PubMed Health⌕ Search

Biomedical subjects

M P Murphy

Publications and source records attributed to M P Murphy.

At least 91 records · Page 5Linked to original sources
PubMed1994

Prevention of complement-induced pulmonary hypertension and improvement of right ventricular function by selective thromboxane receptor antagonism.

The effect of complement activation on the pulmonary vascular system and on right ventricular function was studied in sheep (n = 12) by injection of cobra venom factor. Animals were instrumented for measurement of pulmonary flow, mean pulmonary artery pressure, right ventricular stroke work, arterial blood gases, and systemic vascular resistance. Blood was sampled from the left atrium and pulmonary artery to measure thromboxane B2, the metabolite of thromboxane A2, by radioimmunoassay. After baseline measurements, animals were randomly assigned to receive a selective thromboxane receptor antagonist SQ30741 as a 10 mg/kg bolus with an infusion of 10 mg/kg per hour or else to receive vehicle. Cobra venom factor was then injected (30 U/kg) in all animals, and data were recorded at 15, 30, 60, 90, and 120 minutes. In control animals there was a 2.4-fold increase in mean pulmonary artery pressure and a 76% increase in right ventricular stroke work at 15 minutes from baseline (p < 0.05); these values remained elevated for 30 minutes and returned to baseline by 1 hour with no change in systemic vascular resistance. Arterial oxygenation decreased by 124% at 15 minutes and remained depressed through the experiment, but in treated animals oxygen tension remained unchanged from baseline. Thromboxane B2 increased 95% from baseline in the control group and 1.5 fold in treated animals and followed a similar time course as the functional measurements (p < 0.05). A pulmonary vascular thromboxane B2 gradient of approximately 1000 pg/ml was measured at 15 and 30 minutes in both control and treated groups. (p < 0.05) We conclude that after complement activation in this model pulmonary hypertension and decreased oxygen tension are mediated by thromboxane release from the pulmonary vascular bed. This increased afterload causes a stress on the right ventricle as demonstrated by the increased right ventricular stroke work. Selective thromboxane receptor antagonism may be a beneficial therapy for pulmonary hypertension in patients after cardiopulmonary bypass.

Animals↗
PubMed1993

Prevention of CD18-mediated reperfusion injury enhances the efficacy of UW solution for 15-hr heart preservation.

University of Wisconsin solution (UW) has been demonstrated to improve donor heart preservation. During reperfusion, however, myocardial performance may still remain limited by neutrophil (PMN)-mediated injury, manifested by the "low-reflow" phenomenon and myocardial "stunning." Since PMN adhesion is an important mechanism of PMN-mediated injury, we tested whether blocking PMN adhesion molecule CD18 would enhance the efficacy of UW for 15-hr heart preservation. Rabbit hearts (n = 15) were arrested with, and preserved for 15 hr in, 4 degrees C UW. After insertion of an left ventricular (LV) balloon, hearts were heterotopically transplanted into recipients pretreated with either intravenous (i.v.) saline (vehicle, n = 8) or i.v. anti-CD18 monoclonal antibody R15.7 (anti-CD18, n = 7). After 1 hr reperfusion the slope of the peak systolic pressure-volume (P-V) relation (Emax), the exponential coefficient (beta), the volume-axis intercept (Vo) of the end-diastolic P-V relation, and the time constant of the exponential LV pressure decay after dP/dt min (tau) were measured. Blood flow was measured with microspheres from which coronary vascular resistance (CVR) was calculated. Tissue %H2O was also measured. Between groups there were no significant differences in Emax (70.5 +/- 6.1 vs 63.7 +/- 6.0 mm Hg/ml, P > 0.05), beta (3.3 +/- 0.5 vs 4.3 +/- 0.5, P > 0.05), Vo (-0.4 +/- 0.1 vs -0.4 +/- 0.2 ml, P > 0.05) or %H2O (81.3 +/- 1.1 vs 80.0 +/- 0.9, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1993

The effect of L-deprenyl on behavior, cognitive function, and biogenic amines in the dog.

Behavioral and pharmacological effects of oral administration of L-deprenyl in the dog are described. Spontaneous behavior is unaffected at doses below 3 mg/kg while at higher doses there was stereotypical responding. There was evidence of improved cognitive function in animals chronically treated with a 1 mg/kg dose but the effectiveness varied considerably between subjects. Chronic administration produced a dose dependent inhibition in brain, kidney and liver monoamine oxidase B, and had no effect on monoamine oxidase A. There were also dose dependent increases in brain phenylethylamine and in plasma levels of amphetamine. Dog platelets did not have significant levels of MAO-B. Brain dopamine and serotonin metabolism were unaffected by L-deprenyl at doses up to 1 mg/kg. It appears that for the dog, deamination of catecholamines is controlled by MAO-A. Nevertheless, it is suggested that L-deprenyl serves as a dopaminergic agonist, and there is also evidence that it affects adrenergic transmission. These catecholaminergic actions may account for the effects of L-deprenyl on behavior and cognitive function.

Administration, Oral↗
PubMed1993

Monoamine oxidase inhibition by L-deprenyl depends on both sex and route of administration in the rat.

The monoamine oxidase B (MAO-B) inhibitor L-deprenyl, widely used to treat Parkinson's disease, has frequently been studied in animal models. We have examined the effects of several variables on activity levels of MAO-A and B in rat brain and liver following chronic (3 wks) treatment with L-deprenyl. Significant effects were observed for sex (females showed lower overall MAO-B activity in the liver), dose (MAO-A and B inhibition increased with dose, with females exhibiting greater sensitivity), route of administration (subcutaneous injection was more efficient than oral dosing), and dosing interval (MAO-B was significantly inhibited when dosing interval was increased to as long as 168 hours). Our results thus indicate that the effectiveness of L-deprenyl in vivo is dependent on several factors and that these must be taken into account in studies involving the benefits or risks of this drug.

Administration, Oral↗
PubMed1993

Use of an electrode selective for 1-methyl-4-phenylpyridinium (MPP+) to measure its uptake and accumulation by mitochondria.

An ion-selective electrode specific for the 1-methyl-4-phenylpyridinium ion (MPP+) was developed which allowed the measurement of the initial rate of uptake and the extent of accumulation of MPP+ by rat liver mitochondria. Using this electrode we demonstrated that the initial rate of uptake of MPP+ was not saturable and that the distribution of MPP+ across the mitochondrial inner membrane did not equilibrate with the membrane potential, in contrast to other lipophilic cations such as the methyltriphenyl phosphonium ion (TPMP+). Furthermore, incubation of mitochondria respiring on succinate with MPP+ decreases the membrane potential. The possibility that the interaction of MPP+ with mitochondria may be more complex than accumulation followed by inhibition of site 1, suggested by these and other data, is discussed.

1-Methyl-4-phenylpyridinium↗
PubMed1992

Uptake and accumulation of 1-methyl-4-phenylpyridinium by rat liver mitochondria measured using an ion-selective electrode.

The compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes selective destruction of nigrostriatal dopaminergic neurons in primates, giving rise to a condition resembling Parkinson's disease. The toxicity of MPTP is believed to be due to its metabolite 1-methyl-4-phenylpyridinium (MPP+). MPP+ is an inhibitor of mitochondrial respiration at the NADH-ubiquinone oxidoreductase site and this, together with its selective transport into dopaminergic nerve terminals, accounts for its neurotoxicity. In this paper an electrode selective for MPP+ was developed and used to measure the rate of uptake and the steady-state accumulation of MPP+ in rat liver mitochondria. The initial rates of MPP+ uptake were not saturable, confirming previous work that the transport of MPP+ is not carrier-mediated. The membrane potential of mitochondria respiring on succinate was decreased by MPP+ and the steady-state accumulation ratio of MPP+ did not come to equilibrium with the mitochondrial transmembrane potential gradient (delta psi). The effect of the cation exchanger tetraphenylboron (5 microM) was to increase the initial rate of MPP+ uptake by about 20-fold and the steady-state accumulation by about 2-fold. This suggests that there may be a mechanism of efflux of MPP+ from mitochondria which allows MPP+ to cycle across the membrane and thus decrease delta psi. These data indicate that MPP+ interacts with mitochondria independently of its inhibition of NADH-ubiquinone oxidoreductase, and these alternative interactions may be of relevance for its mechanism of neurotoxicity.

1-Methyl-4-phenylpyridinium↗
PubMed1992

Effects of chronic ethanol feeding on rat liver mitochondrial energy metabolism.

Chronic alcohol consumption is known to decrease hepatic mitochondrial respiration rate. It was shown here that the proton leak through the mitochondrial inner membrane was unaffected by chronic ethanol treatment. This indicates that changes in proton leak are not responsible for the alterations in respiration found in mitochondria isolated from ethanol-treated rats. Therefore, the lowered coupled respiration rate is solely due to a decrease in the activity of the electron transport chain. However, this alteration was only evident in coupled respiration (i.e. state 4) and was not apparent in uncoupled respiration. Thus, chronic ethanol treatment decreases the activity of the mitochondrial electron transport chain components which have control over coupled, but not uncoupled, respiration. Mitochondrial energy metabolism is regulated by thyroid hormone status. It was shown that the chronic alcohol treatment did not affect the circulating levels of thyroxine. Furthermore, the activity of mitochondrial alpha-glycerophosphate dehydrogenase, which is strongly affected by thyroid hormones, was unaltered by alcohol treatment. Thus, the effects of ethanol treatment on mitochondria occur independently of changes in circulating thyroid hormone levels.

Animals↗
PubMed1992

Interaction of butylated hydroxyanisole with mitochondrial oxidative phosphorylation.

The antioxidant, butylated hydroxyanisole (BHA), has a number of effects on mitochondrial oxidative phosphorylation. In this study we apply the novel approach developed by Brand (Brand MD, Biochim Biophys Acta 1018: 128-133, 1990) to investigate the site of action of BHA on oxidative phosphorylation in rat liver mitochondria. Using this approach we show that BHA increases the proton leak through the mitochondrial inner membrane and that it also inhibits the delta p (proton motive force across the mitochondrial inner membrane) generating system, but has no effect on the phosphorylation system. This demonstrates that compounds having pleiotypic effects on mitochondrial oxidative phosphorylation in vitro can be analysed and their many effects distinguished. This approach is of general use in analysing many other compounds of pharmacological interest which interact with mitochondria. The implications of these results for the mechanism of interaction of BHA with mitochondrial oxidative phosphorylation are discussed.

Adenosine Triphosphate↗
PubMed1992

Studies on the rapid stimulation of mitochondrial respiration by thyroid hormones.

Injection of L-3,5-diiodothyronine (T2) into rats made hypothyroid by 6-n-propyl-2-thiouracil (PTU) increased the respiration rates of subsequently isolated liver mitochondria; this stimulation of respiration by T2 occurred in the presence of cycloheximide and is therefore independent of protein synthesis on cytoplasmic ribosomes. Injection of T3 into PTU-treated rats had a lesser effect than T2 on the respiration rates of subsequently isolated mitochondria; as PTU is an inhibitor of 5'-iodothyronine deiodinases, which convert T3 into T2 in vivo, the rapid stimulation of mitochondrial respiration by T3, which has been shown in a range of systems, may not be due directly to T3 itself, but may be mediated by its deiodination product T2. Injection of T2, or T3, into hypothyroid or euthyroid rats had no effect on the percentage activity of mitochondrial pyruvate hydrogenase assayed 30 min later. The amount of active pyruvate dehydrogenase is regulated by changes in mitochondrial calcium concentration and matrix ATP/ADP ratio; therefore these parameters are not persistently affected by treatment with T3 or T2. In addition, the total amount of pyruvate dehydrogenase present was the same in euthyroid and hypothyroid rats, indicating that the expression of this enzyme is not stringently controlled by thyroid hormone status.

Adenosine Diphosphate↗
PubMed1992

The effects of the peripheral-type benzodiazepine acceptor ligands, Ro 5-4864 and PK 11195, on mitochondrial respiration.

The role of the peripheral-type benzodiazepine acceptor is unclear. It has been suggested that the acceptor ligands, Ro 5-4864 and PK 11195, stimulate mitochondrial respiration by binding to the peripheral-type benzodiazepine acceptor. We determined the effect of the benzodiazepine Ro 5-4864 and of the isoquinoline carboxamide PK 11195 on the respiration rates of liver, kidney and adrenal mitochondria during coupled, uncoupled and phosphorylating respiration. These ligands inhibited uncoupled and phosphorylating respiration, but only at concentrations substantially greater than their KD values for binding to the acceptor. There was a slight stimulation of coupled respiration by these ligands at concentrations similar to their KD values for the acceptor, but this stimulation was markedly greater at higher concentrations. These results suggest that the ligands Ro 5-4864 and PK 11195 affect respiration in a non-specific way, independently of binding to the acceptor. There was no correlation between the effect of these ligands on respiration and the density of the acceptor in mitochondria from liver, kidney and adrenals. We suggest that the earlier reported alteration of respiration by these ligands was due to non-specific effects and was not mediated by the peripheral-type benzodiazepine acceptor.

Adrenal Glands↗
PubMed1992

Complete prevention of myocardial stunning, contracture, low-reflow, and edema after heart transplantation by blocking neutrophil adhesion molecules during reperfusion.

This study tested the hypothesis that preventing neutrophil adhesion during reperfusion, by blocking either the neutrophil membrane CD18 integrin complex or its endothelial and myocyte ligand, intercellular adhesion molecule-1 (ICAM-1), would reduce myocardial inflammation and edema and improve reflow and ventricular function after heart preservation and transplantation. After cardioplegia and insertion of a left ventricular balloon, rabbit hearts were heterotopically transplanted into recipient rabbits either immediately (immediate, n = 12) or after preservation in 4 degrees C saline (3 hours of ischemia, n = 33). Forty-five minutes before reperfusion, recipients of preserved hearts received intravenous infusions of either saline (vehicle, n = 13), anti-CD18 monoclonal antibody (Mab) R15.7 (2 mg/kg) (anti-CD18, n = 10), or anti-ICAM-1 Mab R1.1 (2 mg/kg) (anti-ICAM, n = 10). During 3 hours of reperfusion the slope of the peak-systolic pressure-volume relation and its volume-axis intercept, the exponential elastic coefficient of the end-diastolic pressure-volume relation, the unstressed ventricular volume, and the time constant of the exponential left ventricular pressure decay after dP/dtmin were serially measured. Myocardial blood flow was measured with microspheres from which coronary vascular resistance was calculated. After explanation, the degree of myocardial inflammation, estimated by tissue neutrophil sequestration (myeloperoxidase assay) and myocardial water content were determined. Within each group no significant differences in measurements made at 1, 2, and 3 hours of reperfusion were noted. Compared with the immediate transplantation group, the vehicle group demonstrated a significant increase in myeloperoxidase activity (3380 +/- 456 versus 1712 +/- 552 microU/gm, p < 0.05), coronary vascular resistance (115.5 +/- 13.4 versus 70.5 +/- 10.6 U/gm, p < 0.05), and myocardial water content (79.8% +/- 0.4% versus 75.6% +/- 1.3%, p < 0.05), a significant decrease in unstressed ventricular volume (a leftward shift in the end-diastolic pressure-volume relation) (-0.49 +/- 0.24 versus 0.28 +/- 0.21 ml, p < 0.05), and a marked prolongation in exponential left ventricular pressure delay after dP/dtmin (156.64 +/- 3.81 versus 37.25 +/- 3.34 msec, p < 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

Abdomen↗
PubMed1992

Calcium uptake by liver mitochondria from hypothyroid rats is inhibited in vitro by triiodothyronine.

The rate of Ca2+ uptake by liver mitochondria from hypothyroid and euthyroid rats was determined as a function of the mitochondrial membrane potential (delta psi). At large values of delta psi Ca2+ uptake was a linear function of delta psi and its dependence on delta psi was the same in mitochondria from euthyroid and hypothyroid rats. However, at small values of delta psi the rates of Ca2+ uptake for mitochondria from euthyroid or hypothyroid rats deviated slightly from each other. Triiodothyronine (T3), at a concentration of 10 nM, inhibited the rate of Ca2+ uptake in vitro, suggesting that T3 in vivo may regulate mitochondrial Ca2+ transport and thus alter the matrix free Ca2+ concentration, which has control over respiration.

Animals↗
PubMed1991

The interaction of antioxidants and structurally related compounds with mitochondrial oxidative phosphorylation.

The antioxidants, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), interact with mitochondrial oxidative phosphorylation in two ways. They uncouple phosphorylation from oxidation by making the mitochondrial inner membrane more permeable to protons. They also inhibit respiration by a direct interaction with the electron transport chain. Here we separated out these two properties of BHA and BHT by determining their effects on respiration in coupled and uncoupled mitochondria. Similar experiments were carried out with compounds structurally related to BHA and BHT. Most of these compounds had uncoupling and inhibitory properties essentially similar to BHA and BHT. In contrast, the dimer of BHA had no inhibitory effects on uncoupled respiration and little uncoupling activity. The implications of these results for the interactions of BHA and BHT with mitochondrial oxidative phosphorylation and the design of antioxidants are discussed.

Animals↗
PubMed1989

Slip and leak in mitochondrial oxidative phosphorylation.

During oxidative phosphorylation by mammalian mitochondria part of the free energy stored in reduced substrates is dissipated and energy is released as heat. Here I review the mechanisms and the physiological significance of this phenomenon.

Adenosine Triphosphate↗