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Biomedical subjects

D L Roerig

Publications and source records attributed to D L Roerig.

At least 55 records · Page 3Linked to original sources
PubMed1989

Effect of propranolol on the first pass uptake of fentanyl in the human and rat lung.

The first pass uptake of fentanyl in the human lung was studied in two groups of patients using a double indicator dilution technique. A bolus containing fentanyl and indocyanine green dye (ICG) was rapidly injected into the central venous catheter of patients prior to anesthesia. Sequential arterial blood samples were collected at 1-s intervals for 45 s after injection. The total amount of fentanyl taken up by the lung during the first pass and the instantaneous extraction of fentanyl at each time point during the first pass were calculated from the differences in the arterial blood concentration versus time curves of the nondiffusible indicator (ICG) and the drug. In patients who had been receiving no other drugs prior to the experiment, the total first pass uptake (mean +/- SE) of fentanyl was 82.6% +/- 1.4% of the injected dose. In patients who had been receiving 30-120 mg/day of propranolol the total first pass uptake (mean +/- SE) of fentanyl decreased to 52.8% +/- 6.3% of the injected dose. In one patient on 120 mg of propranolol per day, first pass uptake of fentanyl was only 20.3% of the injected dose. Additional studies in a rat isolated perfused lung preparation coperfused with fentanyl and propranolol also demonstrated that one basic lipophilic amine (propranolol) could inhibit the pulmonary uptake of a second basic lipophilic amine (fentanyl). The high first pass uptake of fentanyl in the human lung limits the rate of entry of this drug into the systemic circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Effect of transit time on metabolism of a pulmonary endothelial enzyme substrate.

Fractional hydrolysis (M) of the synthetic angiotensin-converting enzyme (ACE) substrate [3H]benzoyl-Phe-Ala-Pro (BPAP) on passage through the isolated dog lung lobe was found to be relatively independent of flow rate and transit time (t). The most commonly expressed explanation for this kind of observation is that recruitment of ACE-containing surface area occurs when flow is increased. To test this, as well as other hypotheses that might explain the behavior of this substrate, we compared M obtained after the first pass of a BPAP-containing bolus through isolated rabbit lungs with that obtained after two sequential passes through the lungs. In this way, we could double t with no change in flow or vascular pressure. We found that, when the second pass occurred within a few seconds of the first, M after both the first and second pass was only slightly larger than that after the first pass alone. If the time between passes was increased to a few minutes, M after the second pass was substantially increased. These results are contrary to the recruitment hypothesis and suggest that this substrate may exist in alternative forms that are in slow equilibrium relative to the capillary t. When albumin was present in the perfusate, an albumin-bound fraction appeared to be one such alternative form. However, experiments carried out using protein-free perfusate suggest the possibility that conformational variants of the substrate may also exist.

Animals↗
PubMed1989

Plasma protein binding and endothelial enzyme interactions in the lung.

The influence of plasma albumin binding of the synthetic angiotensin-converting enzyme (ACE) substrate [3H]benzoyl-phenylalanyl-alanyl-proline (BPAP) on BPAP hydrolysis by pulmonary endothelial ACE was studied in isolated rabbit lungs perfused with a salt solution containing either 5% bovine serum albumin (BSA) or 5% dextran. The single-pass indicator-dilution method was used to measure the fraction (M) of [3H]BPAP hydrolyzed. Lung M was greater with albumin-free perfusate than when BSA was present. M decreased as the time (ti) that the BPAP was in contact with the BSA before reaching the lung was increased, suggesting that some BSA binding sites for BPAP were not in equilibrium during bolus transit through the lungs. The M vs. ti data were correlated using a model incorporating both rapid and slow binding kinetics of BPAP and BSA. For the slow BPAP-BSA interaction, the dissociation rate constant was approximately 0.015 s-1, and the fraction of the BPAP bound to these slowly equilibrating sites at equilibrium was approximately 22%. The results indicate that transient plasma protein binding kinetics can affect lung BPAP hydrolysis.

Animals↗
PubMed1989

Evaluation of endothelial injury in the human lung.

The pulmonary endothelium plays a crucial role in the normal function of the lungs. Damage to the pulmonary endothelium is thought to be a primary event leading to deficits in pulmonary function in diverse forms of lung injury, but it is difficult to detect until these secondary deficits are manifest. Indicator dilution methods are practical for evaluation of endothelial function in patients. Interpretation of the information contained in the data is potentially complex, and specificity may be improved by using multiple indicators, each of which interacts with the endothelium in a different way. The general clinical utility of the methods is not yet established. However, encouraging experimental results, clinical studies, and improved technologies suggest that the methods have the potential to be of significant diagnostic and prognostic value.

Capillary Permeability↗
PubMed1989

First-pass uptake of verapamil, diazepam, and thiopental in the human lung.

The first-pass uptake of verapamil, diazepam, and thiopental in the human lung was determined using multiple-indicator dilution techniques. These three drugs represent lipid-soluble agents that differ in their ionic characteristics at physiological pH. Verapamil, a basic lipophilic amine, underwent significant uptake, with 50% of the drug accumulating in lung tissue during the first pass. With diazepam, a nonbasic lipophilic amine, there was 30% uptake during the first pass through the human lung--significantly less than that observed with verapamil. With thiopental, an acidic lipophilic barbiturate, only 14% of the injected drug accumulated in the lung during the first pass. Taken together, these data are consistent with observations from animal studies, which indicate that extensive pulmonary uptake is greater with basic amine drugs that are moderately to highly lipid-soluble. Also, the relatively high first-pass uptake of verapamil in the human lung suggests a quantitatively significant role of this nonrespiratory function of the lung in the early pharmacokinetics of intravenous verapamil.

Adult↗
PubMed1988

Omega-hydroxylation of prostaglandin E1 in the isolated perfused lungs of pregnant rabbits.

Cytochrome P450PG omega is induced in the rabbit lung in a gestational age-dependent manner and hydroxylates certain eicosanoids at their terminal, or omega (omega), carbon. This enzyme has been isolated from microsomal fractions and its activity has been characterized (Williams, D.E., et al., J. Biol. Chem. 259; 14600-14608, 1984). The experiments presented here examine the omega-hydroxylation activity of the intact lung during presentation of an eicosanoid substrate, prostaglandin E1 (PGE1), to the lung vasculature. Isolated, perfused lungs from three pregnant and four nonpregnant rabbits were injected with [3H]-PGE1. One-second fractions were collected from the perfusion effluent and were analyzed for metabolism of PGE1. Lungs isolated from pregnant rabbits metabolized PGE1 mainly to two polar derivatives, 20-hydroxy-PGE1 and 13,14-dihydro-15-keto-20-hydroxy-PGE1, whereas lungs from nonpregnant rabbits yielded mainly a relatively nonpolar metabolite, 13,14-dihydro-15-keto-PGE1. These metabolites were identified by coelution with standards that were generated enzymatically in vitro and whose structures were confirmed by gas chromatography/mass spectrometry (GC/MS).

Alprostadil↗
PubMed1988

Early effects of experimental diabetes on central catecholamine concentrations.

Six days after induction of diabetes norepinephrine (NE), 3,4-dihydroxyphenylalanine and dopamine concentrations were determined in spinal cord, cerebellum, pons/medulla oblongata and the remaining brain of diabetic rats. Only cerebellar NE levels were significantly increased by 21% compared to age-matched controls. This effect was not seen when diabetic rats received insulin replacement therapy. Fifty-two days after induction of diabetes cerebellar NE levels in diabetic rats were further increased (+37%), implying an enduring and progressive effect. The data show that even with a short period of uncontrolled diabetes central neurochemical alterations occur.

Animals↗
PubMed1988

Effects of halothane on acetylcholine release and sympathetic ganglionic transmission.

Depression of synaptic transmission is one of the actions common to many general anesthetics. They appear to act primarily on the chemical transmission process itself without affecting the conduction of impulses in nerve axons. The objective of the present study was to directly examine the effects of halothane on the release of acetylcholine and overall ganglionic transmission. The effects of halothane on ganglionic transmission were studied in the stellate ganglion of the cat in vitro. The preganglionic nerves of the stellate ganglion were stimulated electrically to generate threshold and suprathreshold evoked potentials in the postganglionic nerves. The picomole levels of released acetylcholine in the superfusate were determined with a radioenzymatic method using 32P-ATP following a 5-min preganglionic stimulation before and after the addition of 0.28 and 0.59 mM halothane (vaporizer settings of 1% and 2%, respectively). Halothane at both concentrations: 1) depressed sympathetic ganglionic transmission induced by either threshold or suprathreshold stimulation of the preganglionic nerves; and 2) caused a dose-dependent decrease in acetylcholine release during threshold stimulation with no change in neurotransmitter release during suprathreshold stimulation. In summary, the interruption of synaptic transmission by halothane involves at least two mechanisms: 1) decrease in acetylcholine release during low level of synaptic transmission; and 2) postsynaptic decrease in sensitivity to acetylcholine during low and high levels of synaptic transmission.

Acetylcholine↗
PubMed1987

Altered splenic catecholamine concentrations during experimental allergic encephalomyelitis.

Catecholamine concentrations of the spleen were studied with neurochemical techniques in rats injected with myelin basic protein to produce an experimental allergic encephalomyelitis (EAE). Thirteen to 14 days postinoculation the affected rats showed peak clinical signs of weakness, especially in the lower extremities. Resolution of the disease then progressed rapidly with full clinical recovery at day 21. Splenic concentrations of norepinephrine (NE), 3,4-dihydroxyphenylalanine (DOPA), epinephrine (EPI) and 3,4-dihyxroxyphenylethylamine (DA) were determined by HPLC with electrochemical detection. DOPA concentrations were significantly increased (+62%) while DA concentrations were decreased (-29%) in the EAE rats on day 14 postinoculation. NE and EPI concentrations tended to be elevated in the EAE group, but this was not statistically significant. No differences in splenic catecholamines were detected on day 7 and 52 postinoculation between EAE and control animals. These results indicate that changes in the metabolic pathways of splenic catecholamines occur at the peak of the clinical symptoms of EAE; the increase in DOPA and the decrease in DA concentrations suggest that the activity of DOPA-decarboxylase or its co-factor is altered.

Animals↗
PubMed1987

First pass uptake of fentanyl, meperidine, and morphine in the human lung.

The first pass uptake of fentanyl, meperidine, and morphine in human lung was studied in patients using a double indicator dilution technique. A bolus containing one of the drugs and indocyanine green dye (ICG) was rapidly injected into the central venous catheter of patients prior to anesthesia for surgery. Sequential arterial blood samples were collected at 1-s intervals for 45 s after injection. The total amount of drug taken up by the lung during the first pass and the instantaneous extraction of drug at each time point during the first pass were calculated from the differences in the arterial blood concentration versus time curves of the nondiffusible indicator (ICG) and the drug. The total uptake (mean +/- SE) during the first pass through the human lung for fentanyl and meperidine was 75.2 +/- 3.2% and 64.7 +/- 7.8% of the injected dose, respectively. The pulmonary uptake of morphine was very small, with 96.5 +/- 7.1% of the injected dose recovered in arterial blood after the first pass through the lung. The arterial blood concentration of drug and dye versus time showed a slight delay of the fentanyl and meperidine peaks compared to ICG. It was also observed that greater than 90% of these drugs were extracted from the blood in the early part of the first pass, but the extraction decreased with time during the first pass through the lung. These findings indicate that some of the drug taken up by the lung can diffuse back out into the blood.2+off

Aged↗
PubMed1986

Effects of fentanyl-diazepam-nitrous oxide anaesthesia on arterial baroreflex control of heart rate in man.

The effects of fentanyl 7.5 micrograms kg-1 (group I), 10.0 micrograms kg-1 (group II) and 12.5 micrograms kg-1 (group III) with diazepam 0.25 mg kg-1 and 70% nitrous oxide on baroreflex control of heart rate in humans were investigated. Phenylephrine (the pressor test), sodium nitroprusside (the depressor test) and graded neck suction provoked baroreflex responses. In group I the pressor, depressor and neck suction baroreflex slopes decreased during anaesthesia. In groups II and III the depressor test slopes were also decreased during anaesthesia. However, the slopes derived from the pressor and neck suction tests did not decrease. These data suggest that baroreflex control of heart rate is attenuated during low doses of fentanyl (7.5 micrograms kg-1). Baroreflex mediated tachycardia is decreased by higher doses of fentanyl (10.0 and 12.5 micrograms kg-1). However, baroreflex-mediated bradycardia is maintained during the higher doses of fentanyl. We suggest this effect is the result of enhanced vagal efferent activity mediated by fentanyl.

Adult↗
PubMed1986

The effects of morphine on sympathetic transmission in the stellate ganglion of the cat.

The aim of this study was to investigate which of the processes involved in synaptic transmission are affected by morphine in concentrations comparable to those used during surgical procedures. The effects of morphine sulfate on ganglionic transmission were studied in the stellate ganglion of the cat using intracellular and extracellular recordings in vitro. The neurons of the stellate ganglion were depolarized using preganglionic nerve stimulation, postganglionic nerve stimulation, and intracellular stimulation before and after introduction of morphine sulfate (up to 20 micrograms/mL). Tissue concentrations of morphine were estimated using radiolabeled morphine. Axonal transmission and the excitability of the postganglionic neurons to direct intracellular stimulation was not affected at the concentrations of morphine studied. In addition, morphine had a dose-dependent depolarizing effect on the resting membrane potential of most of the neurons in the stellate ganglion. Such neuronal depolarizations alone could initially produce excitation in some cell populations, followed by inhibition, secondary to the membrane depolarization, leading to depression of sympathetic nerve activity. The overall ganglionic transmission as recorded using an evoked potential was biphasic. At low doses morphine facilitated transmission, while at larger doses morphine attenuated evoked potentials. These effects do not appear to be mediated through classical opiate receptors since they are not blocked by naloxone.

Animals↗
PubMed1984

Baroreceptor reflex control of heart rate during morphine sulfate, diazepam, N2O/O2 anesthesia in humans.

The effect of morphine, diazepam, N2O/O2 anesthesia on baroreflex control of heart rate in humans was investigated in this study. Group 1 subjects (n = 11) received morphine 0.5 mg/kg, diazepam 0.25 mg/kg, and 70% N2O with O2. Group 2 subjects (n = 10) received morphine 0.75 mg/kg, diazepam 0.25 mg/kg, and 70% N2O with O2. Phenylephrine (the pressor test), sodium nitroprusside (the depressor test), and graded neck suction were employed to alter the stimulation of baroreceptor sites. The pressor, the depressor, and neck suction baroreflex slopes declined significantly in both groups from awake to anesthetized. There was no significant difference in the degree of depression between the two groups for all three tests. Neck suction derived slopes compared favorably to the pressor test slopes (r = 0.70, P less than 0.01). This study indicates that the depression of arterial baroreflex-heart rate responses under morphine, diazepam, N2O/O2 anesthesia is similar to that seen with potent inhalational anesthetics such as isoflurane. Furthermore, there was no difference between the two morphine doses that were studied.

Adult↗
PubMed1984

Influence of plasma protein on the inhibitory effects of indocyanine green and bromcresol green on pulmonary prostaglandin E1 extraction.

The purpose of this study was to examine the influence of plasma protein on the inhibitory effects of the anionic dyes indocyanine green and bromcresol green on prostaglandin E1 (PGE1) uptake by the lungs. Dog lung lobes were isolated and perfused with either autologous plasma or Krebs-Ringer bicarbonate solution (KRB) containing no protein but with dextran used as a colloid. PGE1 uptake was determined by injecting a bolus, containing radiolabelled PGE1 into the lobar artery and then analysing ethanolic extracts of the venous effluent for radioactivity in PGE1 and PGE1 metabolites by thin layer chromatography and scintillation counting. When the lobes were perfused with KRB, bromcresol green at an average initial concentration of 28.5 microM, reduced PGE1 by an average of 56%. When the lobes were perfused with plasma, similar concentrations of bromcresol green reduced the uptake by less than 2%. A similar result was obtained with indocyanine green, which at an average initial concentration of 17.5 microM reduced uptake by about 70% when the lobes were perfused with KRB, but when the lobes were perfused with plasma similar concentrations of the dye reduced uptake by less than 3.5%. The results suggest that plasma protein binding interferes with the inhibitory effects of these dyes on PGE1 uptake in the lungs.

Alprostadil↗
PubMed1980

Enterohepatic circulation of l-alpha-acetylmethadol in the rat.

The enterohepatic circulation of the biliary metabolites of l-alpha[3H]acetylmethadol ([3H]LAAM) was studied in rats. Bile was collected for 48 hr from a biliary-cannulated donor rat after s.c. administration of [3H]LAAM. This bile containing tritium-labeled LAAM metabolites was then infused into the small intestine of a recipient rat for 48 hr and the appearance of radioactivity in bile formed in the liver of the recipient rat was monitored. Forty-eight hours after the start of infusion, 40% of the infused radioactivity had been excreted into the bile of the recipient rat, indicating extensive enterohepatic circulation of the biliary metabolites of LAAM. The data indicated that only a small percentage of the infused [3H]LAAM metabolites were present in the systemic circulation at any one time. This was further investigated by comparing the plasma levels of tritium with time and the tissue concentrations at 24 and 48 h after s.c. [3H]LAAM administration in biliary-cannulated and sham-operated control rats. Complete diversion of the bile did not significantly decrease the levels of [3H]LAAM or its metabolites in the systemic pool. These findings tend to minimize the contribution of enterohepatic circulation in the recirculation of active metabolites of LAAM and ultimately in its long duration of opiate-like action.

Animals↗