Biomedical subjects

S A McCune

Publications and source records attributed to S A McCune.

At least 37 records · Page 2Linked to original sources

PubMed1996

Exercise training and the glucose transport system in obese SHHF/Mcc-fa(cp) rats.

The effects of a similar exercise training stimulus on maximal insulin-stimulated (MIS) plasma membrane glucose transporter number and glucose transport were determined in lean and obese SHHF/Mcc-facp rats. Six-week-old lean and obese male rats were randomly divided into four groups: lean sedentary (LSed), obese sedentary (OSed), lean exercise (LEx), and obese exercise (OEx). An 8- to 12-wk treadmill running program equalized daily muscular work for LEx and OEx. Plasma membranes were isolated from control and MIS muscles of mixed fiber types. MIS significantly increased glucose transport (3.4- and 2.8-fold) in LSed and OSed, respectively. MIS significantly increased glucose transporter number (2.5-fold) in LSed, but there was no increase in glucose transporter number in OSed. Peak oxygen uptake and citrate synthase activity were increased a similar amount for LEx and OEx groups, demonstrating a similar training stimulus. MIS significantly and similarly increased glucose transport in LEx and OEx (4.4- and 5.1-fold, respectively). The effects of MIS on plasma membrane glucose transporter number in the exercise-trained rats were similar to the responses observed in the sedentary lean and obese groups. MIS significantly increased glucose transporter number (2.6-fold) in LEx, whereas there was no increase in glucose transporter number in OEx. The reduction in MIS glucose transport in OSed appears to be related to a defect in the processes associated with the translocation of glucose transporters to the plasma membrane. Exercise training of the obese rats apparently did not alter this defect. Similar increases in peak oxygen uptake, citrate synthase, and MIS glucose transport in LEx and OEx groups suggest that insulin resistance does not limit the ability of the glucose transport system to adapt to exercise training in the obese male SHHF/Mcc-facp rats.

4-Nitrophenylphosphatase↗

PubMed1996

Myocyte remodeling during the progression to failure in rats with hypertension.

Regional changes in cardiac myocyte shape during the progression to failure with hypertension have not been clearly established. To address this issue, we examined left and right ventricular myocytes from lean, female spontaneously hypertensive/heart failure rats with compensated hypertrophy (approximately 12 months of age) and congestive heart failure (approximately 24 months of age). During this period, body weight did not change, but heart weight increased 59% and lung weight increased 93%. Left ventricular function declined with the onset of failure. Left ventricular myocyte volume increased 27% exclusively because of myocyte lengthening (29% increase). The onset of left ventricular failure resulted in a 72% increase in right ventricular myocyte volume. Right ventricular myocyte growth, however, was proportional, with a 23% increase in myocyte length and 18% increase in myocyte width. Changes in left ventricular myocyte shape were virtually identical to data collected previously from patients with similar disease, suggesting that this is a relevant animal model. Evidence suggests that left ventricular myocyte transverse growth is defective because dilation and failure were associated with cell lengthening, without a change in myocyte diameter. Although severe hypertrophy was present in the right ventricle as a result of left ventricular failure, myocyte growth was proportional, suggesting that cell shape was properly regulated in this chamber.

Animals↗

PubMed1995

Effects of obesity and gender on insulin receptor expression in liver of SHHF/Mcc-FAcp rats.

In SHHF/Mcc-FAcp rats (formerly SHR/Mcc-cp), obesity and male gender synergistically modulate hyperinsulinemia, insulin resistance and predisposition to diabetes. Our previous studies showed gender and obesity modulate hepatic cell surface insulin binding and insulin clearance additively. Hepatic insulin receptors (IR) bind insulin as a first step in insulin clearance through internalization and degradation. We hypothesize that the synergistic effects of obesity and gender on hepatic insulin binding and clearance result from interaction of these two factors on hepatic IR expression. To address IR expression in SHHF/Mcc-FAcp rats, we quantitated IR protein levels in detergent-solubilized liver homogenates by Western blotting and IR mRNA levels by a solution hybridization/RNase protection assay. Obesity reduced total hepatic IR content in males and females, 50% and 68% respectively. Male gender reduced IR protein content 24% in lean, but had no effect on IR protein content in obese rats. Neither gender nor obesity affected hepatic IR mRNA content. Thus, obesity appears to affect hepatic IR protein content and cell surface binding through post-transcriptional mechanisms; similarly, male gender in lean rats reduces IR protein levels and cell surface binding through mechanisms not involving changes in mRNA levels. In obese rats, the synergistic effects of male gender appears to involve changes in IR trafficking and consequently cell surface insulin binding and processing.

Animals↗

PubMed1995

Echocardiographic characterization of left ventricular adaptation in a genetically determined heart failure rat model.

This study uses echocardiography to characterize the pattern of left ventricular hypertrophy in a new hypertensive heart failure-prone rat strain designated SHHF/Mcc-cp (SHHF). M-mode echocardiograms of the left ventricle in nine 10- to 12-month old SHHF rats and nine age-matched spontaneously hypertensive rats (SHR) were compared. Wistar-Kyoto and Sprague-Dawley strains served as the normotensive control group. SHHF rats had significantly greater left ventricular mass than did rats in the normotensive control group. Although left ventricular mass was not different between SHHF and SHR, significant differences were seen in the pattern of left ventricular remodeling as determined by relative wall thickness. These differences in left ventricular remodeling may explain the earlier development of heart failure in SHHF. The different patterns of left ventricular hypertrophy in SHHF and SHR suggests that heart failure in SHHF is not mediated by hypertension alone.

Adaptation, Physiological↗

PubMed1995

Copper deficiency alters isomyosin types and levels of laminin, fibronectin and cytochrome c oxidase subunits from rat hearts.

The relative amounts of cardiac proteins such as laminin, fibronectin, cytochrome c oxidase, and isomyosin types were studied by gel electrophoresis and Western blotting in control and copper-deficient Sprague-Dawley rats of both sexes fed their respective diets from weanling for 3 weeks. Isomyosin types appeared to shift from V1 to greater levels of V3 in copper deficient rats for both genders. Male copper deficient rats had increased cardiac levels of fibronectin, decreased laminin levels, cardiac hypertrophy and anemia. Both male and female rats fed copper-deficient diet had lower levels of cytochrome c oxidase (CCO) subunit IV, and low liver copper, and high heart-to-body weight ratios compared with their respective controls.

Animals↗

PubMed1995

Mechanical alternans and the force-frequency relationship in failing rat hearts.

We examined contractile performance in perfused ventricles from normal rats and from SHHF/Mccfacp rats with end-stage heart failure. Changes in pacing frequency from 3 to 5 Hz evoked a complex response in normal rat myocardium. The first beat after a switch to 5 Hz was extremely weak, but each successive beat was stronger until force exceeded the 3 Hz steady state value by approximately 30%. Force then gradually declined to a new steady state where developed pressure was depressed but rate-pressure product was slightly greater than that at 3 Hz. By contrast, in failing SHHF/Mcc-facp hearts, an increase in pacing frequency from 3 to 5 Hz did not increase force development. Instead, the isovolumic left ventricles exhibited mechanical alternans. This alternation between weak and strong beats was abolished by 1 mM caffeine but restored by its washout. Inhibition of SR Ca2+ accumulation by 50-500 nM thapsigargin in normal ventricles did not evoke alternans when pacing frequencies were increased. The results indicate that mechanical alternans in failing rat hearts is due to altered reactions of the sarcoplasmic reticulum, but a decreased rate of Ca2+ accumulation is not the primary cause.

Animals↗

PubMed1994

Effects of acute running exercise on whole body insulin action in obese male SHHF/Mcc-facp rats.

This study utilized the obese male spontaneously hypertensive heart failure rat (SHHF/Mcc-facp), which has metabolic features very similar to human non-insulin-dependent diabetes mellitus. The purpose of this study was to assess the insulin sensitivity and responsiveness of whole body glucose disposal and insulin suppressability of hepatic glucose production with use of the euglycemic-hyperinsulinemic clamp procedure in 12- to 15-wk-old SHHF/Mcc-facp rats at rest (OS) and 2.5 h after a single session of acute exercise (OE). Lean male SHHF/Mcc-facp rats were sedentary (LS) control animals. At least three clamps producing different insulin-stimulated responses were performed on each animal in a randomized order. At this age the obese animals are normotensive and have not developed congestive heart failure. Compared with LS, OS were significantly hyperglycemic and hyperinsulinemic and insulin sensitivity and responsiveness of whole body glucose uptake and insulin suppressability of hepatic glucose production were significantly decreased. Compared with LS and OS, acute exercise significantly decreased resting plasma glucose but did not alter plasma insulin. Compared with OS, acute exercise significantly increased the insulin responsiveness of whole body glucose disposal but did not affect the sensitivity of whole body glucose disposal or insulin suppressability of hepatic glucose production. Compared with LS, however, acute exercise did not "normalize" the insulin responsiveness of whole body glucose disposal. Thus a single acute exercise session improves but does not normalize whole body insulin resistance in the SHHF/Mcc-facp rat.

Animals↗

PubMed1993

Treatment of obese female and male SHHF/Mcc-fa(cp) rats with antihypertensive drugs, nifedipine and enalapril: effects on body weight, fat distribution, insulin resistance and systolic pressure.

Little is known about the effects of common antihypertensive drugs in obese, insulin-resistant females. Nine-month-old obese female SHHF/Mcc-fa(cp) rats that received either nifedipine, a calcium channel antagonist, or enalapril, an angiotensin-converting-enzyme inhibitor, for three months were compared with untreated SHHF/Mcc-fa(cp) rats (controls). After one month, nifedipine significantly decreased body weight in obese females compared to either enalapril or controls. After three months of treatment, total, abdominal, and subcutaneous fat masses were decreased in obese females given nifedipine compared to either enalapril or controls. Enalapril treatment was associated with a redistribution of fat mass from abdominal to subcutaneous depots. Nifedipine reduced plasma triglyceride and fasting glucose levels and improved insulin response to an oral glucose load in obese females, whereas enalapril did not appear to affect glycemic control. Systolic pressure was not significantly decreased until after two months of treatment with nifedipine or three months of treatment with enalapril in obese females and may have coincided with improvement in insulin-resistance. Similarly, plasma atrial natriuretic peptide concentrations were significantly lower in obese females given nifedipine. To determine how obese males responded to a calcium channel antagonist, six-month-old obese male SHHF/Mcc-fa(cp) rats were treated for three months with either nifedipine or placebo (controls). Nifedipine-treated obese males showed a mild but significant decrease in weight gain that was due to a decrease in fat deposition in both subcutaneous and abdominal depots and systolic blood pressure was significantly reduced after one month of treatment. Nifedipine did not affect other plasma biochemical parameters in obese males. In conclusion, nifedipine improved systolic pressure and glycemic control in obese female SHHF/Mcc-fa(cp) rats, effects that may be associated with a marked loss in body weight and fat mass and improved lipid metabolism. Nifedipine-treated obese males exhibited only a diminished weight gain that was not associated with changes in diabetic characteristics.

Animals↗

PubMed1993

Effects of obesity and hypertension on ventricular myocytes: comparison of cells from adult SHHF/Mcc-cp and JCR:LA-cp rats.

OBJECTIVE: The aim was to compare beta adrenergic receptors, cAMP production, and Ca2+ accumulation by the sarcoplasmic reticulum in ventricular cardiomyocytes from female SHHF/Mcc-cp and JCR:LA-cp rats. Whereas rats from both strains exhibit gross obesity when the animals are homozygous for the recessive "corpulent" gene, the SHHF rats, which are hypertensive, all develop heart failure during their second year of life. The normotensive JCR:LA-cp animals do not. METHODS: beta Adrenergic receptor number, ligand affinity, isoprenaline and forskolin stimulated cyclic AMP production, and ATP dependent, phosphate supported 45Ca2+ uptake by the sarcoplasmic reticulum were compared in ventricular cardiomyocytes isolated from 6 months old obese female SHHF/Mcc-cp and obese and lean female JCR:LA-cp rats. RESULTS: Bmax and Kd for (-)-[125iodo]-cyanopindolol (125ICYP) binding were each approximately 50% lower in SHHF/Mcc-cp v JCR:LA-cp myocytes. Cyclic AMP production in response to isoprenaline, isoprenaline plus isobutylmethylxanthine (IBMX), and forskolin plus IBMX was also significantly depressed in the SHHF/Mcc-cp cells. In addition, sarcoplasmic reticular 45Ca2+ uptake by SHHF/Mcc-cp cells was 35% lower than in lean or obese JCR:LA-cp myocytes. Isoprenaline stimulated cAMP production and sarcoplasmic reticular Ca2+ uptake by the lean JCR:LA-cp cells were comparable to that described previously for myocytes from normal Sprague-Dawley rats. By contrast, Bmax and Kd for 125ICYP binding by the JCR myocytes differed substantially from previously described results for normal Sprague-Dawley rats, whereas values for the SHHF cells did not. CONCLUSIONS: Declines in Ca sequestration by the sarcoplasmic reticulum of ventricular cardiomyocytes from obese, hypertensive SHHF rats are not related to their obesity. However, obesity may contribute to the decline in cAMP production. This may account, in part, for the exacerbation by obesity of cardiac dysfunction in essential hypertension.

Animals↗

PubMed1993

The effect of atrial natriuretic peptide infusion on renal haemodynamics and plasma lipoproteins in puromycin aminonucleoside nephrosis in rats.

1. The effect of continuous intravenous administration of 1 microgram/h atrial natriuretic peptide (ANP) for 4 days was studied in normal male Sprague-Dawley rats and rats made nephrotic with puromycin aminonucleoside (PA). 2. ANP infusion significantly increased urinary sodium and potassium excretion by 3 days of infusion in control rats but not in PA-treated rats. ANP infusion significantly increased glomerular filtration rate in PA-treated rats, while effective renal plasma flow was similarly decreased compared with non-infused nephrotic rats. 3. Plasma high density lipoproteins (HDL) were significantly decreased and low density lipoproteins (LDL) were increased in PA-treated rats that received ANP; HDL were increased in normal rats infused with ANP. 4. Competitive binding studies demonstrated a lower density of specific ANP receptors in glomerular membranes from rats injected with PA, while binding affinity was unchanged. 5. Infusion with exogenous ANP did not promote natriuresis in PA nephrosis despite an enhancement of glomerular filtration rate (GFR), thus suggesting that sodium retention in this model is due to a post-glomerular defect. Plasma lipoprotein composition in both normal and nephrotic rats may be affected by ANP.

Animals↗

PubMed1993

Electrocardiographic findings in rats with cardiomyopathy.

The purpose of this study was to evaluate changes in the ECG in a strain of rats, SHHF/Mcc-cp that developed cardiomyopathy and congestive heart failure naturally. Lead-I, -aVF, and -V5 ECG were obtained from male rats at approximately 6, 10, and 19 months of age, corresponding to early, mild, and severe heart failure, respectively. Electrocardiograms also were obtained from male Wistar-Furth rats matched for age with SHHF/Mcc-cp rats. Heart rate, amplitude and duration of component deflections, degree of notching of P waves and QRS complexes, and orientation of means QRS vectors in the frontal plane were analyzed from the ECG. Durations of P waves, PQ intervals, QRS complexes, and QT intervals were prolonged and amplitude of R waves in lead aVF was decreased only in SHHF/Mcc-cp rats at the 19-month recording. Increased notching in QRS complexes, but not in P waves, was observed more frequently at all ages, in SHHF/Mcc-cp rats than in Wistar rats, and notching was greatest at 19 months. Arrhythmias were not observed in Wistar rats, but infrequent supraventricular premature depolarizations were observed in 2 of 10 SHHF/Mcc-cp rats at 19 months. In leads aVF and V5, T waves increased in amplitude as Wistar rats aged; however, in SHHF/Mcc-cp rats, T-wave amplitude peaked in all leads at 10 months, but returned to the 6-month value at month 19. We conclude that cardiomyopathy, heart failure, or both, resulted in changes in the ECG, but that these changes could be used to detect heart failure only when rats reached 19 months of age and were severely affected.

Aging↗

PubMed1992

Effects of enalapril and clonidine on glomerular structure, function, and atrial natriuretic peptide receptors in SHHF/Mcc-cp rats.

Seven-month-old, lean male SHHF/Mcc-cp rats, a model of spontaneous hypertension, progressive renal dysfunction, and congestive heart failure (CHF), were treated with either clonidine (CL) or enalapril (EN) or received no treatment (CON) for 20 weeks. CL significantly decreased systolic blood pressure (SBP), kidney weights, and severity of renal lesions as compared with untreated CON. EN produced a decrease in SBP comparable to that in CL. Kidney weights and severity of renal histologic changes in the EN group were intermediate between those of the CL and CON groups. Despite similar plasma atrial natriuretic peptide (ANP) concentrations, CL treatment resulted in a significant increase in the density of guanylate cyclase-linked glomerular ANP receptors, whereas EN treatment resulted in a significant decrease in the total number of ANP receptors and in the number of nonguanylate cyclase-linked receptors and an increase in overall binding affinity. These findings demonstrate that antihypertensive agents will slow progression of renal injury in SHHF/Mcc-cp rats and that CL is more effective than EN in alleviating progressive kidney damage in this model. Furthermore, different classes of antihypertensive drugs may alter the density or ratio of biologically active and clearance ANP receptor sites in the glomerulus.

Animals↗

PubMed1990

Synergistic effects of male sex and obesity on hepatic insulin dynamics in SHR/Mcc-cp rat.

The effects of obesity and sex on hepatic insulin metabolism were evaluated in the SHR/Mcc-cp rat. During in situ liver perfusion, insulin clearance rate (CLR) expressed per gram of liver tissue was reduced by 58 and 68% in obese females and males, respectively, compared with lean controls. Male sex resulted in CLR reductions of 46% in lean and 59% in obese animals. Obesity resulted in 50% reduction of insulin-receptor binding to isolated hepatocytes. In both lean and obese animals, male sex also resulted in a decrease of approximately 34% in insulin binding. Scatchard plots indicated that the reduction in insulin binding was primarily due to a decrease in number of cell surface receptors. Receptor-mediated insulin degradation was 40% less in obese than lean animals. Male sex also resulted in 27% less insulin degradation relative to females. Receptor-mediated insulin partitioning between four compartments (cell surface bound, internalized and/or cryptic, degraded, and dissociated or released intact), expressed as a percentage of the initial membrane-bound hormone, did not differ between the animal groups. Thus, male sex and obesity are independently and additively associated with a reduction in hepatic insulin clearance and a decrease in the number of cell surface insulin receptors with a proportional decrease insulin compartmentalization and degradation. This mechanism may partly account for the synergistic effects of male sex and obesity on the degree of hyperinsulinemia and insulin resistance and the predisposition to diabetes.

Animals↗

PubMed1989

Aurintricarboxylic acid is a potent inhibitor of phosphofructokinase.

Aurintricarboxylic acid (ATA) was found to be a very potent inhibitor of purified rabbit liver phosphofructokinase (PFK), giving 50% inhibition at 0.2 microM. The inhibition was in a manner consistent with interaction at the citrate-inhibitory site of the enzyme. The data suggest that inhibition of PFK by ATA was not due to denaturation of the enzyme or the irreversible binding of inhibitor, since the inhibition could be reversed by addition of allosteric activators of PFK, i.e. fructose 2,6-bisphosphate or AMP. Two other tricarboxylic acids, agaric acid and (-)-hydroxycitrate, were found to inhibit PFK. ATA at much higher concentrations (500 microM) was shown to inhibit fatty acid synthesis from endogenous glycogen in rat hepatocytes; however, protein synthesis was not altered.

Animals↗

PubMed1989

Mitochondrial storage forms of acetyl CoA carboxylase: mobilization/activation accounts for increased activity of the enzyme in liver of genetically obese Zucker rats.

In earlier reports, we have described a previously unrecognized mechanism which regulates the activity of acetyl CoA carboxylase in rat liver by the control of its distribution between relatively inactive mitochondrial and active cytosolic forms. In this study, the activity, total quantity and the subcellular distribution of acetyl CoA carboxylase were determined in liver of fed and fasted (48 h) homozygous obese (fa/fa) zucker rats and homozygous lean (Fa/Fa) littermates. The results indicate that neither diet nor genetic obesity affected the total quantity of acetyl CoA carboxylase per unit weight of liver. Instead, increased activity of this enzyme in the liver of the Zucker rat was primarily due to a shift in the subcellular distribution away from relatively inactive mitochondrial forms toward active cytosolic forms. Thus, the Zucker rat appears to be yet another example illustrating the physiological importance of regulating the activity of acetyl CoA carboxylase by controlling its subcellular distribution.

ATP Citrate (pro-S)-Lyase↗

PubMed1988

Hereditary pituitary prolactinomas: a new rat model.

Pituitary adenomas are known to occur spontaneously in several rat strains, especially during aging. Here we report the occurrence of adenomas (prolactinomas) in a new rat model at an early age. The adenomas were characterized by light and electron microscopy and histochemically by immunoperoxidase methods using specific antisera. Of the 53 pituitaries examined, one was normal, two were hyperplastic and the remainder were adenomas. Among the latter, there were 37 prolactinomas (70%), 3 GH-producing tumours and 2 ACTH-containing neoplasms. One microadenoma produced both PRL and GH. The remaining 8 adenomas were histochemically negative for all pituitary hormones. Serum PRL levels were elevated in both sexes while serum testosterone was high in females and low in the males. The serum estrogen levels were elevated in the males with prolactinomas. The prolactinomas appear to be transmitted as an autosomal dominant characteristic with incomplete penetrance and a greater incidence in the male.

Animals↗

PubMed1987

Effect of mevinolin on cholesterol metabolism in obese and lean Zucker rats.

Mevinolin is a potent competitive inhibitor of HMG-CoA reductase, the enzyme catalyzing the major rate-limiting step in cholesterol synthesis. In this study the drug was administered as an intragastric dose at 2.5 mg/kg/day to 10 to 12-week-old lean and obese Zucker female rats over a 5-day period. Mevinolin showed no effect on plasma cholesterol levels in the lean rat; however, in the obese rat there was a significant decrease in plasma cholesterol (about a 40% decrease from initial levels). Although there was a difference in effect on plasma cholesterol levels in obese and lean rats, hepatocytes isolated from both fed lean and obese rats incubated with various concentrations of mevinolin exhibited similar levels of inhibition of cholesterol synthesis and showed no effects on the other metabolic processes studied. These results indicate that the drug was effective acutely on cholesterol synthesis in hepatocytes isolated from both lean and obese rats, but on a chronic treatment basis the hypocholesterolemic effect was observed only in the obese Zucker rat. This study supports the idea that the naturally occurring hypercholesterolemic obese Zucker rat may be a good model for testing potential new cholesterol lowering agents.

Animals↗

PubMed1985

Effect of cell density on metabolism in isolated rat hepatocytes.

Freshly isolated rat hepatocytes show many changes in metabolic activities as a function of cell density in the incubation flask. Fatty acid synthesis, cholesterol synthesis, general protein synthesis, and rates of accumulation of pyruvate, lactate, citrate, acetyl-CoA, acetoacetate and beta-hydroxybutyrate decrease as the cell density increases between 1 mg/ml and 60 mg/ml. Glucose release only decreases between 1-5 mg/ml and the concentration of ATP does not vary at any density. There is a small increase in the lactate/pyruvate ratio and a dramatic decrease in the beta-hydroxybutyrate/acetoacetate ratio with increasing cell concentration. When cells at 8 or 28 mg/ml were incubated with added lactate and pyruvate, or alanine, a two fold increase in fatty acid synthesis and 50% decrease in cholesterol synthesis were observed as compared to rates with endogenous substrate. With added glucose the synthetic rates were similar to those obtained with endogenous substrate. However, regardless of the type of substrate used, the less dense cells gave rates up to three times greater than that of the more dense cells. When conditioned medium isolated after incubation of cells at high density was added to the less dense cells, a decrease in the rates of fatty acid synthesis and cholesterol synthesis was observed in the less dense cells; however, when medium from the less dense cells after incubation for the same period was added to the more dense cells, there was no significant change in fatty acid or cholesterol synthesis. These results suggest that a factor may be released into the medium of incubating hepatocytes that progressively inhibits certain metabolic processes as the cell density increases.

Adenosine↗