摘要:

Systemic vascular effects of hydralazine, prazosin, captopril, and nifedipine were studied in 115 anesthetized dogs. Blood flowand right atrial pressure (Pra) were independently controlled by a right heart bypass. Transient changes in central blood volume after an acute reduction inPraat a constantshowed that blood was draining from two vascular compartments with different time constants, one fast and the other slow. At three dose levels producing comparable reductions in systemic arterial pressure (30–40% at the highest dose), these drugs had different effects on flow distribution and venous return. Hydralazine and prazosin had parallel and balanced effects on arterial resistance of the two vascular compartments, and flow distribution was unaltered. Captopril preferentially reduced arterial resistance of the compartment with a slow time constant for venous return (−26 ± 6%, −30 ± 6%, −50 ± 5% at 0.02, 0.10, and 0.50 mg∙kg−1∙h−1, respectively;) without altering arterial resistance of the fast time-constant compartment. Blood flow to the slow time-constant compartment was increased 43 ± 14% at the highest dose, and central blood volume was reduced 108 ± 15 mL. In contrast, nifedipine had a balanced effect on arterial resistance with the lowest dose (0.025 mg/kg) but caused a preferential reduction in arterial resistance of the fast time-constant compartment at higher doses (−38 ± 4% and −55 ± 2% at 0.05 and 0.10 mg/kg, respectively). Blood flow to the slow time-constant compartment was reduced 36 ± 5% at the highest dose of nifedipine, and central blood volume was increased 66 ± 12 mL. Total systemic venous compliance was unaltered or slightly reduced by each of the four drugs. These results add further evidence to the hypothesis that peripheral blood flow distribution is a major determinant of venous return to the he

ISSN:0008-4212    

DOI:10.1139/y85-222

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

Previousin vitrostudies have demonstrated enhanced active and passive intestinal uptake of nutrients in streptozotocin-diabetic rats, but the effect of diabetes on thein vivoabsorption of glucose and amino acids remains controversial, and the effect of diabetes on thein vivouptake of lipids has not been reported. Accordingly, anin vivoperfusion technique was used in rats to examine the uptake of nutrients from the intestinal lumen, their transfer to the body, their mucosal and submucosal content, and the percentage of uptake transferred. Diabetes was associated with reduced uptake of fatty alcohols, indicating that the effective resistance of the unstirred water layerin vivois higher in diabetic than in nondiabetic control rats. The mucosal and submucosal content of dodecanol was lower in diabetic than in control rats, but the percentage of the dodecanol uptake transferred to the body was higher. Although the uptake of varying concentrations ofD-galactose was similar in diabetic and in control animals, kinetic analysis corrected for unstirred layer effects demonstrated lower mean values of the passive permeability coefficients (Pd) for galactose in diabetic than in control animals, with lower values of the Michaelis constant (Km) and higher values of the maximal transport rate. The uptake of lauric acid was reduced in diabetic rats, whereas the uptake of deconoic acid and of cholesterol was unchanged. With correction for unstirred layer effects, it was apparent that the jejunum of diabetic rats was in fact more permeable to decanoic and lauric acid as well as to cholesterol. The results suggest that (i) in diabetic rats the effective resistance of the unstirred water layer between the jejunal lumen and the brush border membrane is lower; (ii) the differences in unstirred layer resistance between the diabetic and control animals obscure the changes in the kinetic constants (Pd,Km,) describing the uptake of galactose, medium chain length fatty acids and cholesterol; and (iii) the kinetic changes in nutrient uptake observedin vitromay be confirmedin vivoonce the effect of intestinal unstirred layers has been taken into account.

ISSN:0008-4212    

DOI:10.1139/y85-223

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

It is known that parathyroidectomy, administration of parathyroid hormone (PTH), and dietary phosphate depletion or excess result in variations in phosphaturia and in phosphate transport through brush border membrane vesicles isolated from the kidneys of various animals. Parathyroid hormone has been shown to ultimately phosphorylate some brush border membrane proteins and it has been postulated that the resulting phosphaturia is related to this phosphorylation. However, it is not known whether the regulation of phosphate transport by the diet is affected through similar pathways. Our experiments were designed to study the phosphorylation of brush border membrane with [γ-32P]ATP using the intrinsic protein kinase of the membranes. Five groups of rats were used: normal, phosphate loaded, phosphate depleted, and thyroparathyroidectomized and acutely loaded with parathyroid hormone. In each series of animals, the proteins whose phosphorylation was cAMP dependent were detected by sodium dodecyl sulfate polyacrylamide gel electrophoresis, and their phosphorylation with various concentrations of ATP, in the presence or absence of cAMP in the incubation medium, was quantified. In the normal rat, 17 proteins were phosphorylated, the phosphorylation of two of them (Mr, 71 000 and 84 000) being cAMP dependent. Maximal response to cAMP for these two proteins was obtained with 10 μMcAMP. The peaks of phosphorylation were observed at pH 7 for protein 71 000 and pH 10 for protein 84 000. When brush border membranes from normal rats were incubated with 10–100 μMATP, cAMP-dependent phosphorylation increased to reach a maximal phosphorylation of 4.44 ± 0.90 pmol/mg protein for protein 71 000 and 1.32 ± 0.15 pmol/mg protein for protein 84 000. TheKmvalues were 51.1 ± 6.4 and 23.2 ± 0.4 μM, respectively. With 10 μMATP, cAMP-dependent phosphorylation of protein 71 000 was not significantly influenced by the PTH status nor the diet. In contrast, both the parathyroid hormone status and the diet affected the cAMP-dependent phosphorylation of protein 84 000 by changing theKmvalues for ATP: 14.7 ± 1.7 and 14.6 ± 2.9 μMATP in thyroparathyroidectomized and phosphate-depleted animals; 31.3 ± 4.4 and 29.8 ± 3.5 μMATP in parathyroid hormone and phosphate-loaded animals, respectively. It is concluded that (i) the rat brush border membrane contains two main proteins whose phosphorylation is cAMP dependent, (ii) both the PTH status and diet similarly affect the protein kinase responsible for the phosphorylation of protein 84 000 by changing its affinity for ATP, (iii) unless the concentration of ATP available for this enzyme approximates theKmvalues observed by us and others (50–100 μM), these changes in affinity for ATP have no impact on final membrane phosphorylation.

ISSN:0008-4212    

DOI:10.1139/y85-224

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

We have demonstrated the in vitro production of a potentially toxic metabolite of sulfadiazine. Human lymphocytes were incubated with sulfadiazine and a murine hepatic microsomal drug metabolizing system. Toxicity to cells was assessed by trypan blue dye exclusion. Covalent binding of labelled sulfadiazine to microsomes also was studied. Sulfadiazine toxicity to cells was dependent on microsomes and NADPH. Binding and toxicity were decreased when microsomes were boiled or cytochrome P-450 inhibited, and by the addition ofN-acetylcysteine or glutathione. The data suggest the production of a toxic intermediate of oxidative metabolism of sulfadiazine which is detoxified by conjugation with glutathione. Covalent binding of such metabolites to cell macromolecules could lead to cell death and, by acting as haptens, to secondary hypersensitivity reactions.

ISSN:0008-4212    

DOI:10.1139/y85-225

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

The distribution of atrial natriuretic factor (ANF) binding sites in Wistar rat tissues, as well as tissues from other species was studied. Using autoradiography of slide mounted tissue sections incubated with125I-labelled ANF, high densities of binding sites were found in the renal glomeruli and papilla, aortic smooth muscle, iliac vein, choroid plexus, anterior pituitary, lung, and adrenal zona glomerulosa. Results from renal, aortic, adrenal, and lung tissues from spontaneously hypertensive rats did not differ from those of Wistar rats. Binding sites were also observed in guinea pig glomeruli, renal medulla, and aorta as well as in the rabbit aorta.

ISSN:0008-4212    

DOI:10.1139/y85-226

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

The elastic properties of the abdominal aorta at regions of junctions were studied using strips from 17 dogs. Strips of tissue cut longitudinally and circumferentially at the celiac, mesenteric, and renal branches were used to compare the properties of the proximal and distal junctions, as well as the aorta and artery regions adjoining. The tissues were stored for at least 24 h to ensure that no active component of the smooth muscle remained. The elastic properties measured here are due to elastin and collagen, with a small contribution from dead smooth muscle cells. The tissue strips were tested at 20 °C while immersed in saline using an Instron tensile testing machine. Elongation of the three regions was measured from photographs taken as the tissue was stretched. Stress values went to 200 kN/m2as the strain increased to approximately 0.8. (The physiological range for the dog was calculated as 40–85 kN/m2.) The distal junctional region was found to be the most extensible for both longitudinally and circumferentially oriented strips. These results have important implications for flow models as they imply that the shape of the junctional region probably changes between diastole and systole.

ISSN:0008-4212    

DOI:10.1139/y85-227

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

Both phases of the calcium paradox were associated with major alterations in myocardial energy metabolism. During calcium-free perfusion contractility of the heart ceased, resulting in a dramatic decrease in anaerobic and aerobic metabolism but no change in tissue high energy phosphate levels. Tissue content of most citric acid cycle intermediates were elevated, while there was a net decrease in the content of transaminase-linked amino acids. Reperfusion of the calcium-depleted heart with calcium-containing buffer failed to restore either the contractile or the metabolic state of the heart. Within seconds following calcium repletion, tissue high energy phosphate content plummeted. This occurred even though glucose utilization increased significantly and aerobic metabolism remained at levels observed in the calcium-depleted heart. Analogous to changes seen in acidosis and ischemia, α-ketoglutarate and citrate levels decreased abruptly. After a short delay, the levels of several key amino acids also dropped. The results support the hypothesis that the impairment of mitochondrial function contributes to the depletion of high energy phosphate stores during the calcium paradox.

ISSN:0008-4212    

DOI:10.1139/y85-228

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

Calcium-translocating activity of linoleic acid and its lipoxygenase (linoleate: oxygen oxidoreductase; EC 1.13.11.12) metabolites or autoxidation products was determinedin vitroby estimation of45Ca transport from a bulk aqueous to a bulk organic phase. Fresh commercial linoleic acid, tested immediately after removal from a sealed vial, stimulated calcium translocation only at concentrations greater than 1 mM. In contrast,45Ca translocation by linoleic acid exposed to air was detectable at 10 μM. Oxidation products of linoleic acid obtained either by incubation with lipoxygenase or by autoxidation were much less potent than the calcium ionophore A23187. The products obtained by enzymic oxidation of linoleic acid enhanced contractility in the Langendorff-perfused guinea pig heart up to 45% over control (at 3 × 10−8 M). The inotropic response was transient with rapid onset and not affected by the beta-adrenergic antagonist, propranolol. The autoxidation products of linoleic acid increased cardiac contractility up to 43% at 10−6 M. In contrast, fresh linoleic acid caused only a negative inotropic effect at 10−8to 3 × 10−7 M, progressing to contracture at 10−6 M. These findings suggest that conflicting reports on the cardiostimulant effect of linoleic acid may be due to varying levels of the autoxidation products. Linoleic acid metabolitesin vivomay have a physiological role in myocardial function related to their Ca2+-ionophoric activity.

ISSN:0008-4212    

DOI:10.1139/y85-229

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

The rise in cortisol in fetal sheep during late pregnancy has been related to increased responsiveness of the adrenal to ACTH. Most reports have suggested that plasma ACTH concentrations rise coincident with or after the prepartum increase in cortisol. To reexamine the relationship of cortisol with basal immunoreactive ACTH (IR-ACTH) throughout the last 40 days of pregnancy and to determine changes in fetal pituitary responsiveness during this time, we measured basal and synthetic ovine corticotrophin-releasing factor (oCRF) (10 ng – 10 μg) induced rises in ACTH and cortisol in fetal sheep at days 110–115, 125–130, and 135–140 of pregnancy. The fetuses were catheterized on day 105–120 and entered spontaneous labour at > 140 days. Basal IR-ACTH (picograms per millilitre ± SEM) rose from 16.7 ± 2.9 pg/mL at day 110–115 to 34.8 ± 8.7 pg/mL at day 141–145. There was a significant effect of time on basal ACTH concentrations with a mean increase of approximately 5 pg ACTH per millilitre of plasma per 5-day sampling interval. Plasma cortisol changed gradually between day 110 and 125 of gestation and then more rapidly to term. At day 110–115 of gestation there was no significant change in plasma ACTH after 10 or 100 ng oCRF, but there was a significant increase in ACTH after 1 μg of oCRF. Plasma cortisol did not change after any CRF injection. The change in IR-ACTH after oCRF at day 125–130 of gestation was significantly greater than that at day 110–115. Plasma cortisol concentrations were elevated following 1- and 10-μg injections of oCRF. At day 135–140, significant rises in plasma ACTH were seen in response to 1 and 10 μg oCRF, but the response was less than that at day 125–130. In contrast, the response of plasma cortisol was significantly greater than at any of the other times in gestation. We conclude the following: (i) basal ACTH concentrations rise before the major prepartum increase in plasma cortisol; (ii) pituitary responsiveness to oCRF, measured as ACTH in plasma, increases between days 110–115 and 125–130 of gestation. The ACTH response decreased at day 135–140, perhaps reflecting negative feedback control by the rising basalcortisol concentrations; (iii) adrenal responsiveness increases progressively between days 110–115 and 135–140 of gestation, as reflected by changes in the plasmacortisol concentration in response to endogenously released ACTH.

ISSN:0008-4212    

DOI:10.1139/y85-230

出版商:NRC Research Press    

年代:1985

数据来源: NRC

摘要:

Preparations of frog atrial muscle were stimulated at 0.33 Hz under voltage clamp, and the resulting membrane currents and the twitch contractions (phasic and tonic components) were recorded in presence or absence of D600. It has been suggested earlier that the tonic contractions are regulated by an electrogenic Na+–Ca2+exchange, while the phasic contractions are closely related to the calcium inward current (Isi). In this study we investigated the effect of D600 on (i) the tonic contractions elicited by long depolarizing pulses of high amplitude and (ii) the tonic contractions increased by veratrine and resulting in a positive inotropic effect (PIE). While 1 μMD600 reducedIsiand the corresponding phasic contractions to < 30% of their initial values within 5 min, the inhibitory effect of D600 on tonic contractions developed more slowly or higher concentrations of D600 were needed to achieve similar levels of inhibition within the same time. Furthermore, applications of 5–50 μMD600 inhibited the veratrine-induced increase inINaand in tonic contractions, and both of these effects again fully developed within a few minutes of D600 being removed. The results demonstrate that D600 inhibits not onlyIsiand phasic contractions, but it also decreases the tonic contractions in frog heart. The effect on the tonic component is associated with inhibition of the tetrodotoxin-sensitive Na+inward current, and the results are interpreted as an effect of D600 on the electrogenic Na+–Ca2+exchange. These additional effects of D600 should be considered when using this drug as the "specific" calcium channel blocker.

ISSN:0008-4212    

DOI:10.1139/y85-231

出版商:NRC Research Press    

年代:1985

数据来源: NRC