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Biomedical subjects

R A Rhoades

Publications and source records attributed to R A Rhoades.

At least 19 recordsLinked to original sources
PubMed1992

Pulmonary arterial hypoxic contraction: signal transduction.

The response of isolated rat pulmonary arteries to acute hypoxia has previously been reported to be biphasic, consisting of an initial rapid contraction of short duration, followed by partial relaxation (phase 1) and then a second slowly developed but sustained contraction (phase 2). The purpose of this study was to determine the following: 1) whether products from the endothelium might be required, 2) whether extra- and/or intracellular calcium or protein kinase C might be second messengers in mediating the pulmonary arterial hypoxic contraction, and 3) whether or not guanosine 3',5'-cyclic monophosphate (cGMP), endothelium-derived relaxing factor (EDRF), prostaglandin I2 (PGI2) or A2 adenosine receptor activation is involved in phase 1 relaxation. Neither Ca(2+)-free media nor verapamil (a Ca2+ channel blocker) altered the phase 1 contraction, but the phase 2 contraction was abolished by either of these treatments. Ryanodine (a sarcoplasmic reticulum Ca2+ depleter) had no effect on phase 1 contraction. H-7 (a PKC inhibitor) inhibited the phase 2 contraction, whereas it had no effect on phase 1 contraction. Removal of the endothelium abolished phase 1 contraction in either Ca(2+)-free media or normal Ca2+ media but did not alter phase 2 contraction or phase 1 relaxation. Neither methylene blue (guanylate cyclase inhibitor), N omega-nitro-L-arginine, (EDRF blocker), acetylsalicylic acid (cyclooxygenase inhibitor), xanthine amino congener (adenosine receptor blocker), nor glybenclamide blocked the phase 1 relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1992

Evans blue dye as a marker of albumin clearance in cultured endothelial monolayer and isolated lung.

Determination of protein transfer across the endothelial barrier or the entire alveolar capillary membrane is critical for investigation of mechanisms leading to pulmonary edema. The purpose of this study was to evaluate Evans blue dye for determination of protein clearance across cultured bovine pulmonary artery endothelial cell monolayers and as a quantitative marker for albumin leakage to the air spaces in isolated perfused rat lungs. Evans blue dye bound tightly to albumin (EBA) as determined by lack of transfer through dialysis membranes and specific elution with albumin from a molecular exclusion column. EBA was equivalent to 125I-labeled albumin for calculation of albumin clearance rates (Calb) across intact and challenged monolayers [Calb (+ vehicle) = 0.12 microliters/min; Calb (+10 nM alpha-thrombin) = 0.47 microliters/min; Calb (+5 mg/ml trypsin) = 1.29 microliters/min]. Transfer of EBA was linear with time in both the endothelial cell monolayer model and the perfused lung. EBA was a sensitive marker for early edema in the perfused lung (before detectable weight gain) as well as for severe edema in the oxidant-injured lung (marked EBA accumulation in lavage fluid) and was a more specific marker for protein transfer than lavage fluid protein. EBA transfer is a convenient, reproducible, and accurate means to assess alterations in vascular permeability.

Albumins↗
PubMed1992

Activated neutrophils alter contractile properties of the pulmonary artery.

Activated neutrophils produce a wide array of products (free radicals, arachidonate metabolites, degradative enzymes), cause hemodynamic effects and increased permeability in isolated blood-free perfused lungs, and evoke direct injury to cultured endothelial cells. The aims of this study were to investigate the response of isolated rat pulmonary arterial rings to activated neutrophils, the role of intact endothelium in these responses, and which neutrophil products were responsible for the observed effects. Neutrophils activated with phorbol myristate acetate caused an initial increase in tension and a subsequent decreased recovery contraction to KCl. Neutrophils activated with formylmethionylleucylphenylalanine also caused an increase in tension but did not result in decreased recovery, suggesting different mechanisms for these two effects. The contractile response was dependent on endothelium, whereas the decline in recovery still occurred in the absence of endothelium. Filtrate from activated neutrophils did not cause the contractile response, but recovery was decreased. Neither addition of catalase + superoxide dismutase nor decreased superoxide release due to prior activation of neutrophils altered the initial contraction or the decline in recovery contractile ability, suggesting that oxygen free radical products were not responsible for either effect. The cyclooxygenase inhibitors (ibuprofen and indomethacin), the thromboxane A2 synthetase inhibitor (OKY-046), and pretreatment of the neutrophils with aspirin inhibited the contractile response but did not prevent the decrease in recovery. A mixture of antiproteases did not protect the arterial muscle from the decline in recovery. Although cyclooxygenase products may be involved in initiating the contraction in response to activated neutrophils, the mechanism resulting in subsequent loss of force-developing ability is unclear.

Animals↗
PubMed1991

Reactive oxygen-mediated contraction in pulmonary arterial smooth muscle: cellular mechanisms.

Reactive oxygen species (at least relatively high doses) cause contraction of pulmonary arterial smooth muscle. The objective of the present study was to elucidate the possible cellular mechanisms involved in reactive oxygen-mediated contraction. Isolated arterial rings from Sprague-Dawley rats were placed in tissue baths containing Earle's balanced salt solution. The maximum active force production (Po) in response to 80 mM KCl was obtained. All other responses were normalized as percentages of Po for comparative purposes. Exposure to reactive oxygen (generated from either the xanthine oxidase reaction (XO) or the glucose oxidase reaction) resulted in pulmonary arterial muscle developing mean active tension of 17.1 +/- 3.0% Po. This contraction was independent of extracellular calcium, since it was not affected by verapamil (a calcium channel blocker) or by placement of the arterial muscle in calcium-free media. Phentolamine (an alpha 1-receptor blocker) and propranolol (a beta-receptor blocker) did not diminish the response to XO. Ryanodine (a SR calcium release inhibitor), while reducing the response to norepinephrine, did not affect the response to XO. However, H-7 (an inhibitor of protein kinase C) decreased the XO-mediated contraction by 49%. These results indicate that while Ca2+ may not be involved as a second messenger, protein kinase C activity appears to play a role in the transduction pathway of reactive oxygen species mediated contraction of pulmonary arterial smooth muscle.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1991

Intracellular pH: effect on pulmonary arterial smooth muscle.

To investigate the effect of changes in intracellular H+ concentration [( H+]i) on pulmonary arterial tone, isolated canine intrapulmonary arteries were exposed to NH4Cl (4-120 mM). Above 4 mM, NH4Cl caused contraction. When induced by less than or equal to 30 mM, contraction was not endothelium dependent and was unaffected by calcium-free medium or by nifedipine (10 microM). Exposure to ryanodine or norepinephrine in calcium-free medium reduced subsequent NH4Cl-induced contraction. Measurements of [H+]i and tension indicated that contraction induced by 30 mM NH4Cl occurred simultaneously with development of peak intracellular alkalosis (delta [H+]i = -47 +/- 9 nM, n = 7). Withdrawal of NH4Cl produced a rapid cytosolic acidification (delta [H+]i = + 131 +/- 29 nM, n = 7), which coincided with a transient nifedipine-sensitive contraction. In the isolated perfused rat lung, addition and removal of NH4Cl similarly increased pulmonary arterial pressure. These data suggest that intracellular alkalosis stimulates pulmonary arterial smooth muscle contraction directly and through release of calcium from intracellular sites. Intracellular acidification appears to stimulate transient contraction by allowing calcium entry from extracellular sources through voltage-activated channels. We conclude that modifications in intracellular pH effect pulmonary arterial smooth muscle tone and consequently can alter blood flow through the lung.

Ammonium Chloride↗
PubMed1991

Biphasic contractile response of pulmonary artery to hypoxia.

Isolated perfused lungs exposed to low O2 exhibit a hypoxic pulmonary vasoconstriction response that is transient in nature. The purpose of this study was to determine whether the isolated pulmonary artery behaves similarly in response to hypoxia. Rat pulmonary arterial rings were placed in tissue baths (37 degrees C, air-5% CO2, pH = 7.4) and attached to force transducers. Maximum contractile responses (Po) to high K+ were elicited. After washout, arterial rings were submaximally contracted and made hypoxic (PO2 = 33.7 +/- 1.3, pH = 7.38 +/- 0.01). Aortic rings were used to obtain comparative data. The isolated pulmonary arterial hypoxic response was biphasic, displaying an initial rapid contraction of short duration (phase 1) then, before complete relaxation of this first response, a second slow but sustained contraction occurred (phase 2). Aortic rings did not exhibit a biphasic response, but showed only an initial short contraction followed by complete relaxation. The contractile response of the pulmonary artery was diminished when the endothelium was rendered nonfunctional. However, the phase 2 response was not endothelium dependent. Neither inhibitors of the lipoxygenase or cyclooxygenase pathways nor scavengers of extracellular reactive oxygen species had any effect on the biphasic hypoxic response. Pulmonary arterial hypoxic contractions were blunted when glucose was absent and appear to be dependent on glycolytic ATP. Results of this study show that hypoxia causes a biphasic contractile response of pulmonary arterial muscle and that two different mechanisms appear to be involved, since the transient phase 1 response is endothelium dependent, whereas the sustained contraction of phase 2 is endothelium independent.

Animals↗
PubMed1990

Reactive oxygen species alter contractile properties of pulmonary arterial smooth muscle.

Reactive oxygen species alter pulmonary arterial vascular tone and cause changes in pulmonary vascular resistance. The objective of this investigation was to determine direct effects of oxygen radicals on the contractile properties of pulmonary arterial smooth muscle. Isolated pulmonary arterial rings from Sprague-Dawley rats were placed in tissue baths containing Earle's balanced salt solution (gassed with 95% O2 - 5% CO2, 37 degrees C, pH 7.4). Vessels were contracted with 80 mM KCl to establish maximum active force production (Po). All other responses were normalized as percentages of Po for comparative purposes. Reactive oxygen metabolites were generated enzymatically with either the xanthine oxidase (XO) reaction or the glucose oxidase (GO) reaction, or hydrogen peroxide (H2O2) was added directly to the muscle bath. Exposure to XO, GO, or to H2O2 resulted in a contractile response that was sustained during the 30-min exposure period. The muscle fully relaxed following removal of the reactive oxygen species. Resting tension remained unchanged throughout the experimental period, suggesting no functional change in membrane potential. The contractile response was dose dependent and was not prevented by either cyclooxygenase or lipoxygenase inhibition, or by removal of the endothelium. Pretreatment of vessels with superoxide dismutase (SOD) partially blocked the XO-induced contraction, while mannitol or deferoxamine had no effect on the response to XO. However, pretreatment with catalase (CAT) completely blocked the XO-induced contraction. These data suggest that superoxide ions and hydrogen peroxide are the major causative agents. Following O2-radical exposure, vessels showed a decrease in contractile responsiveness to 80 mM KCl (recovery response), suggesting damage to the smooth muscle cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Break it off. Identifying a destructive love relationship.

1. Destructive love is an active process of destroying the affection and tenderness between two people. 2. If people are unable to distinguish the difference between an argument that was formulated to clear up a misunderstanding from an argument that is destructive, they will be unable to function properly. 3. Five basic therapeutic elements needed for recovery are: a willingness to seek help; a move toward a more realistic form of thinking; spirituality in one's personal and professional life; a circle of friends who support emotional honesty; and a personal appreciation of one's own values instead of the values of a past partner.

Dependency, Psychological↗
PubMed1989

Substrate utilization in the perinatal lung.

Lung cellular metabolism is fundamental to both respiratory and nonrespiratory function. The lung has very little energy reserve and is highly dependent on circulating substrates. The pattern of substrate utilization is determined primarily substrate availability, competition between certain substrates, and the ability of lung cells for uptake and metabolism. The lung uses a number of substrates (glucose, lactate, fatty acids, choline, ketone bodies, and amino acids) as basic building blocks for synthesis, as energy-providing fuels, to provide NADPH for lipid biosynthesis, and for glutathione production. Since the availability of substrates, the cellular profile, the hormonal environment, and the physiological state of the lung are drastically altered during perinatal lung development, this review focuses on current knowledge of lung substrate utilization during this critical period. Because development of the surfactant system has been specifically linked to infant respiratory distress syndrome, the majority of investigations relate to substrate utilization for phospholipid synthesis. It is hoped that this review will outline basic principles for interpretation of information on perinatal substrate utilization, collate available data, and provide a stimulus for future research.

Aging↗
PubMed1989

Role of microvascular pressure in reactive oxygen-induced lung edema.

O2 radicals are important in the pathogenesis of acute lung injury. The purpose of this investigation was to determine the role that microvascular pressure plays in edema induced by reactive O2 species generated by xanthine oxidase. In isolated rat lungs perfused with Krebs buffer plus 4% albumin, 5 mM glucose, and 2 mM xanthine at constant flow (13 ml/min), addition of xanthine oxidase (0.02 U/ml) caused a progressive increase in both pulmonary arterial and microvascular pressure (double occlusion method), which preceded the onset of edema. Both the pressure rise and edema formation were blocked by catalase, suggesting that vascular injury was related to H2O2 production. Lungs not exposed to free radicals that had microvascular pressure elevated to match that of the xanthine oxidase-perfused lungs showed only a small, reversible (nonedematous) weight gain. Lungs exposed to xanthine oxidase but perfused at constant microvascular pressure (5 Torr, similar to control lungs) showed a significant delay in protein-rich edema formation. These data indicate that reactive O2 metabolites induced lung injury, which is accompanied by increased microvascular pressure. Although the rise in microvascular pressure was shown not to be essential for edema formation, it does play a role in acceleration of the rate of transvascular fluid loss.

Animals↗
PubMed1989

The role of activation of neutrophils and microvascular pressure in acute pulmonary edema.

Activated polymorphonuclear neutrophils (PMN) can mediate vascular injury in the lung. This study compared activated aggregate PMN (emboli) to activated PMN that were previously adhered to the microvasculature (non-embolic) in the isolated perfused rat lung. Permeability and microvascular pressure (Pmv), components of PMN-induced edema, were examined by continuous measurement of wet weight, pulmonary arterial and left atrial pressures, and by intermittent determination of double occlusion pressure. PMN that were activated with phorbol myristate acetate and then perfused into the lung formed aggregates that lodged primarily in the precapillary bed, increasing arterial resistance. Although these PMN had minimal direct contact with the capillary endothelium, edema rapidly developed and Pmv was progressively elevated. If PMN were allowed to adhere in the capillary bed, a minimal and nonprogressive increase in Pmv and lung weight occurred. When these adherent PMN were then activated, there was a progressive rise in both Pmv and lung weight. The free radical scavenger catalase prevented this edema formation but not the rise in pressure. In control lungs with matched elevation of Pmv, edema did not develop. In another group of lungs with activation of pre-adherent PMN in which Pmv was maintained at control levels, edema formation was greatly delayed. These data show that: (1) the activated PMN free radical products alone caused permeability injury in the lung because neither contact of the PMN with the capillary endothelium nor embolization was necessary, and (2) increased Pmv does not cause edema but greatly increases the rate of edema formation when the endothelium is injured.

Animals↗
PubMed1978

Selective action of hypoxia on rat lung cyclic AMP.

The effect of three different levels of 24-h hypobaric hypoxia (630 mm Hg, 520 mm Hg, and 340 mm Hg) on rat lung cAMP and cGMP was studied. Liver was also examined to evaluate comparatively with lung. Lung cAMP concentration averaged 33.6 +/- 2.2 (SE) pmol/mg protein, and cGMP averaged 2.4 +/- 0.21 (SE) pmol/mg protein. Twenty-four-hour hypoxia resulted in a significant 40% decrease in lung cAMP at 520 and 340 mm Hg. The magnitude of change was the same for both hypoxic levels suggesting threshold dependency. In contrast, liver cAMP was not affected by the hypoxic exposure. Lung and liver cGMP were also relatively refractory to hypoxia. The decreased cAMP concentration seen in the hypoxic lung returned to normal level within 24 hours. These data show that acute hypoxia has a selective action on lung cAMP.

Animals↗
PubMed1978

Lactate metabolism in perfused rat lung.

Glucose utilization and lactate metabolism were studied in isolated rat lungs perfused with a Krebs-Henseleit bicarbonate buffer, pH 7.4, containing either [U-14C]lactate, [U-14C]glucose, or [U-14C]alanine. Glucose uptake showed an apparent Km of 4.7 mM and a Vmax of 107 mumol-g dry wt-1-h-1. Lactate production under these conditions showed a Vmax of 82.9 mumol-g dry wt-1-h-1. At high circulating lactate level (7 mM), the perfused lung showed an increased capacity to utilize [U-14C]lactate with preferential incorporation into lung lipids. At equal molar concentration (5 mM) [U-14C]lactate was preferentially incorporated over [U-14C]glucose. Addition of 5 mM lactate to the perfusion medium did not affect lactate production. Perfused lungs from fasted rats showed higher lactate production, with increased amounts of [U-14C]alanine converted to lactate by the perfused lung, indicating lactate can also be derived from noncarbohydrate sources. These data show that under aerobic conditions the perfused lung can produce and utilize lactate simultaneously, and lactate can serve as a potential substrate for lung lipids.

Animals↗