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Biomedical subjects

B R Pitt

Publications and source records attributed to B R Pitt.

At least 109 records · Page 6Linked to original sources
PubMed1984

Depression of pulmonary metabolic function by cardiopulmonary bypass procedures increases levels of circulating norepinephrine.

We measured plasma levels of endogenous norepinephrine radioenzymatically in mixed venous and arterial blood simultaneously sampled from anesthetized dogs before, during, and after 1 to 4 hours of total cardiopulmonary bypass (CPB) or 2 hours of left heart bypass. Prior to bypass, arterial levels of norepinephrine were 0.41 +/- 0.04 ng/ml and pulmonary extraction of norepinephrine was 25 +/- 3% (N = 20). During bypass, norepinephrine levels significantly increased from control to 1.41 +/- 0.15 (1 or 2 hours of CPB; N = 8) and 1.97 +/- 0.30 (3 or 4 hours of CPB; N = 8) or 0.97 +/- 0.29 (2 hours of left heart bypass) ng/ml. Restoration of normal pulmonary blood flow was associated with a rapid and significant decrease in arterial levels of norepinephrine, which, after 1 or 2 hours of CPB or 2 hours of left heart bypass, returned to levels obtained before bypass. However, arterial levels of norepinephrine remained higher than 1 ng/ml in the 3-hour recovery period after prolonged bypass. In these animals, pulmonary extraction of norepinephrine was significantly less than control. These data suggest that the lung's ability to remove norepinephrine is altered by CPB and that the severity of the alterations is directly related to pump time. The impairment in extraction allows higher than normal concentrations of norepinephrine to enter the arterial circulation and may contribute to systemic hypertension after bypass.

Animals↗
PubMed1984

Kinetics of pulmonary angiotensin-converting enzyme activity in conscious developing lambs.

Apparent enzyme kinetics were determined for pulmonary angiotensin-converting enzyme (ACE) as a function of postnatal development and alveolar hypoxia in intact conscious lambs (9 newborn and 7 sheep, 8-23 wk). We injected into the right atrium a mixture of indocyanine green and 3H-labeled benzoyl-phenylalanyl-alanyl-proline (BPAP), a synthetic substrate for ACE, and sampled blood from the aorta at 1-s intervals. From this, we quantified the %BPAP metabolism during a single pass through the lungs by use of indicator-dilution techniques. By adding unlabeled BPAP to the injectate, combining outflow data from two to three measurements, and applying a nonlinear model of pulmonary metabolism (J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 51:405-414, 1981), we could determine 1) apparent maximum velocity (Vmax); 2) concentration at which velocity was one-half Vmax (Km); and 3) alpha, a measure of perfusion heterogeneity. All animals were studied during normoxia and while breathing 10% O2 for at least 15 min. Seven of the newborn lambs were studied 1 wk later. Km in the newborn was 15 +/- 3 microM and did not change significantly with age or hypoxia. Vmax increased markedly with development (newborn: 14 +/- 2 nmol X s-1 X g dry lung-1; sheep: 38 +/- 5 nmol X s-1 X g dry lung-1; P less than 0.01). Alveolar hypoxia significantly decreased Vmax in the newborn only (P less than 0.05); there was no significant change in Vmax in the same animal studied 1 wk later or in the older group.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1984

Metabolic functions of the lung and systemic vasoregulation.

Several important vasoactive substances are taken up and/or metabolized during a single transpulmonary passage. Such substances include 5-hydroxytryptamine, prostaglandins (PGs) of the E and F series, and peptide substrates (angiotensin I and bradykinin) for angiotensin-converting enzyme (ACE). When these metabolic processes are altered, predictable changes in systemic hemodynamics can follow because of altered arterial concentrations of the vasoactive substances. For example, a single dose of captopril (2 mg/kg, i.v.) given to conscious rabbits caused prolonged depression in pulmonary ACE activity, an effect that coincided with a significant reduction in mean systemic arterial pressure. In another study, total cardiopulmonary bypass in anesthetized dogs was associated with a time-dependent increase in arterial levels of immunoreactive PGE. Coincident with this elevation in PGE was a significant decrease in total systemic vascular resistance. The decrease in resistance was inhibited by pretreatment with indomethacin or by maintaining lung perfusion during extracorporeal circulation (i.e., left heart bypass). Thus, in the intact animal, significant reduction in lung metabolism, induced by either pharmacological or other experimental means, may modify vasoregulation of peripheral circulation. Furthermore, measurement of these metabolic functions may provide biochemical information about the pulmonary microcirculation, which is both the locus of these activities and an early site of acute lung injury.

Animals↗
PubMed1984

Functional assessment of the pulmonary microcirculation during postnatal development.

It has been well documented that the lungs are able to remove or metabolize several vasoactive substances passing through the pulmonary circulation. One such function, the conversion of angiotensin I to angiotensin II and hydrolysis of bradykinin to inactive peptide fragments is performed by angiotensin-converting enzyme (ACE). Although a precise role of these functions for systemic vasoregulation has not been defined, measurement of pulmonary metabolic capacity has the potential for providing substantial information about the integrity and physiology of the pulmonary microcirculation. Studies are described using 3H-benzoyl-phenylalanyl-alanyl-proline (a synthetic substrate for pulmonary ACE) in developing conscious lambs and older sheep. Outflow curves from indicator dilution measurements contain information regarding apparent kinetics of ACE activity. Using a nonlinear model for saturable pulmonary metabolic functions, the derived data demonstrate a) a marked increase in Vmax, the apparent maximal velocity of ACE, with age; and b) no significant change with age in apparent Km, the concentration at which the velocity of ACE is one-half Vmax. This approach has the potential for providing a biochemical tool for examining postnatal growth of the pulmonary microcirculation as well as functional integrity of the pulmonary endothelium during a variety of conditions.

Animals↗
PubMed1984

Correlation between lung and plasma angiotensin converting enzyme and the hypotensive effect of captopril in conscious rabbits.

We measured both pulmonary and plasma angiotensin converting enzyme (ACE) activity in conscious rabbits before and for 6 days after administration of captopril (2 mg/kg i.v.). Pulmonary ACE activity was measured by means of modified indicator-dilution techniques after bolus injection of [3H]benzoyl-phenyl-alanyl-alanyl-proline ( BPAP , synthetic substrate for ACE). Plasma ACE activity was also determined radiometrically with [3H] BPAP as substrate. In addition, we measured the systemic pressor response to i.v. bolus dose of angiotensin I both before and after captopril. Twenty-four hours after captopril, pulmonary metabolism of BPAP had decreased from control of 73 +/- 5 to 8 +/- 2%; even 6 days after drug treatment there was still evidence of inhibition. In contrast, plasma ACE activity was significantly (P less than .05) reduced within 15 min of treatment (to 20% of control levels) but recovered within 24 hr. The time course of changes in the pressor response to angiotensin I, after captopril, resembled that of plasma ACE activity. Mean systemic arterial blood pressure was 81 +/- 4 torr at control and reached its nadir at 24 hr (64 +/- 2 torr; P less than .05); thereafter a gradual recovery ensued, similar in time course to that of pulmonary ACE. These data suggest that inhibition of plasma ACE and also the pressor response to angiotensin I are unrelated temporally to the hypotensive effects of captopril.

Angiotensin I↗
PubMed1983

Pulmonary metabolic function in the awake lamb: effect of development and hypoxia.

The effect of postnatal development and acute alveolar hypoxia on pulmonary metabolic function was studied in conscious newborn lambs. Measurements of the ability of the lungs of these animals to metabolize [3H]benzoyl-L-phenyl-alanyl-L-alanyl-L-proline ([3H]BPAP; a synthetic substrate for angiotensin-converting enzyme, ACE) and to remove 5-hydroxy-[14C]tryptamine (5-[14C]HT) were made by modified indicator-dilution techniques during normoxic and hypoxic (fraction of inspired O2 = 0.10) conditions at 1 day, 1 wk, and 1 mo of age. Six additional sheep (8-23 wk old) were studied acutely as "adult" controls. BPAP metabolism in the 1-day-old group was 48 +/- 3% and increased slowly to 57 +/- 1% (P less than 0.05) at 1 mo of age and to 79 +/- 3% (P less than 0.01) by 23 wk of age. Pulmonary 5-[14C]HT removal was adultlike at birth (69 +/- 2%). Alveolar hypoxia significantly decreased BPAP only in the 1-day-old group (41 +/- 3%; P less than 0.05) and had no significant effect on 5-[14C]HT removal over the range of ages studied. These data demonstrate a selective and gradual postnatal development of pulmonary ACE which could be due to alterations in either the affinity or maximal capacity of pulmonary ACE, or increased endothelial cell surface area secondary to rapid growth of small blood vessels in this period. Alveolar hypoxia does not appear to closely regulate either ACE activity or 5-HT removal in conscious lambs greater than 1 day old when trace amounts of substrate are used.

Animals↗
PubMed1983

Drug-induced impairment of pulmonary [3H]prostaglandin E1 removal in vivo.

Pulmonary removal of [3H]prostaglandin (PG)E1 was measured from multiple indicator dilution techniques using [14C]dextran as an intravascular marker in mechanically ventilated anesthetized rabbits. Removal of PGE1 was 87 +/- 1% (n = 23) at the peak of the [14C]dextran outflow curve and decreased in a dose-dependent manner when: 1) indocyanine green (ICG) was coadministered in the injection mixture (n = 18; IC50 = 16 microM); or 2 ICG was administered i.v. to achieve a steady-state level (n = 5; IC50 = 80 microM). Cumulative doses of either furosemide (0.1 mmol/kg b.wt.; n = 5) or probenecid (1.0 mmol/kg; n = 10) administered over 2 hr did not significantly affect the removal of PGE1. However, when 0.5 mumol of ICG was added to the injection, both furosemide and probenecid (0.01 mmol/kg) were associated with greater decreases in the removal of PGE1 than would be expected by the effect of ICG alone (P less than .01). These data show that in vivo measurements of pulmonary removal of [3H]PGE1 are predictably affected by various inhibitors of this transport process previously shown in isolated perfused lungs.

Alprostadil↗
PubMed1982

The fate of circulating amines within the pulmonary circulation.

Pulmonary biogenic amine clearance is a carrier-mediated drug sensitive process associated with uptake into endothelial cells and subsequent metabolism by monoamine oxidase and other enzymes. Its function seems to be maintenance of arterial circulatory homeostasis by biochemically regulating circulating vasoactive hormones. Numerous pulmonary pathologic conditions are associated with alterations in these functions. However, a more precise physiologic role remains to be defined. Areas for further research include: 1. Comparative studies on the ability of endothelium from extrapulmonary and pulmonary vasculatures to extract and metabolize vasoactive amines and other humoral substances. This work must be done both in intact animals and in isolated cultured endothelium derived from organ microvasculatures. 2. Study of factors (e.g. steroids, development, etc) that may regulate pulmonary metabolic functions. 3. Measurements in humans under various clinical conditions. To this end, indicator dilution estimates and transpulmonary gradients have provided intriguing promise of means to assess endothelial metabolic functions in both normal and injured lung.

Animals↗
PubMed1982

Selective effect of microembolization on pulmonary removal of biogenic amines.

Pulmonary amine extraction (E) was measured by triple-indicator dilution techniques from bolus injections of trace amounts of 5-hydroxy[14C]tryptamine ([14C]HT)m [3H]norepinephrine ([3H]NE), indocyanine green dye before and after glass-bead embolization in 23 anesthetized dogs. Control E(5-[14C]-HT) was 89.7 +/- 1.7%; 10 min after embolization (which approximately doubled pulmonary artery pressure and pulmonary vascular resistance), E(5-[14C]HT) was significantly reduced to 65.9 +/- 3.0% (kappa +/- SE; n = 10) (P less than 0.01). Control E([3H]NE) (40.1 +/- 4.5%) was unaffected by embolization. Imipramine (8 mg/kg) depressed control E(5-[14C]HT) to 38.7 +/- 1.5% and control E([3H]NE)d to 35.0 +/- 3.9% (P less than 0.05; n = 4). In these animals, pulmonary hemodynamic changes secondary to embolization were comparable to those in non-drug-treated dogs, but E(5-[14C]HT) and E([3H]NE) were not further depressed. Progressive pulmonary lobar artery ligation (n = 5) did not affect amine extraction until perfusion was limited to one lobe. The selectivity of the effect of embolization on E(5-[14C]HT), the lack of an effect on imipramine-insensitive E(5-[14C]HT) extraction, and the much smaller changes after progressive lobar ligation indicate that, although derecruitment of vascular surface area secondary to mechanical obstruction may contribute to postembolization depression of E(5-[14C]HT), additional mechanisms such as local saturation of 5-HT uptake or selective damage to endothelial cell transport of 5-HT may underlie these observations.

Animals↗
PubMed1982

Depressed pulmonary removal of [3H]prostaglandin E1 after prolonged cardiopulmonary bypass.

Pulmonary removal of [3H]prostaglandin E1 ([3H]PGE1) was measured by double indicator-dilution techniques after bolus injections of indocyanine green and trace amounts of [3H]PGE1 before and after 1-3 h of total cardiopulmonary bypass (CPB) or 3 h of left-heart bypass (LHB) in 18 anesthetized dogs. Before bypass, pulmonary removal was 85.7 +/- 1.2% (means +/- SE, n = 18) and was unchanged on restoration of normal circulation after 1-2 h of CPB (80.6 +/- 1.8%, n = 7) or 3 h of LHB (87.4 +/- 1.6%, n = 4). However, on restoration of normal pulmonary arterial blood flow after 3 h of CPB, removal was significantly decreased to 74.5 +/- 2.2% (P less than 0.01, n = 7). Postbypass depression of [3H]PGE1 removal may explain our previous observations that intrabypass elevations in endogenous immunoreactive prostaglandin E in dogs were not entirely reversible on cessation of 3-4 h of CPB. Possible factors underlying depression of post-CPB pulmonary removal of [3H]PGE1 include: 1) local saturation of [3H]PGE1 removal secondary to intrapulmonary or intravascular release of prostaglandin E, 2) inhibition of prostaglandin dehydrogenase activity, or 3) damage to endothelial cell transport of [3H]PGE1 from the pulmonary microcirculation.

Alprostadil↗
PubMed1982

Comparison of pulmonary and extrapulmonary extraction of biogenic amines.

Multiple indicator-dilution technique was used to study the effect of altered blood flow and imipramine (8 mg/kg) on extraction (E) of trace amounts of 5-hydroxy[14C]tryptamine (5-[14C]HT) and [3H]norepinephrine ([3H]NE) in pulmonary (n = 6) and hindlimb (n = 6) circulations of anesthetized dogs. Increasing cardiac output (via right-heart bypass) from 63 to 112 ml.min-1.kg-1 did not significantly affect pulmonary amine extraction [E(5-[14C]-HT), 73 +/- 4%; E([3H]NE), 51 +/- 3%], whereas decreasing cardiac output to 13 ml.min-1.kg-1 led to significant increases in extraction of either amine (P less than 0.05). Imipramine significantly decreased pulmonary amine extraction with greatest inhibition noted at the lowest cardiac output. Hindlimb E(5-[14C]HT) and E([3H]NE) was 49 +/- 6 and 33 +/- 3%, respectively, at hindlimb blood flow of 104 ml/min and was not affected by changes in hindlimb blood flow from 47 to 202 ml/min. Although hindlimb (5-[14C]HT) was significantly less than pulmonary E(5-[14C]-HT), it was similar in that imipramine significantly decreased hindlimb E(5][14C]HT) to 26% (P less than 0.01) suggesting that part of hindlimb 5-HT extraction may involve a drug-sensitive carrier-mediated process as has been shown in lung. The difference in magnitude between the two beds may be a function of decreased endothelial cell surface area in the hindlimb compared with lung. Since pulmonary and hindlimb extraction of trace amounts of these amines appears to be insensitive to changes in blood flow near normal regional blood flow, indicator-dilution techniques appear to be useful in evaluating alterations in the metabolic capacity of the microcirculation of intact animals.

Animals↗
PubMed1982

Reversible changes in norepinephrine extraction by the lungs in children with pulmonary hypertension.

Extraction of circulating vasoactive hormones by the lung may influence systemic vasomotor tone. Since this process occurs in the pulmonary microcirculation, we evaluated the effects of pulmonary artery hypertension (PAH) secondary to congenital heart disease (CHD) on this metabolic function of lung. Eleven patients with varying congenital cardiac lesions were studied preoperatively and postoperatively. Five had normal pulmonary artery pressure (PAP) (group I), and six had PAH with peak systolic PAP greater than 40 mm Hg (group II). PA and postpulmonary arterial blood samples were collected before and after surgery at the time of pressure measurements. Norepinephrine (NE) and epinephrine (EPI) levels were determined by radioenzymatic assay. Preoperatively, circulating NE levels were higher (P less than 0.05) and NE extraction measured was lower (P less than 0.01) in group II patients as compared with group I. Extraction increased in group II postoperatively after PA pressures were reduced, becoming equivalent to group I postoperative values. EPI extraction was negligible in either group at any time. These data demonstrate that lungs of children are capable of selective catecholamine uptake and that elevated PAP occuring with CHD is associated with a decrease in this capability and an increase in circulating NE levels. Additionally, the decrease in NE extraction observed with PAH is reversible once PAP is reduced by surgical repair of the cardiac defect.

Adolescent↗
PubMed1981

Influence of the lung on arterial levels of endogenous prostaglandins E and F.

Arterial and mixed venous levels of immunoreactive prostaglandins E (IRPGE) and F (IRPGF) were measured before, during, and after total cardiopulmonary bypass (CPB) or left-heart bypass (LHBP) in 22 anesthetized dogs. Mean arterial levels of IRPGE and IRPGF increased with time on bypass from prebypass levels of less than 0.01 ng/ml to 6.12 +/- 1.71 and 4.85 +/- 1.31 ng/ml, respectively, after 3-4 h of CPB. There was no significant difference between right atrial and femoral arterial prostaglandin levels during CPB. Upon restoration of normal pulmonary blood flow, arterial levels decreased toward control, and significant pulmonary artery-left ventricular gradients were observed. During LHBP, with similar extracorporeal pathophysiological conditions as CPB, but with the lungs normally perfused, arterial levels of IRPGE and IRPGF were not significantly different from prebypass levels. These data suggest that elevations in endogenous arterial IRPGE and IRPGF are due to the absence of the prostaglandin clearance function of the lung when blood is temporarily diverted from the pulmonary circulation during CPB. Therefore, the prostaglandin clearance function of the lung appears to be important in regulating arterial levels of endogenous prostaglandins E and F.

Animals↗
PubMed1981

Coordination of mucociliary transport in human trachea and intrapulmonary airways.

A wide range of both mucus velocities in the trachea and rates of bronchial mucociliary clearance have been measured in humans. To investigate the coordination of mucociliary transport in the intrapulmonary and extrapulmonary airways, simultaneous measurements of tracheal mucus velocity and lung clearance were made in 22 healthy nonsmoking adults. Each subject inhaled several breaths of an iron oxide aerosol tagged with 99mTc. Measurements of retained activity in the right lung were made for 2.25 h with a pair of 5 x 2 in. NaI (T1) detectors. Tracheal mucociliary transport rates (TMTR) were measured with a probe containing six vertically aligned rectangular NaI (T1) detectors. The mean TMTR was 5.1 +/- 2.9 mm/min. The mean time for the first bolus to be detected on the multidetector probe (large airway transit time, LATT) was 52 +/- 24 min. At this time the percent cleared (Bi) was 24 +/- 15% and the rate of clearance (Bi) was 0.64 +/- 0.35%/min. The mean percent cleared within a 2-h interval (B120) was 51 +/- 22%. The TMTR was closely correlated with Bi and Bi with B120. The TMTR was also correlated to B120, but not closely correlated with LATT. It is suggesting that coordination of mucus transport throughout the airways of the lung represents the nonchallenged state and is responsible for the maintenance of normal bronchial toilet.

Adult↗
PubMed1981

Effects of drugs on mucociliary transport in the trachea and bronchial airways.

Pharmacologically active agents may change transport rates regionally within the airways of the lung, as well as affect the overall magnitude of the clearance of inhaled deposited radioaerosols. To investigate these possibilities the response of ethanol on pulmonary retention was determined and the responses of both the trachea and bronchial airways were measured after either oral administration of metaproterenol or inhalation of sulfuric acid mist. In the healthy nonchallenged lung, the velocity of mucociliary transport in the trachea was related to the percentage of activity cleared from the lung in two hours. Indices representing different portions of the pulmonary retention curve were also correlated. Changes in this interdependence of mucociliary transport within airways were produced by all agents. Metaproterenol increased tracheal mucus velocity but not lung clearance. Alcohol changed pulmonary retention in both magnitude and direction depending on the individual, resulting in an increase in variability of pulmonary mucociliary clearance between persons. Thus, to evaluate the effects of drugs or pollutants on the lower respiratory tract, measurements of mucociliary transport should be made in both the trachea and the bronchial airways.

Aerosols↗
PubMedDate not supplied

Beagle pup model of perinatal asphyxia: nimodipine studies.

Calcium antagonists may be of significant benefit in the pharmacotherapy of cerebral ischemia, possibly by improving postischemic cerebral blood flow (CBF). This study evaluated the effects of the calcium antagonist nimodipine on CBF in a newborn beagle pup model of perinatal asphyxia lasting 5 minutes. Immediately after the asphyxial episode, nimodipine (2 micrograms/kg/min) or saline was infused for 10 minutes, following which [14C]iodoantipyrine determinations of CBF were performed. In noninsulted pups, nimodipine caused both significant decreases in CBF to cortical and deep gray structures as well as a decrease in mean arterial blood pressure (MABP) (p less than 0.05). In insulted pups, nimodipine similarly decreased MABP (p less than 0.001) and CBF to cortical and deep gray matter regions. Nimodipine appeared to have no effect on arterial blood gases and EEG tracings in either insulted or noninsulted pups. Although nimodipine may be shown to improve neurologic outcome in asphyxiated newborn infants, the limits of this study do not show the mechanism to be that of improving CBF.

Animals↗