摘要:

Although chronic cocaine use is cardiotoxic, its use remains problematic in athletics. Hence adaptive changes induced in the heart by superimposing chronic cocaine use on an exercise training are of interest but remain poorly understood. Therefore this study investigated the effects of cocaine treatment combined with exercise training on the metabolic and contractile properties of the heart. Male Sprague–Dawley rats were assigned to one of four groups: normal sedentary (NS,n = 6), cocaine sedentary (CS,n = 6), normal trained (NT,n = 6), and cocaine trained (CT,n = 6). Trained animals were sprint trained 4 times/week. CS and CT animals received cocaine (25 mg/kg, ip) 6 times/week, 15 min before each exercise bout and 2 additional times per week. After 12 weeks, all animals were sacrificed, and the hearts were removed and analyzed for citrate synthase activity, 3-hydroxyacyl-CoA dehydrogenase activity, Ca2+-activated myofibrillar ATPase activity, and myosin isoform distribution. None of the groups demonstrated altered cardiac metabolic properties, but cocaine alone and in conjunction with exercise reduced myofibrillar ATPase activity (p < 0.05) and increased expression of the low ATPase myosin isoform, V3. These data suggest that the potential of the citric acid cycle and β-oxidation is not sensitive to chronic cocaine treatment, but the distribution of cardiac myosin among its three isoforms is affected. Furthermore, high-intensity treadmill training does not interact with cocaine to further alter these properties.Key words: cocaine, exercise, cardiac metabolism, myosin.

ISSN:0008-4212    

DOI:10.1139/y94-001

出版商:NRC Research Press    

年代:1994

数据来源: NRC

摘要:

The mechanism whereby chronic rapid ventricular pacing induces severe heart failure is unclear, but the phenomenon is associated with a reduction in left ventricular ATP levels. Accordingly, the current study was undertaken to evaluate the acute effects of rapid ventricular pacing on hemodynamics, left ventricular adenine nucleotide levels, myocardial blood flow, and oxygen consumption. Anesthetized dogs (n = 7) were studied in sinus rhythm and during 30 min of pacing at 250 beats/min. Pacing caused a significant (means ± SD, allp < 0.001) decrease in cardiac output (3.0 ± 0.6 to 2.0 ± 0.6 L/min) and peak left ventricular systolic pressure (133 ± 14 to 82 ± 10 mmHg (1 mmHg = 133.3 Pa)) and an increase in pulmonary wedge pressure (10 ± 2 to 18 ± 3 mmHg). Following pacing, the peak first derivative of left ventricular pressure and the relaxation time constant, τ, remained unchanged compared with baseline values. Myocardial blood flow and oxygen consumption both increased by 70% with pacing. The transmural distribution of myocardial blood flow and myocardial lactate consumption remained unchanged. There was no change in left ventricular ATP or ADP levels with the observed increase in myocardial oxygen consumption. Therefore, the hemodynamic deterioration associated with acute rapid ventricular pacing, in contrast to that of chronic pacing, is not associated with perturbed myocardial energetics.Key words: canine, ventricular pacing, ATP, ADP, myocardial blood flow, ventricular function.

ISSN:0008-4212    

DOI:10.1139/y94-002

出版商:NRC Research Press    

年代:1994

数据来源: NRC

摘要:

Bronchoconstriction induced by inhaled neurokinins, leukotriene D4(LTD4), and histamine was examined in conscious guinea pigs, using a double-chamber plethysmograph. The reliability of the plethysmograph was established by obtaining stable baseline values of key pulmonary parameters, including specific airway resistance, over a 4-day period. As well, the usefulness of the setup was confirmed using LTD4and the LTD4antagonist MK-571. Aerosols of MK-571 inhibited the bronchoconstriction induced by LTD4(0.3 μM, 3 min aerosol) with an IC50value of 65 ± 16 nM. Inhaled neurokinin A (NKA), substance P (SP), [βAla8]NKA(4–10), or [Sar9,Met(O2)11]SP at concentrations up to 10 μM had no bronchoconstrictive effect, unless the guinea pigs were pretreated with the neutral endopeptidase inhibitor thiorphan (0.2 mg/mL, 5 min aerosol). The rank order of bronchoconstriction potency was LTD4> [βAla8]NKA(4–10) ≈ NKA > [Sar9,Met(O2)11]SP ≈ SPhistamine. Hyperresponsiveness to NKA-induced bronchoconstriction was evident after 1 day and lasted for 4 days. The response to NKA was not inhibited by mepyramine, indomethacin, or MK-571 but was significantly reduced by atropine and hexamethonium, suggesting the involvement of a cholinergic mechanism. Aerosols of SR-48,968, a selective NK2 antagonist, had potent effects on the bronchoconstriction induced by NKA (1 μM, 3 min aerosol), with an IC50value of 17 ± 3 nM. SR-48,968 was also active when administered intraperitoneally. The NK1 antagonist CP-99,994 (0.1 μM, 10 min aerosol) inhibited the responses to SP by 70% but had no effect on NKA-induced responses at concentrations up to 10 μM. Interestingly, combination of SR-48,968 (3 nM) and CP-99,994 (100 nM) resulted in more complete inhibition of the NKA-induced bronchoconstriction than was obtained with either antagonist alone. It is concluded that NKA-induced bronchoconstriction in conscious guinea pigs is mediated predominantly by NK2 receptors, with only a minor involvement of NK1 receptors. Although a direct comparison of the potency of SR-48,968 in man and guinea pig is not feasible, our data suggest that it is in the same range in these two species.Key words: neurokinins, NK1 antagonist, NK2 antagonist, conscious guinea pigs, plethysmogra

ISSN:0008-4212    

DOI:10.1139/y94-003

出版商:NRC Research Press    

年代:1994

数据来源: NRC

摘要:

Mechanical stretch applied to canine cerebral artery produced myogenic contraction. The contraction of the artery in response to quick stretch was dependent on not only the transmembrane influx of Ca2+through 1,4-dihydropyridine-sensitive Ca2+channels but also the release of Ca2+from intracellular storage sites: the stretch-produced contractile component that was resistant to 0.1 μM nicardipine, a Ca2+-channel antagonist, was inhibited by about 50% after treatment with ryanodine, and was almost completely suppressed by 0.1 mM 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate, a putative phospholipase C inhibitor, or by lowering the temperature from 35 to 20 °C. The results suggest that in addition to transmembrane influx of Ca2+through L-type Ca2+channels, the release of Ca2+from both ryanodine-sensitive and -insensitive intracellular storage sites, which increases intracellular Ca2+, accounts for the stretch-induced contraction of canine basilar artery. It seems also possible that inositol 1,4,5-trisphosphate is a common mediator for the release of Ca2+from both types of intracellular storage sites.Key words: stretch-induced contraction, cerebral artery, phospholipase C, ryanodine, Ca2+storage sites, inositol 1,4,5-trisphosphate, Ca2+release, Ca2+-channel antagonist.

ISSN:0008-4212    

DOI:10.1139/y94-004

出版商:NRC Research Press    

年代:1994

数据来源: NRC

摘要:

Intracerebroventricular administration of vasoactive intestinal peptide (VIP) disturbed the learning by rats of the location of a platform submerged in a water pool. When the platform was removed from the pool, VIP injection produced marked impairment of the ability to find a previously learned location in the pool. This spatial memory impairment caused by VIP was restored by peripheral pre-administration of cerulein.Key words: vasoactive intestinal peptide, cerulein, Morris water maze task, memory, learning.

ISSN:0008-4212    

DOI:10.1139/y94-005

出版商:NRC Research Press    

年代:1994

数据来源: NRC

摘要:

There is clinical and experimental evidence to indicate that cigarette smoking may increase the risk of skin ischemic necrosis in flap surgery but the pathogenic mechanism remains unclear. The objectives of this project were to investigate the potential deleterious effects and mechanism of action of nicotine, a major by-product of cigarette smoking, in skin flap surgery in the pig. It was observed that 4–5 weeks of intramuscular nicotine injections (4 mg/kg; twice daily) significantly (p < 0.05) decreased the skin flap capillary blood flow and the length and area of skin flap viability in the pig. This nicotine treatment also induced a 1.6-fold increase in skin flap tissue content of norepinephrine compared with the saline-treated control. The estimated mean wet skin tissue content of norepinephrine (5 × 10−7 M) was much higher than the circulating level of norepinephrine (1.8 × 10−9 M) in nicotine-treated pigs. This level of norepinephrine (5 ×10−7 M) was seen to induce a significant vasoconstrictor effect (75% increase over basal perfusion pressure) in isolated perfused pig skin flaps. It was also observed that the vasoconstrictor effect of norepinephrine was significantly (p < 0.05) enhanced in the presence of 10−4 MNω-monomethyl-L-arginine orNG-nitro-L-arginine, an endothelium-derived relaxing factor – nitric oxide (EDRF/NO) synthesis inhibitor. This vasoconstrictor effect was further enhanced in the presence ofNG-nitro-L-arginine and 10−5 M indomethacin, a cyclooxygenase inhibitor. Taken together, these observations indicate that 4–5 weeks of nicotine treatment significantly reduced the skin capillary blood flow and viability in skin flap surgery in the pig and this deleterious effect was likely to be mediated, at least in part, by locally released norepinephrine induced by nicotine treatment. Furthermore, norepinephrine also induced skin flap local release of EDRF/NO and a vasodilating prostanoid that in turn attenuated norepinephrine's vasoconstrictor effect in the skin vasculature. We speculate that skin vasculature with compromised endothelial cell function as a result of trauma or disease is more susceptible to the vasoconstrictor effect of norepinephrine released by nicotine.Key words: chronic nicotine, norepinephrine, skin vasoconstriction, flap surgery.

ISSN:0008-4212    

DOI:10.1139/y94-006

出版商:NRC Research Press    

年代:1994

数据来源: NRC

摘要:

Three Holstein steers (345 ± 22 kg) surgically fitted with a pancreatic cannula were used in two 3 × 3 Latin square design experiments to examine the effects of slaframine (SF), a muscarinic agonist, or 4-diphenylacetoxy-N-methylpiperidine methiodide (4DAMP), an M3muscarinic glandular receptor antagonist, on pancreatic exocrine secretion. Pancreatic exocrine secretion was collected for 8 h postdosing at 30-min intervals beginning 1 h postfeeding. In experiment 1, steers were dosed with 0, 25, or 50 μg∙kg−1body weight (BW) of SF. Secretion of pancreatic juice and the pH of the secreted juice increased linearly (p < 0.05) with SF; however, secretion rate showed a time by treatment interaction (p < 0.05), as treatments converged 7 h postdosing. Trypsin secretion tended (p < 0.10) to show a quadratic response to SF administration, with the 25 μg SF∙kg−1BW dose having the lowest value. In experiment 2, steers received 50 μg∙kg−1BW of SF (positive control), 113 μg∙kg−1BW of 4DAMP (isomolar with SF), or both. SF caused a greater pancreatic fluid secretion (p < 0.10) than 4DAMP, with SF plus 4DAMP intermediate. A time by treatment interaction (p < 0.04) was found, since treatments converged 8 h postdosing. Trypsin secretion was higher (p < 0.05) for SF than the other treatments. Chymotrypsin, α-amylase, and protein secretion were not affected. SF and 4DAMP alter pancreatic fluid secretion in the steer but have minimal effects on enzyme secretions.Key words: slaframine, 4-diphenylacetoxy-N-methylpiperidine methiodide, bovine, pancreatic exocrine se

ISSN:0008-4212    

DOI:10.1139/y94-007

出版商:NRC Research Press    

年代:1994

数据来源: NRC

摘要:

We have modified an assay utilizing ion-pair high-performance liquid chromatography with electrochemical detection to measure dihydroxyphenylalanine and dyhydroxyphenylglycol simultaneously with noradrenaline. We measured these agents at control, 1 and 3 weeks following the onset of rapid ventricular pacing, as well as 4 weeks after the cessation of a 3-week period of pacing. Our findings were as follows. Plasma noradrenaline increased significantly at 1 week and increased further after 3 weeks of pacing (control, 202 ± 16; 1 week, 528 ± 62; 3 weeks, 750 ± 139 pg∙mL−1). Plasma dihydroxyphenylalanine did not change throughout, while plasma dihydroxyphenylglycol was significantly elevated at 3 weeks (513 ± 48 vs. 388 ± 35 pg∙mL−1for the control). Four weeks after discontinuation of pacing, all parameters did not differ from the control. These results imply that during the development of heart failure, the rise in circulating noradrenaline does not reflect simply an increase in catecholamine synthesis, but that there are more dynamic changes associated with noradrenaline spillover, uptake, and metabolism.Key words: heart failure, dihydroxyphenylglycol, sympathetic nervous activity, noradrenal

ISSN:0008-4212    

DOI:10.1139/y94-008

出版商:NRC Research Press    

年代:1994

数据来源: NRC

摘要:

We previously reported thatS-(N-methylcarbamoyl)glutathione (SMG), a conjugate formed by the reversible reaction between methyl isocyanate and glutathione, inhibited the development of mouse embryos in culture. The present study was done to determine whether SMG produced embryotoxicity by inhibiting yolk sac functions. For this purpose we determined the effects of an embryotoxic concentration of SMG on mouse yolk sac uptake mechanisms and lysosomal proteolysis as well as on the incorporation of [3H]leucine in mouse embryonic and limb-bud proteins. After 5 h of culture, SMG inhibited the uptake of [14C]sucrose and125I-labelled bovine serum albumin in isolated day 15 yolk sacs to 62 and 77% of control, respectively. Lysosomal proteolysis was not inhibited, as judged by the release of trichloroacetic acid soluble radioactivity into the culture media. Uptake and incorporation of [3H]leucine from free [3H]leucine or from [3H]leucine-labelled protein in SMG-treated day 9 embryos were inhibited, respectively, to 61 and 25% of the control uptake during a 16-h labelling period. SMG also inhibited the incorporation of free [3H]leucine into limb-bud proteins. SMG-induced inhibition of125I-labelled bovine serum albumin uptake by yolk sacs was partially prevented by the thiol donorsN-acetylcysteine and glutathione but not by acivicin (γ-glutamyl transpeptidase inhibitor) and aminooxyacetic acid (cysteine conjugate β-lyase inhibitor). These data suggest that SMG suppresses embryonic growth primarily by an inhibition of nutrient uptake by the yolk sac. We postulate that this inhibition is due to tissue carbamoylation by methyl isocyanate released from SMG.Key words: yolk sac functions, methyl isocyanate, glutathione conjugate, embryo toxicity, pinocytosis, embryo culture, limb bud.

ISSN:0008-4212    

DOI:10.1139/y94-009

出版商:NRC Research Press    

年代:1994

数据来源: NRC

摘要:

Ingestion of the anticonvulsant drag valproic acid and of the angiotensin converting enzyme inhibitor captopril during pregnancy has been associated with abnormal fetal outcome in humans. In contrast, the use of the antiinflammatory drug ibuprofen and the antihistamine diphenhydramine has not been documented to be embryotoxic in humans. We evaluated the rat embryo culture system as a predictive model of teratogenesis, using these four drugs as test agents. Valproic acid, ibuprofen, and diphenhydramine were embryotoxic, inducing concentration-dependent decreases in growth and a significant increase in anomalies. Valproic acid caused an increase in neural tube defects, ibuprofen increased the incidence of abnormal maxillary processes, and diphenhydramine increased the number of embryos with distorted body morphology. These abnormalities were induced at concentrations of valproic acid and diphenhydramine that are used clinically, but ibuprofen only induced toxicity at concentrations greatly exceeding the therapeutic range. Captopril was not embryotoxic up to 5 mM, the highest concentration tested. These results suggest that the rat embryo culture system produces both false positive and false negative data on the teratogenic potential of drugs. Although such an in vitro assay may be suitable to determine the mechanism of teratogenesis, it is not a sensitive indicator of potential human teratogens on its own. These data support the view that in vitro systems can only supplement clinical and epidemiological observations in humans, possibly as a method to determine mechanisms of actions of teratogens.Key words: embryo culture, teratogenesis, valproic acid, captopril, ibuprofen, diphenhydramine.

ISSN:0008-4212    

DOI:10.1139/y94-010

出版商:NRC Research Press    

年代:1994

数据来源: NRC