摘要:

The resistance of the action potential to ischemic inactivation observed in diabetic patients has been reproducedin vivoin rat rendered diabetic with streptozotocin and, acutely, in normal rats given p.o. a load of glucose. The resistance phenomenon was not detected in galactosemic rats. The preservation of the action potential was reversed by the administration of insulin, but not by treatment with an aldose reductase (AR) inhibitor. The ischemic resistance is attributed to the metabolic availability of excess glucose to the nerve. AR does not appear to be involved in the phenomenon.

ISSN:0008-4212    

DOI:10.1139/y85-128

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

The metabolism of the β2-adrenoceptor agent methoxyphenamine was investigated in rats of the Lewis and Dark Agouti strains, which are proposed models for human extensive and poor metabolizers of debrisoquine, respectively. Following oral ingestion of 20 mg kg−1of methoxyphenamine, Dark Agouti excreted, on the average, significantly more methoxyphenamine and less (O-demethylmethoxyphenamine and 5-hydroxymethoxyphenamine in 0- to 24-h urine than Lewis. In contrast, theN-demethylation of methoxyphenamine showed no interphenotype differences between the two strains. It is possible that in rats, the form of cytochrome P-450, which controls the 4-hydroxylation of debrisoquine, may also control theO-demethylation and aromatic 5-hydroxylation of methoxyphenamine.

ISSN:0008-4212    

DOI:10.1139/y85-129

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

The effect of increased sympathetic activity on skeletal muscle blood flow during acute anemic hypoxia was studied in 16 anesthetized dogs. Sympathetic activity was altered by clamping the carotid arteries bilaterally below the carotid sinus. One group (n = 8) was beta blocked by administration of propranolol (1 mg/kg); a second group (n = 8) was untreated. Venous outflow from the left hindlimb was isolated for measurement of blood flow and O2uptake. After a 20-min control period, both carotid arteries were clamped (CC) for 20 min followed by a 20-min recovery period. The sequence was repeated after hematocrit was lowered to about 15% by dextran exchange for blood. Prior to anemia, CC did not alter cardiac output or limb blood flow in either group. After induction of anemia, hindlimb resistance was higher with CC in the beta block than in the no block group. Both limb blood flow andfell in the β-block group with CC during anemia. Beta block also prevented the additive increases in whole bodyseen with CC and induction of anemia. The data showed that the increased vasoconstrictor tone that was obtained with beta block during anemia was successful in redistributing the lower viscosity blood away from resting skeletal muscle, even to the point that musclewas decreased.

ISSN:0008-4212    

DOI:10.1139/y85-130

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

Coronary sinus pressure (Pcs) elevation shifts the diastolic coronary pressure–flow relation (PFR) of the entire left ventricular myocardium to a higher pressure intercept. This finding suggests thatPcsis one determinant of zero-flow pressure (Fzf) and challenges the existence of a vascular waterfall mechanism in the coronary circulation. To determine whether coronary sinus or tissue pressure is the effective coronary back pressure in different layers of the left ventricular myocardium, the effect of increasingPcswas studied while left ventricular preload was low. PFRs were determined experimentally by graded constriction of the circumflex coronary artery while measuring flow using a flowmeter. Transmural myocardial blood flow distribution was studied (15-μm radioactive spheres) at steady state, during maximal coronary artery vasodilatation at three points on the linear portion of the circumflex PFR both at low and high diastolicPcs(7 ± 3 vs. 22 ± 5 mmHg;p < 0.0001) (1 mmHg = 133.322 Pa). In the uninstrumented anterior wall the blood flow measurements were obtained in triplicate at the twoPcslevels. From low to highPcs, mean aortic (98 ± 23 mmHg) and left atrial (5 ± 3 mmHg) pressure, percent diastolic time (49 ± 7%), percent left ventricular wall thickening (32 ± 4%), and percent myocardial lactate extraction (15 ± 12%) were not significantly changed. IncreasingPcsdid not alter the slope of the PFR; however, thePzf, increased in the subepicardial layer (p < 0.0001), whereas in the subendocardial layerPzfdid not change significantly. Similar slopes andPzfwere observed for the PFR of both total myocardial mass and subepicardial region at low and highPcs. Subendocardial: subepicardial blood flow ratios increased for each set of measurements whenPcswas elevated (p < 0.0001), owing to a reduction of subepicardial blood flow; however, subendocardial blood flow remained unchanged, while starting in the subepicardium toward mid-myocardium blood flow decreased at highPcs. This pattern was similar for the uninstrumented anterior wall as well as in the posterior wall. Thus asPcsincreases it becomes the effective coronary back pressure with decreasing magnitude from the subepicardium toward the subendocardium of the left ventricle. Assuming that elevatingPcsresults in transmural elevation in coronary venous pressure, these findings support the hypothesis of a differential intramyocardial waterfall mechanism with greater subendo- than subepi- cardial tissue pressure.

ISSN:0008-4212    

DOI:10.1139/y85-131

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

The effect of acetylsalicylic acid, ibuprofen, indomethacin, ketoprofen, naproxen, phenylbutazone, and salicylic acid on the microsomal oxidative drug metabolism of rat liver was studied. Pretreatment of the rats with pharmacologic doses of acetylsalicylic acid, indomethacin, and ketoprofen decreased both the demethylase and hydroxylase activities of rat liver microsomes. These effects were paralleled by decreases in microsomal cytochrome P-450 content. The rate of the microsomal reactions was increased after pretreatment with ibuprofen and naproxen but only the former increased the concentration of cytochrome P-450. Phenylbutazone and salicylic acid had no in vivo effect on the hepatic monooxygenase. The addition of 1 mMof ibuprofen, indomethacin, ketoprofen, naproxen, and phenylbutazone to rat liver microsomes inhibit both the aminopyrineN-demethylase andp-nitro-anisoleO-demethylase activities. The extent of the inhibition varied between 21 and 73% of the control incubation. Indomethacin, naproxen, and phenylbutazone also decreased the aniline hydroxylase activity to roughly 60% of the control value. Acetylsalicylic acid and salicylic acid had no in vitro effect on the microsomal monooxygenase. The nonsteroidal anti-inflammatory drugs produced a reverse type I binding spectrum with oxidized cytochrome P-450; indomethacin and phenylbutazone were the strongest ligands. There is no correlation between the effect of addition of nonsteroidal anti-inflammatory drugs to the hepatic microsomal homogenate and their in vivo effect on the monooxygenase activity.

ISSN:0008-4212    

DOI:10.1139/y85-132

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

The production of arrhythmias in the isolated heart by perfusion with lysophosphatidylcholine has been well documented. However, the role of the lysophospholipid as a physiological factor in the generation of cardiac arrhythmias is not clear. In this study, a pharmacological approach was used to delineate the physiological significance of lysophosphatidylcholine during this cardiac dysfunction. Lidocaine (5–20 mg/L) was found to be effective in the protection of the isolated rat heart from the lysophospholipid-induced arrhythmias at pharmacological concentrations. The effect of lidocaine in the protection of lysophospholipid-induced membrane dysfunction was studied with red blood cells. Lidocaine (2 mg/mL) protected red blood cells from hemolysis in the presence of lysophosphatidylcholine. Lidocaine did not inhibit the binding of the lysophospholipid to the red cell membrane, but inhibited hemolysis in a manner similar to cholesterol. The results are consistent with the postulate that lysophosphatidylcholine is a physiological factor in the pathogenesis of cardiac arrhythmias during myocardial ischemia.

ISSN:0008-4212    

DOI:10.1139/y85-133

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

Because of very low density lipoprotein's (VLDL) potential atherogenicity and the demonstration that VLDL can bind to other cells, we examined the interaction of human VLDL with cultured porcine aortic endothelium. The lipoprotein–cell interaction had many properties similar to those seen with the binding of a ligand to a cell surface receptor. It was time and temperature dependent, saturable, and reversible. Scatchard analysis of competition data suggested that there may be more than one class of binding site. The affinity of the low affinity site was similar to that for low density lipoprotein (LDL). Also, the capacity of endothelial cells to bind VLDL was similar to that for LDL, when related to apo B (i.e., particle) concentration. Not only was unlabelled VLDL able to compete for VLDL binding sites, but so was LDL and high density lipoprotein (HDL). The maximal competition either by LDL or by HDL was less than that by VLDL. The maximal competition by HDL was more than by LDL. The VLDL binding was dependent on Ca2+. It was not changed by the content of lipoprotein in the medium in which cells were grown prior to the binding studies. These observations suggest that VLDL binding to endothelial cells is similar in some respects, but not in all, to the binding of LDL. Comparison of the data with endothelial cells to previous data with adipocytes also indicated differences between the interaction of these two cell types with VLDL. It is possible that this binding process may be involved in the formation of atherogenic remnants of triglyceride-rich lipoproteins on the endothelial surface of large blood vessels.

ISSN:0008-4212    

DOI:10.1139/y85-134

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

It has recently been reported that stimulation of the region of the subfornical organ (SFO) elicits an increase in arterial pressure. However, the mechanisms and forebrain neural circuitry that are involved in this cardiovascular response have not been elucidated. The present study was done in urethane-anaesthetized rats to determine whether selective activation of SFO neurons elicit cardiovascular responses and whether these responses were mediated by a pathway involving the paraventricular nucleus of the hypothalamus (PVH). Stimulation sites which required the lowest threshold current (30 μA) to elicit a pressor response and at which the largest rise in mean arterial pressure (MAP; 22 ± 2 mmHg) was elicited at a constant current intensity (150 μA) were histologically localized in the region of the SFO. Short (mean peak latency; 4 ± 2 s) and long (mean peak latency; 61 ± 8 s) latency increases in MAP were observed during and after electrical stimulation of the SFO, respectively. Cardiac slowing accompanied the short latency pressor response and cardioacceleration was observed in most (57%) of the cases to accompany the late pressor response. Microinjection ofL-glutamate into the SFO consistently elicited cardiovascular responses qualitatively similar to those observed during electrical stimulation. Ganglionic blockade abolished the short latency increase in MAP and the accompanying bradycardia. However, the long latency pressor and cardioacceleratory responses were not altered by ganglionic blockade and adrenalectomy. Selective bilateral electrolytic or kainic acid lesions of the region of the PVH significantly attenuated the cardiovascular responses elicited by stimulation of the SFO. These data suggest that activation of neurons in the SFO elicit cardiovascular responses partially mediated by sympathetic outflow through a neural pathway involving the PVH.

ISSN:0008-4212    

DOI:10.1139/y85-135

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

Conventional intracellular recordings, from central mammalian neurones, are used to assess the actions of putative transmitters on neuronal membrane parameters such as input conductance and to determine reversal potentials. Ohm's Law and constant current methods can be employed to accurately assess such parameters provided the putative transmitter activates a voltage-independent response. However, several likely transmitter candidates act via voltage-dependent mechanisms to alter neuronal excitability; as a consequence, results from this method of analysis must be cautiously interpreted. Under this constraint of possible voltage dependence, constant current methods can lead to spurious conclusions about the physiological and pharmacological characterization of the response.

ISSN:0008-4212    

DOI:10.1139/y85-136

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

It is commonly thought that central nervous system depressant drugs exert their actions through enhancement of γ-aminobutyrate (GABA)-mediated mechanisms. Recently, the cellular electrophysiological evidence from this laboratory and others suggests that both sedative hypnotics and general anaesthetics inhibit central neurons by increasing potassium conductance (GK). We have utilized the mammalian in vitro hippocampal and cerebellar slice preparations at 34 – 36 °C. Intracellular recordings from CA1, CA3, and cerebellar Purkinje cells were obtained. Low dose (sedative) concentrations of ethanol (≤20 mM), two different benzodiazepines (midazolam and clonazepam in low nanomolar concentrations), and pentobarbital (10−6to 10−4 M) were applied by pressure ejection or were bath perfused. All drugs caused a hyperpolarization with decreased spontaneous activity, and enhanced post spike afterhyperpolarizations (AHPs). These long-lasting AHPs are presumably due to enhanced calcium-mediatedGK. Increased responsiveness to focally applied GABA was only seen at higher doses (ethanol, 100 mM; midazolam, 10−7 M; pentobarbital, 10−4 M). These data suggest that the above neurodepressant drugs, when applied at sedative doses to hippocampal pyramidal cells, enhanceGKand not the actions of GABA.

ISSN:0008-4212    

DOI:10.1139/y85-137

出版商:NRC Research Press    

年代:1985

数据来源: NRC