pulmonary vascular V-P relationship regardless of which measure of distending pressure was used. These results suggest that beta-receptor stimulation by isoproterenol increases pulmonary vascular capacitance by increasing the unstressed volume.     

Effect of volume expansion on hemodynamic variables in nephrectomized dogs

We have previously demonstrated that blood pressure elevation by acute blood volume expansion is volume-dependent during the infusion period and resistance-dependent in the post-infusion period in normal anesthetized dogs, and that such an increase in blood pressure is associated with a potentiation of the pressor response to norepinephrine. To evaluate the possible renal contribution to these hemodynamic changes, blood volume expansion was performed for 1 h with dextran dissolved in lactated Ringer's solution (20 ml/kg) in 15 nephrectomized dogs. The mean blood pressure, cardiac output and total peripheral resistance at the end of infusion were 126%, 225% and 60%, respectively; 3 h after volume expansion they were 126%, 151%, and 92% respectively. However, in 4 dogs, there was an increase in mean blood pressure (138%) 3 h after volume expansion. This was thought to result from an increase in the total peripheral resistance (133%) associated with the recovery of cardiac output (106%). The pressor response to norepinephrine (0.5 microgram/kg) was potentiated after volume expansion. These results indicate that the handling of volume by the kidney contributed to the maintenance of an elevated level of cardiac output. However, nephrectomy did not seem to interfere with the hemodynamic switching of the causative factor for blood pressure elevation from increased cardiac output to increased total peripheral resistance. Neither was the potentiation of pressor response to norepinephrine affected.     

Hemodynamic and renal effects of acute and progressive nitric oxide synthesis inhibition in anesthetized dogs

This study evaluated the effects of progressive nitric oxide (NO) inhibition in the regulation of systemic and regional hemodynamics and renal function in anesthetized dogs. The N(G)-nitro-L-arginine methyl ester group (n = 9) received progressive doses of 0.1, 1, 10, and 50 microg. kg(-1). min(-1). Renal (RBF), mesenteric (MBF), iliac (IBF) blood flows, mean arterial pressure (MAP), pulmonary pressures, cardiac output (CO), and systemic and pulmonary vascular resistances were measured. During N(G)-nitro-L-arginine methyl ester infusion, MAP and systemic vascular resistances increased in a dose-dependent manner. Mean pulmonary pressure and pulmonary vascular resistances increased in both the N(G)-nitro-L-arginine methyl ester and the control group, but the increase was more marked in the N(G)-nitro-L-arginine methyl ester group during the last two infusion periods. CO decreased progressively, before any significant change in blood pressure was noticeable in the N(G)-nitro-L-arginine methyl ester group. IBF decreased significantly from the first N(G)-nitro-L-arginine methyl ester dose, whereas RBF and MBF only decreased significantly during the highest N(G)-nitro-L-arginine methyl ester dose. Urinary volume and sodium excretion only increased significantly in the time control group during the two last time periods. The pulmonary vasculature was more sensitive than the systemic vasculature, whereas skeletal muscle and renal vasculatures showed a greater sensitivity to the inhibition of NO production than the mesenteric vasculature. NO synthesis inhibition induces a progressive antidiuretic and antinatriuretic effect, which is partially offset by the increase in blood pressure.     

Changes in systemic hemodynamics following administration of synthetic angiotensin II to dogs of different ages]

Experiments were conducted on dogs aged 18-22 days, 2-3 month-old and adult dogs. Arterial blood pressure, cardiac output, heart rate and total peripheral resistance during the infusion of synthetic angiotensin-II-amide in a dose of 2 mug/kg per minute were studied. An increase of arterial pressure in adult dogs during the action of angiotensin-II was connected with the elevation of the total peripheral resistance. An increase of the total peripheral resistance and also of the cardiac output was seen in the puppies. The differences in the degree of increase of the arterial blood pressure in adult dogs and puppies were not marked.     

The effects of substance P on the preconstricted pulmonary vasculature of the anesthetized dog

Substance P is a vasoactive peptide. Nerve fibers containing substance P are present in the media of pulmonary arteries but the physiologic function of substance P in the pulmonary vasculature is unknown. Several doses of substance P were infused intravenously in the anesthetized dog to ascertain its effects on the pulmonary vasculature, both during normoxia and following preconstriction with hypoxia (F1O2 0.1) or prostaglandin F2 alpha (PGF2 alpha 5 mug/kg/min). Substance P resulted in systemic vasodilation during normoxia but had minimal effect on the pulmonary vasculature. During hypoxia and PGF2 alpha-induced pulmonary vasoconstriction, substance P significantly lowered pulmonary artery pressure, pulmonary vascular resistance, mean aortic pressure, and total systemic resistance. It had no effect on cardiac output, wedge pressure, and arterial blood gases. To investigate possible mechanisms for substance P-induced vasodilation, substance P was studied following pretreatment with N-acetylcysteine (a radical scavenging agent), methylene blue (an inhibitor of guanylate cyclase), meclofenamate (a cyclooxygenase inhibitor), and atropine (a muscarinic receptor antagonist). None of these agents impaired substance P-induced vasodilation. Substance P given intravenously is a nonselective vasodilator in the dog but the mechanism of its action remains uncertain.     

The effects of clonidine on the kidney function in the anesthetized dog

Studies were performed to determine the mechanism by which the antihypertensive agent clonidine increased urine flow. The response of the kidney has been examined in four combinations. The parameters of renal function have been compared during volume expansion by 1.5-2.0% body weight Ringer solution. In the control animals, volume expansion by 2% body weight, resulted in a slight increase in sodium excretion and urine flow. In 10 anesthetized dogs 1.0 microgram/kg/min of clonidine infused i.v. during 30 minutes (the total amount of clonidine infused was 30 micrograms/kg) decreased the arterial blood pressure from 136 +/- 13 mmHg to 127 +/- 12 mmHg and elevated urine flow from 2.95 +/- 1.65 ml/min to 4.34 +/- 1.77 ml/min while the urine osmolality diminished from 399 +/- 107 mosm/l to 265 +/- 90 mosm/l and the glomerular filtration remained constant. In 5 animals 0.1 microgram/kg/min of clonidine was infused into the left renal artery (this dose is corresponding to the renal fraction of the cardiac output) without any effects in the left kidney. 1.0 microgram/kg/min of clonidine infused directly into the left renal artery produced vasoconstriction in the ipsilateral kidney, decreased the glomerular filtration rate and the urine flow. By contrast in the right kidney the urine flow rose without hemodynamic changes, and the urine osmolality became hypoosmotic compared to the plasma. In ten dogs 1.0 microgram/kg/min of clonidine and 1 mU/kg/min of arginine-vasopressin were infused intravenously. The vasopressin infusion superimposed on the clonidine could not inhibit the increase of the urine excretion, and the fall of the urine osmolality. The results suggest that the clonidine increases the renal medullary blood flow possibly via a direct mechanism, decreases the sympathetic outflow to the kidney and via an indirect pathway, mediated by the renin-angiotensin system. The renal medullary flow increase produces a washout of the medullary osmotic gradient, and the water reabsorption diminishes.     

The effects of dopamine on renal excretion of sodium, phosphate and cyclic AMP in thyroparathyroidectomized dogs.

With dopamine (0.5 microgram/kg/min) infusion into the renal artery of thyroparathyroidectomized dogs, urine output and inorganic phosphate excretion increased significantly (p less than 0.05), but the increase in sodium excretion was low and not statistically significant. However, natriuresis and phosphaturia due to the infusion of dopamine were accelerated more markedly by the pretreatment with phenoxybenzamine. Dopamine was infused into the renal artery indoses too small to affect renal hemodynamics (0.02-0.05 microgram/kg/min) after the treatment with phenoxybenzamine and alprenolol with the result that phosphate and sodium excretion increased significantly (p less than 0.05). The excretion rate of cAMP did not change. This suggests that the effect of dopamine on sodium and phosphate excretion is directly influenced by alpha adrenergic activity in the kidney. The mechanism of natriuresis and phosphaturia by dopamine is, however, independent of changes in parathyroid hormone and the adenyl cyclase-cAMP system.     

Diamide inhibits pulmonary vasoconstriction induced by hypoxia or prostaglandin F2 alpha

Diamide oxidizes glutathione and other cellular sulfhydryl groups. It decreases calcium ATPase activity and alters mitochondrial calcium flux, probably as a result of the sulfhydryl oxidation. We examined the effect of diamide (5 mg/kg, iv) on pulmonary vascular reactivity in 12 anesthetized dogs. Diamide reversed the pulmonary vasoconstriction caused by hypoxia in seven dogs (control delta PVR + 2.5 +/- 0.6 mm Hg/liter/min; postdiamide delta PVR - 0.1 +/- 0.4 mm Hg/liter/min; P less than 0.01). The pulmonary pressor response to prostaglandin F2 alpha (5 micrograms/kg/min, iv) was also reduced (control delta PVR + 3.8 +/- 0.5 mm Hg/liter/min; postdiamide delta PVR + 1.1 +/- 0.7 mm Hg/liter/min; P less than 0.01). However, in a further five dogs, diamide had only a small effect on the pulmonary vasoconstriction caused by angiotensin II, while the pressor response to hypoxia was again inhibited. The mechanism by which diamide reverses pulmonary vasoconstriction is not certain but the effect is rapid, consistent, and reversible. Because the intravenous infusion of diamide does not produce systemic hypotension, during its period of action on the pulmonary vasculature, unlike the drugs currently available for the clinical treatment of pulmonary hypertension, further studies of its mechanism of action are indicated.     

Canine bronchoconstriction, gas trapping, and hypoxia with methacholine

The effects of an intravenous methacholine infusion on cardiovascular-pulmonary function were measured in seven mongrel dogs (22.0 +/- 2.8 kg), anesthetized with chloralose and urethan and beta-adrenergically blocked with propranolol. In a volume-displacement plethysmograph, physiological measurements were made at base line and 25 min after establishing a methacholine infusion (0.1-1.0 mg X kg-1 X h-1). Methacholine significantly (P less than 0.05) increased airways resistance (1.9 +/- 0.8 to 8.2 +/- 2.9 cmH2O X l-1 X s), decreased static lung compliance (84.7 +/- 18.5 to 48.2 +/- 9.4 ml/cmH2O), depressed arterial PO2 (81 +/- 17 to 56 +/- 10 Torr), and lowered blood pressure (132 +/- 10 to 69 +/- 18 Torr) and cardiac output (5.7 +/- 1.9 to 4.1 +/- 1.2 l/min). These effects persisted during a further 80 min of methacholine infusion conducted in five of the animals. During the initial 25-min period of methacholine, the end-expired volume (volume-displacement Krogh spirometer) rose in all animals, indicating an increase in functional residual capacity from 997 +/- 115 to 1,623 +/- 259 ml (P less than 0.0005). Analysis of pulmonary pressure-volume curves revealed no change in total lung capacity but an increase in residual volume from 489 +/- 168 to 1,106 +/- 216 ml (P less than 0.001). Thus methacholine caused 617 ml of gas trapping, which was not detected by the Boyle's law principle, presumably because gas was trapped at high transpulmonary pressure. We suggest that intravenous methacholine-induced canine bronchoconstriction, which causes gas trapping and hypoxia, may be a useful animal model of clinical status asthmaticus.     

Verapamil attenuates lung vascular responses to endotoxin in sheep

Experiments were conducted on five chronically instrumented unanesthetized sheep to determine the effects of verapamil, a calcium channel inhibitor, on the pulmonary hemodynamic and microvascular permeability responses to endotoxemia. Paired control endotoxemia experiments (E) and endotoxemia with verapamil treatment (30-60 micrograms.kg-1.min-1) experiments (V + E) were conducted on each sheep in random order. In the V + E experiments sheep were pretreated with a continuous intravenous infusion of verapamil 1.5-2.0 h before endotoxin infusion (1.0 microgram/kg, given over 15 min). Verapamil significantly increased base-line pulmonary arterial pressure, left atrial pressure, lung lymph flow rate, and circulating blood leukocyte levels and significantly decreased base-line cardiac output. During the endotoxin response, verapamil significantly attenuated both phase I pulmonary arterial hypertension and phase II lung lymph flow rate compared with control endotoxin experiments. The results indicate that verapamil attenuates both the pulmonary hemodynamic and increased lung microvascular permeability response to endotoxin in sheep. In a series of in vitro experiments, verapamil was found to be a potent inhibitor of phorbol myristate acetate-induced superoxide production in isolated sheep granulocytes. These data suggest that the beneficial in vivo effects of verapamil during endotoxemia may in part be due to its inhibition of increased free cytosol calcium concentration and/or inhibition of toxic O2 metabolite production.     

Prevention of hypoinsulinemia modifies catecholamine effects in fetal sheep

Increased epinephrine (Epi) and norepinephrine (NE) production plays an important role in fetal adaptation to reduced oxygen and/or nutrient availability, inhibiting insulin secretion and slowing growth to support more essential processes. To assess the importance of hypoinsulinemia for the efficacy of catecholamines, normoinsulinemia was restored by intravenous insulin infusion (0.18 mU. kg(-1). min(-1)) during prolonged infusion of either Epi (0.25-0. 35 microgram. kg(-1). min(-1) for 12 days, n = 7) or NE (0.5-0.7 microgram. kg(-1). min(-1) for 7 days, n = 6) into normoxemic fetuses in twin-pregnant ewes, from 125-127 days of gestation. Insulin infusion for 8 days during Epi infusion or for 4 days during NE infusion decreased arterial blood pressure, O(2) content, and plasma glucose, but increased heart rate significantly (all P <0.05), despite continuation of Epi or NE infusion. Cessation of insulin infusion reversed these changes. Estimated growth of fetuses infused with insulin during Epi or NE infusion (55 +/- 13.9 and 83 +/- 15.2 g/day) did not differ significantly from that of untreated controls (72 +/- 15.4 g/day, n = 6). Growth of selected muscles and hindlimb bones was not altered either. Restoration of normoinsulinemia evidently counteracts the redistribution of metabolic activity and decreased anabolism brought about by Epi or NE in the fetus. Inhibition of insulin secretion by Epi and NE, therefore, appears essential for the efficacy of catecholamine action in the fetus.