American Journal of Physiology-Legacy Content

Published by American Physiological Society

Print ISSN: 0002-9513

Articles


Levels and reduction
  • Article

October 1977

·

62 Reads

This paper addresses the problem of reconciling pluralism with reductionism, i.e., acknowledging both the variety of the world and the need and possibility to explain it. First the various kinds of monism and pluralism that litter the scientific and philosophical literature are examined cursorily. Then certain maligned notions are examined, mainly those of novelty, self-assembly, level, and levels "hierarchy." They are shown to be amenable to analysis and even mathematization. Then the logic of reduction is analyzed. Two kinds of reduction are distinguished: full or straight, and partial or roundabout. And three stands on reduction are examined: anti-, radical, and moderate reductionism. The former is dismissed for being obscurantist and the second for being quixotic. Moderate reductionism, aiming at the (partial) reduction of higher levels to lower ones without skipping any intermediate levels, is adopted. Finally moderate reductionism is found to be consistent with a certain variety of pluralism, characterized as naturalistic.
Share

Heart rate response to hemorrhage-induced 0.05-Hz oscillations in arterial pressure in conscious dogs

May 1991

·

44 Reads

We have previously reported that oscillations at 0.05 Hz can be generated by a simple computer model incorporating a negative-feedback reflex mechanism and an effector mechanism with a time delay. Computer simulations by inhibiting the vagal effector mechanism and activating the adrenergic effector mechanism elicited low-frequency oscillations at a frequency of 0.05 Hz in heart rate. We have observed that the cardiovascular system of the conscious dog, when stressed by the loss of blood, generates oscillations in arterial pressure and heart rate at a frequency of 0.05 Hz. We investigated in six conscious dogs the role of the sympathetic and parasympathetic nervous systems in generating these heart rate oscillations. During baseline conditions, the predominant peak in the arterial pressure and heart rate power spectra was located at the respiratory frequency, while the low-frequency oscillations were small. After a 30-ml/kg hemorrhage or after an 8-, 15-, or 30-ml/kg hemorrhage with glycopyrrolate, a muscarinic-blocking agent, low-frequency oscillations at a frequency of 0.05 Hz predominated, while the respiratory frequency oscillations were negligible. Since respiratory frequency oscillations have been reported to reflect vagal activity, and since the low-frequency oscillations were present after vagal blockade, these hemorrhage-induced low-frequency oscillations in heart rate may be primarily mediated by the cardiac sympathetic nerves. Also cross-correlation analysis between arterial pressure and heart rate showed that a change in arterial pressure caused an opposite change in heart rate with a delay of 2-5 s. We conclude that hemorrhage-induced oscillations in heart rate at 0.05 Hz represent the arterial baroreceptor-beta-sympathetic reflex response to underlying arterial pressure oscillations.

Endogenous nitric oxide buffers blood pressure variability between 0.2 and 0.6 Hz in the conscious rat

February 1997

·

36 Reads

Shear stress is a potent stimulus for the formation and release of nitric oxide (NO). It seems, therefore, possible that a short-term increase in arterial blood pressure (ABP), which leads to a concomitant rise in endothelial shear stress, enhances NO release. The latter elicits a relaxation of vascular smooth muscle cells that, in turn, counteracts the initial rise in blood pressure (BP). Thus this chain of events may constitute a negative feedback loop reducing BP variability (BPV). To test this hypothesis, BP-time series were determined via telemetry in freely moving conscious Sprague-Dawley rats. Because it was reported recently that NO effects on ABP are more pronounced in females, the experiments were performed on 2 groups consisting of 10 female and 11 male animals. This was done under control conditions and after fixing NO plasma levels via an intravenous bolus of 15 mg/kg body wt N(G)-nitro-L-arginine methyl ester together with a continuous infusion of nitroprusside (15 ± 0.8 μg/min). This combined infusion maintained mean ABP and heart rate at physiological levels, thus avoiding as much as possible interferences with other reflexes, e.g., the baroreflex. To quantitate BPV, fast Fourier transforms of the BP-time series were determined. The absolute power in the frequency range below 1 Hz increased during fixed NO to ~350% vs. control animals (female control, 2.1 x 109 ± 1.5 x 108 mmHg2 vs. fixed NO, 8.0 x 109 ± 1.3 x 109 mmHg2, P < 0.005; male control, 3.4 x 109 ± 4.6 x 108 mmHg2 vs. fixed NO, 8.3 x 109 ± 2.0 x 109 mmHg2, P < 0.05). This was mainly caused by a substantial rise in the power ranging from 0.2 to 0.6 Hz, which increased roughly fourfold in both females and males. It is concluded that the NO system is a potent buffer of spontaneous BP oscillations in the freely moving rat. This system is most efficient in buffering frequencies within the range of 0.2- 0.6 Hz and shows no gender-specific differences with respect to its BP buffering capacity.

Kinetics of glucose delivery to subcutaneous tissue in rats measured with 0.3-mm amperometric microsensors

August 1995

·

25 Reads

C P Quinn

·

·

·

[...]

·

A Heller
The time between intravenous injection of a glucose bolus and the time the glucose concentration peaked in the subcutaneous tissue was measured in pentobarbital-anesthetized rats with implanted 290-microns-diameter amperometric sensors. Boluses of 100, 200, and 400 mg/kg body wt were injected. The glucose concentration in the jugular vein was monitored by frequent withdrawal and analysis of samples. The glucose concentration in the subcutaneous tissue was continuously monitored with the sensors. The times required for the subcutaneously implanted sensor to reach its maximum current, corrected for sensor response times, were 7.5 +/- 3.9, 9.8 +/- 5.5, and 10.0 +/- 4.4 min for the smallest to the largest dose, respectively. The shorter delay in response to the smallest dose was statistically significant (P < 0.03). The results were consistent with dilution of the bolus in the cardiovascular system and transport of glucose by both diffusion and facilitated transport via a saturable mediator. An understanding of the differences in the dynamics of venous vs. subcutaneous response to a glucose dose is important in developing algorithms for the control of blood glucose based on a subcutaneous measurement.

Sympathetic activity and blood pressure are tightly coupled at 0.4 Hz in conscious rats

December 1994

·

13 Reads

Interactions of sympathetic nerve activity (SNA) with blood pressure (BP) and heart rate (HR) were assessed in conscious rats while they rested quietly in a cloth sock (n = 7), roamed freely in their home cage (n = 6), and then after anesthesia with pentobarbital (30 mg/kg; n = 7). The power and coherence spectra below 3 Hz were calculated from data collected for 9.56 min. In the conscious rat, SNA spectral power peaked at 0.4 Hz, whereas the majority of spectral power for both BP and HR occurred at frequencies lower than 0.4 Hz. However, there was an inconspicuous peak in the BP power spectra at 0.4 Hz that was not seen in the HR spectra. Coherence between SNA and BP peaked at a frequency of approximately 0.4 Hz, the same frequency at which the SNA spectral peaks occurred. In contrast, at frequencies below 0.4 Hz where maximum BP power occurred, the coherence was considerably lower. Anesthesia with pentobarbital lowered spectral power for BP, SNA, and HR but essentially did not change the coherence between SNA and BP. Interactions between respiration and each of the other variables were weak in the conscious rat. However, prominent respiratory interactions at approximately 1.2 Hz were evident after anesthesia. These data indicate a close coupling between SNA and BP at 0.4 Hz, raising the possibility that the BP spectral power at 0.4 Hz reliably reflects sympathetic activity.

First-order differential-delay equation for the baroreflex predicts the 0.4-Hz blood pressure rhythm in rats

January 1998

·

30 Reads

We have described a 0.4-Hz rhythm in renal sympathetic nerve activity (SNA) that is tightly coupled to 0.4-Hz oscillations in blood pressure in the unanesthetized rat. In previous work, the relationship between SNA and fluctuations in mean arterial blood pressure (MAP) was described by a set of two first-order differential equations. We have now modified our earlier model to test the feasibility that the 0.4-Hz rhythm can be explained by the baroreflex without requiring a neural oscillator. In this baroreflex model, a linear feedback term replaces the sympathetic drive to the cardiovascular system. The time delay in the feedback loop is set equal to the time delay on the efferent side, approximately 0.5 s (as determined in the initial model), plus a time delay of 0.2 s on the afferent side for a total time delay of approximately 0.7 s. A stability analysis of this new model yields feedback resonant frequencies close to 0.4 Hz. Because of the time delay in the feedback loop, the proportional gain may not exceed a value on the order of 10 to maintain stability. The addition of a derivative feedback term increases the system's stability for a positive range of derivative gains. We conclude that the known physiological time delay for the sympathetic portion of the baroreflex can account for the observed 0.4-Hz rhythm in rat MAP and that the sensitivity of the baroreceptors to the rate of change in blood pressure, as well as average blood pressure, would enhance the natural stability of the baroreflex.

Effect of maternal glucocorticoid treatment on fetal fluids in sheep at 0.4 gestation

May 1994

·

9 Reads

Treatment of nine pregnant Merino ewes (64.0 +/- 0.4 days of gestation) with dexamethasone (D; 0.76 mg/h for 48 h) resulted in significant alterations in fetal fluids compared with eight saline-infused control animals (S; 63.0 +/- 0.9 days). There was a substantial increase in allantoic fluid volume (177 +/- 18 ml, D vs. 31 +/- 6, S) but no change in amniotic fluid volume (248 +/- 12 ml, D; 305 +/- 24, S). For allantoic fluid there was a significant decrease in osmolality (213 +/- 4 mosmol/kg water, D; 230 +/- 5, S) and alterations in composition. Amniotic fluid osmolality was unchanged (292 +/- 2 mosmol/kg water, D; 293 +/- 1, S), but amniotic fluid composition was affected. In four fetuses in which bladder and amniotic cannulas were inserted at gestational age 68-75 days, fetal urine flow rate increased from a mean of 4.1 +/- 1.1 to 13.8 +/- 2.6 ml/h after 24 h and 11.8 +/- 3.0 ml/h at 48 h for a similar maternal D infusion, whereas no such increase occurred in four control fetuses. All the fetal urine voided during a 3.5- to 4-h infusion of 51Cr-labeled EDTA into the fetal bladder was directed to the allantois. The results suggest that the increase in allantoic fluid volume resulted from increased fetal urine output into the allantoic compartment, although the composition of the excess allantoic fluid differed substantially from that of fetal urine. There was a greater incidence of abnormal cotyledons in the D-infused ewes.(ABSTRACT TRUNCATED AT 250 WORDS)

Incorporation of glucose carbons into rat lung lipids after exposure to 0.6 ppm ozone

June 1985

·

8 Reads

Continuous exposure to low concentrations of ozone has previously been associated with proliferation of lung alveolar type II epithelial cells. In this study, 14C incorporation into tissue lipids was determined in isolated rat lungs by perfusion with [U-14C]glucose, at a time of maximal hyperplasia brought about by 3 days continuous exposure to 0.6 ppm ozone. Ozone exposed lungs exhibited increased rates of glycolytic energy production, indicated by an 89% increase in 3H2O generation on perfusion with [5-3H]glucose, from a control value of 17.5 +/- 2.1 mumol X h-1 X g-1 X dry wt-1 (+/- SE, n = 4). Ozone exposure resulted in enhanced 14C incorporations into glyceride-glycerol and fatty acid moieties of lung lipids of 95 and 180%, respectively, with a greater proportion of label being recovered in shorter chain fatty acids. Although increased labeling was observed in both neutral and phospholipids, the pattern of 14C recovery suggested a relative increased glucose carbon incorporation into lung free fatty acids, phosphatidic acid, and such membrane associated lipids as phosphatidylinositol and those containing sphingosine. These results are consistent with the needs of a dividing cell population for enhanced energy production and synthesis of new lipids.

Responses to acute hypoxemia in fetal sheep at 0.6-0.7 gestation

April 1989

·

12 Reads

A majority of previous studies of fetal responses to acute hypoxemia has focused on the response of the sheep fetus greater than 120 days of gestation when many regulatory systems have been established. To assess the response of younger, less well-developed fetuses, we exposed two groups of fetal sheep (I, 84-91 days; II, 97-99 days gestational age) to acute hypoxemia by giving the ewe a gas mixture containing 9% O2 to breathe. We decreased descending aortic PO2 in both groups of fetuses [I, 24 +/- 6 to 14 +/- 3 (SD) Torr; II, 23 +/- 3 to 12 +/- 4 Torr] by a degree similar to that achieved in previous studies of fetuses greater than 120 days of gestation. Mean arterial blood pressure (I, 31 +/- 6; II, 40 +/- 3 Torr) did not change significantly from control values, and heart rate (I, 224 +/- 27; II, 203 +/- 16 beats/min) increased significantly in group II fetuses with hypoxemia. In group I and II fetuses, as in older fetuses, cerebral, myocardial, and adrenal blood flows, measured by the microsphere technique, increased, and pulmonary blood flow decreased. These responses mature early and are likely local vascular responses to decreases in oxygen content. Combined ventricular output and umbilical-placental blood flow decreased significantly in both groups. Unlike the response of the fetus greater than 120 days, acute hypoxemia did not decrease blood flow to the musculoskeletal and cutaneous circulations (group I only), gastrointestinal, or renal circulations.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebrovascular reactivity to adenosine analogues in 0.6-0.7 gestation and near-term fetal sheep

June 1992

·

10 Reads

During acute hypoxia, fetal sheep less than 0.7 gestation increase cerebral blood flow (CBF) relatively less than fetal sheep near term. We hypothesized that cerebrovascular reactivity to a hypoxic vasodilator metabolite such as adenosine might be diminished in immature fetuses. This study examined cerebral vasoreactivity to adenosine analogues in nine sheep fetuses less than 0.7 gestation (90-103 days) and nine near term (129-143 days). Fetuses were equipped in utero with a closed cranial window, and pial arterioles were studied by intravital microscopy. 5'-(N-ethylcarboxamido)-adenosine (NECA; 10(-9)-10(-5) M) and N6-cyclopentyladenosine (CPA; 10(-9)-10(-4) M) each caused a dose-dependent increase in arteriolar diameter that was attenuated in the presence of the adenosine receptor antagonist 8-phenyltheophylline (8-PT; 5 x 10(-6) M). Dose-response curves to the agonists were similar for both age groups. NECA was a more potent vasodilator than CPA, in keeping with their affinity for the A2 receptor. Suffusion of 8-PT alone at less than 10(-5) M had no effect on arteriolar diameter. We conclude that adenosine is able to dilate fetal cerebral arterioles as young as 0.6 gestation by acting at an A2 receptor, although resting tone is not influenced by adenosine. The immature fetal sheep CBF response to hypoxia is not attributable to undeveloped vasoreactivity to adenosine.

Rat lung metabolism after 3 days of continuous exposure to 0.6 ppm ozone

March 1986

·

11 Reads

Continuous exposure of rats to low concentrations of ozone has previously been associated with enhanced metabolic enzyme activities, when measured in lung homogenates. In this study, metabolic rates were measured in intact perfused lungs with altered pathology brought about by 3 days continuous exposure to 0.6 ppm ozone. Increased metabolism of ozone-exposed lungs was indicated by a twofold enhancement in glucose utilization, associated with a 62% increase in lactate formation and a 166% increase in the rate of 14CO2 production from D-[U-14C]glucose from control values of 5.2 +/- 0.5 mumol lactate and 4.4 +/- 0.6 mumol 14CO2/h per lung (+/- SE, n = 4), respectively. Mitochondrial metabolism was separately assessed by measurements of 14CO2 production from [U-14C]-pyruvate, which was found not to be significantly altered by ozone exposure, although homogenate oxygen uptake in the presence of succinate was significantly enhanced by 57%. These changes in intermediary metabolism could be correlated with increased glucose carbon incorporation into lipid and elevated activity of glucose-6-phosphate dehydrogenase. The observed elevated metabolic rates were consistent with the energy and synthetic needs of a lung during repair of ozone-induced damage.

Effect of graded umbilical cord compression in fetal sheep at 0.6-0.7 gestation

November 1991

·

4 Reads

To define responses of immature fetuses to asphyxia, we occluded the umbilical cord of 11 chronically instrumented fetal sheep at 82-94 days gestation and measured hemodynamic and catecholamine responses. The fetuses became acidemic, hypoxemic, and hypercarbic: arterial pH and PO2 decreased from 7.36 +/- 0.04 and 22 +/- 3 Torr to 7.10 +/- 0.04 (mean +/- SD, P less than 0.01) and 15 +/- 4 Torr (P less than 0.01), respectively, and PCO2 increased from 56 +/- 5 to 86 +/- 8 Torr (P less than 0.01) when umbilical blood flow was reduced by 75-88%. This degree of reduction in umbilical blood flow decreased cardiac output from 606 +/- 101 to 247 +/- 67 ml.min-1.kg-1 (P less than 0.01) and blood flow to hepatic, renal, musculoskeletal, and pulmonary vascular beds. Plasma norepinephrine concentrations increased from 1,557 +/- 975 to 16,718 +/- 14,672 pg/ml (P less than 0.05) with a 75-88% reduction, but mean arterial blood pressure did not increase. The absence of a hypertensive response probably relates to the decrease in cardiac output. These data indicate that asphyxia severely compromises cardiac output and organ perfusion in the midgestation fetus.


Dexamethasone increases Gα(q-11) expression and hormone stimulated phospholipase c activity in UMR-106-01 cells

September 1997

·

11 Reads

Glucocorticoids regulate responsiveness of many cells to hormones that bind to G protein-coupled receptors. We examined the effect of glucocorticoids on parathyroid hormone (PTH) activation of two G protein-activated signal transduction pathways, phospholipase C (PLC) and adenylyl cyclase, in osteosarcoma UMR-106-01 cells. Dexamethasone (100 nM) increased PTH-stimulated and NaF-stimulated PLC activity by > 100% over 4 days (223 +/- 8 and 293 +/- 8.2% of control after 4 days for PTH and NaF-stimulated activity, respectively). The increase in PTH-stimulated adenylyl cyclase response in the same cells was more modest (162 +/- 5.4 and 171 +/- 6.8% of control after 4 days for PTH and NaF-stimulated activity, respectively). PTH activation of PLC was blocked by antiserums to G alpha q-11 and activation of adenylyl cyclase by G alpha s antiserums. Quantification of these G protein subunits in control and dexamethasone-treated cells showed a 78% increase in G alpha q-11 (from 18.1 +/- 1.2 to 32.2 +/- 1.5 pmol/mg), whereas G alpha s was increased only 34% (from 6.2 +/- 0.5 to 8.2 +/- 0.3 pmol/mg) and G beta-subunits were increased 40% (from 54 +/- 2.3 to 75.2 +/- 3.8 pmol/mg). These results suggest that glucocorticoids are more potent regulators of PLC activity than adenylyl cyclase activity in UMR cells, and this is mediated, at least in part, by differential increases in G alpha q-11 proteins.

Regulation of cell volume by the osteosarcoma cell line UMR-106-01

October 1991

·

5 Reads

Determination of cell volume by an electronic cell-sizing technique was used to study the role of ion transporters in cell volume regulation by the osteosarcoma cell line UMR-106-01. Swelling the cells in hypotonic medium was followed by regulatory volume decrease (RVD). The rate of RVD was strongly dependent on the subpassage used and increased with increasing subpassages. Swelling-evoked changes in cytosolic free Ca2+ ([Ca2+]i) did not account for this behavior, since it was similar in cells from all subpassages. Increasing plasma membrane K+ permeability with valinomycin resulted in a similar rate of RVD in cells from different subpassages, suggesting increased K+ channel activity or other electrogenic transporter with increased subpassages. In contrast, the mechanisms responsible for regulatory volume increase (RVI) were fully active in cells from all subpassages. Increasing medium osmolarity of cells bathed in isotonic medium induced slow and incomplete RVI. In addition, shrinking cells exposed to hypotonic medium before completion of RVD resulted in impaired RVI. Effective RVI could be observed only after completion of RVD of cells exposed to hypotonic medium. Removal of extracellular Na+ or K+ completely blocked RVI, whereas removal of external Cl- partially blocked RVI. The effect of K+ removal probably reflects in part inhibition of Na-K-2Cl cotransport and in part inhibition of the Na+ pump.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin-like growth factor I stimulates sodium-phosphate cotransport in the rat osteoblastic cell line UMR-106-01

May 1992

·

9 Reads

The effect of recombinant insulin-like growth factor I (IGF-I) on Pi uptake by a rat osteoblast-like cell line (UMR-106-01) in culture was investigated. IGF-I (10(-6)-10(-8) M) caused a dose-related stimulation of Na(+)-Pi cotransport. A 30-70% increase in Na(+)-dependent Pi uptake over control values was observed after 1- to 5-h exposure of these cells to 10(-7) M IGF-I. The increase was detected within 45 min, in contrast to the slower action of insulin. This effect of IGF-I was specific for Na(+)-Pi uptake, because Na(+)-independent Pi uptake and Na(+)-alanine cotransport were unaffected by IGF-I. A reversal of IGF-I induced stimulation of Na(+)-Pi cotransport was observed within 1 h of removal of the hormone. Kinetic analysis of the IGF-I effect indicates a significant change only in the apparent maximum velocity (Vmax) of Na(+)-Pi cotransport. The Vmax was 5.22 +/- 0.47 vs. 3.33 +/- 0.45 nmol Pi.mg protein-1.10 min-1 in confluent monolayers exposed to 10(-7) M IGF-I and vehicle alone, respectively, for 3 h (P less than 0.05, group t test). Blocking de novo protein synthesis with cycloheximide had no effect on this stimulatory effect of IGF-I. These observations indicate that IGF-I specifically stimulates Pi uptake in osteoblastic cells. The effect is characterized by an increase in Vmax and is not dependent on de novo protein synthesis. The mechanism remains to be determined.

Beneficial actions of CP-0127, a novel bradykinin receptor antagonist, in murine traumatic shock

March 1994

·

14 Reads

We studied the effects of CP-0127, a novel bradykinin receptor antagonist, in a rat model of traumatic shock. Pentobarbital-anesthetized rats subjected to Noble-Collip drum trauma developed a shock state characterized by marked hypotension, significant increases in plasma-free amino-nitrogen (8.6 +/- 0.97 vs. 2.3 +/- 0.15 U/ml in control rats) and intestinal myeloperoxidase (MPO) activity (2.7 +/- 0.33 vs. 0.08 +/- 0.03 U/100 mg control rats, intestinal tissue), and a survival time of only 110 +/- 9 min. Moreover, superior mesenteric artery (SMA) rings isolated from rats subjected to traumatic shock relaxed to the endothelium-dependent vasodilator acetylcholine (ACh) significantly less than rings isolated from control rats (21 +/- 4 vs. 92 +/- 4%, P < 0.001). Administration of CP-0127 at a dose of 10 mg/kg subcutaneously completely blocked the hypotensive response to 2.5 micrograms/kg bradykinin injected intravenously in sham traumatic shock rats. CP-0127 given immediately posttrauma prolonged survival time to 219 +/- 27 min (P < 0.01) and attenuated the increases in plasma-free amino-nitrogen (3.7 +/- 0.41 U/ml, P < 0.01) and tissue MPO activities (1.2 +/- 0.71 U/100 mg intestinal tissue, P < 0.05). Furthermore, SMA endothelial function was significantly preserved (relaxation to ACh: 57 +/- 6%, P < 0.01) in CP-0127-treated traumatic shock rats. These results indicate that bradykinin plays an important role in tissue injury associated with traumatic shock and that CP-0127 affords significant protection, which may be achieved through inhibition of neutrophil-endothelial interaction and protection of vascular endothelial function.


Novel recombinant serpin, LEX-032, attenuates myocardial reperfusion injury in cats

March 1996

·

9 Reads

We studied the potential cardioprotective effects of the novel recombinant serine protease inhibitor (serpin), LEX-032, which inhibits the serine proteases elastase and cathepsin G. LEX-032 is a recombinant construct of human alpha 1-antichymotrypsin in which six amino acid residues were replaced around the active center with those of human alpha 1-protease inhibitor. Cats were subjected to 90 min of left anterior descending coronary artery (LAD) occlusion and 270 min of reperfusion (MI/R). Either LEX-032 or its vehicle (i.e., phosphate-buffered saline) was administered intravenously 10 min before reperfusion. Control cats were subjected to sham MI/R. Cats treated with LEX-032 demonstrated a marked reduction in cardiac necrosis after MI/R compared with cats receiving only vehicle (10 +/- 3 vs. 31 +/- 3%, P < 0.01). In addition, relaxation of LAD rings to the endothelium-dependent dilators (e.g., acetylcholine and A23187) was greater in the LEX-032-treated group than in cats receiving vehicle (72 +/- 5 vs. 52 +/- 7%, P < 0.05, and 74 +/- 8 vs. 50 +/- 8%, P < 0.05, respectively), indicating that endothelial function was preserved by LEX-032. Moreover, LEX-032 administration resulted in a marked reduction of polymorphonuclear leukocyte (PMN) adherence to ex vivo coronary vascular endothelium compared with vehicle (33 +/- 4 vs. 86 +/- 7 PMNs/mm2, P < 0.01). These data indicate that LEX-032 is a significant cardioprotective agent exerting its protective effect by inhibition of PMN-mediated cellular injury, and this agent represents a novel means of attenuating PMN-mediated reperfusion injury.

Dexamethasone rapidly increases hypothalamic neuropeptide Y secretion in adrenalectomized 06/06 mice

August 1996

·

18 Reads

A single intracerebroventricular injection of dexamethasone (DEX) rapidly (within 30 min) suppresses brown adipose tissue thermogenesis and increases plasma insulin concentrations in adrenal-ectomized (ADX) ob/ob mice but not in ADX lean mice. Intracerebroventricular neuropeptide Y (NPY) administered intracerebroventricularly causes these same metabolic changes within 30 min in both ob/ob and lean ADX mice. We therefore hypothesized that DEX exerts these rapid-onset metabolic actions in ob/ob mice via a phenotype-specific enhancement of NPY secretion within the central nervous system. In support of this hypothesis, DEX (a type II glucocorticoid receptor agonist) administered intracerebroventricularly selectively lowered NPY concentrations in the whole hypothalamus of ADX ob/ob mice by 35% and in the arcuate nucleus region by approximately 70% within 30 min but not in the brain stem or hippocampus or in any of these regions of lean mice. DEX also functioned in vitro to enhance depolarization-dependent release of NPY from hypothalamic blocks of ADX ob/ob mice but not of ADX lean mice. Thus DEX acts in the hypothalamus of ob/ob mice in a phenotype-specific manner to evoke rapid transport of NPY from cell bodies within the arcuate nucleus to terminal regions including the dorsomedial and ventromedial hypothalamic regions for release.


1,2-dioctanoyl-sn-glycerol depresses cardiac L-type Ca2+ current: Independent of protein kinase C activation

March 1996

·

23 Reads

The present study examines the effect of 1,2-dioctanoyl-sn-glycerol (DiC8), a diacylglycerol analogue, on L-type Ca2+ current (ICa,L) in adult rat ventricular myocytes using whole cell patch-clamp techniques. Extracellular application of DiC8 (1-10 microM) resulted in a concentration-dependent inhibition of peak ICa,L (half-maximum inhibitory concentration = 2.2 microM). Results obtained from the current-voltage relationship showed that DiC8 decreased the slope conductance. In addition, DiC8 increased the rate of Ba2+ current inactivation and caused a hyperpolarizing shift in the steady-state inactivation by 6 mV and a decrease in the slope factor. The DiC8-induced inhibition of ICa,L was neither mimicked by activation of protein kinase C (PKC) with 100 nM phorbol 12-myristate 13-acetate (PMA) no prevented by inhibition of PKC with 30 microM H-7, 100 nM staurosporine, or 24-h pretreatment with PMA. These results suggest that in rat ventricular myocytes 1) 1,2-sn-diacylglycerol (DAG) inhibits ICa,L, possibly by facilitating channel inactivation and decreasing channel availability and 2) this inhibitory effect of DAG is independent of PKC activation.

N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, amiloride analogues, and renal Na+/H+ antiporter

April 1987

·

6 Reads

N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) is a carboxyl-activating agent and has been shown to inhibit the renal Na+/H+ antiporter. The purposes of the present studies were to characterize the kinetics of inhibition of the Na+/H+ antiporter by EEDQ and to determine whether amiloride analogues affect the ability of EEDQ to inhibit the rate of Na+/H+ exchange. Brush-border membrane vesicles (BBMV) were prepared from rabbit kidneys; Na+/H+ exchange rate was assessed by the fluorescence quenching of acridine orange. EEDQ produced a concentration-dependent inhibition of Na+/H+ exchange; the effect was to decrease the maximum activity (Vmax) from 5.51 to 2.03 fluorescence units X mg protein-1 X S-1) and Km (from 14.1 to 8.7 mM) compared with control BBMV. Pretreatment of BBMV with amiloride before the addition of EEDQ maintained both Vmax and Km at values that were not significantly different from those for control BBMV. Compared with a series of analogues, amiloride was only the third most potent inhibitor of the rabbit renal Na+/H+ antiporter; amiloride, however, provided the greatest protection against inhibition of the antiporter by the subsequent addition of EEDQ. These findings suggest that the 2-carbonylguanidininum moiety and 6-chloro atom are important for binding of amiloride to sites at or near the antiporter; the group at position 5 is important in determining the ability of amiloride to protect against inhibition of the Na+/H+ antiporter by EEDQ. Finally, the ability of amiloride to protect against inactivation of the renal Na+/H+ antiporter by EEDQ is reversible.

1,2-Diacylglycerol and ceramide levels in rat liver and skeletal muscle in vivo

December 1991

·

6 Reads

1,2-Diacylglycerol and ceramide levels were measured in liver and skeletal muscle of rats under the following four experimental conditions: 1) during rapid fetal growth in the second half of gestation and during postnatal aging, 2) during tissue anoxia lasting up to 10 min, 3) during fasting for up to 6 days, and 4) during stress induced by injection of endotoxin (lipopolysaccharide from Salmonella enteritidis). 1,2-Diacylglycerol and ceramide levels in fetal liver were 77 and 58% lower, respectively, than those of young rats after weaning. 1,2-Diacylglycerol and ceramide concentrations in liver of postnatal rats were not influenced by aging. Anoxia produced a 41-64% increase in liver 1,2-diacylglycerol levels and a 9-21% increase in liver ceramides. Fasting of adult rats for up to 6 days had no effect on 1,2-diacylglycerol and ceramide levels in liver. However, fasting increased skeletal muscle concentrations of 1,2-diacylglycerol and ceramides 88 and 44%, respectively. Injection of endotoxin had a biphasic effect on liver 1,2-diacylglycerol levels, causing a transient 52% increase at 1 h, followed by a 24-38% decrease below the control level at 17 h after endotoxin administration. Liver ceramide levels were increased 66, 52, and 27% at 1, 3, and 5 h after endotoxin, respectively, but did not differ from control at 17 h after injection. Endotoxin had no effect on muscle 1,2-diacylglycerol and ceramide concentrations at any interval.

Effect of 1,2,4-triazole ethylamine on gastric secretion

April 1960

·

8 Reads

3-(beta-aminoethylamine)-1,2,4-triazole, the triazole analogue of histamine, was found to be a potent excitant of gastric secretion, 0.42 mg of the triazole base being equivalent to 0.3 mg histamine in the dog. The action was slightly more prolonged than that of histamine. The evidence in this study along with earlier evidence strongly indicates that aminoguanidine (AG) acts additively with histamine, since AG inhibits the destruction of histamine. It was found that AG also augments the action of the triazole on gastric secretion, the mechanism of which is now uncertain.

Top-cited authors