Search PubMed⌕ Search

Biomedical subjects

J Isgaard

Publications and source records attributed to J Isgaard.

At least 19 recordsLinked to original sources
PubMed2000

In vivo metabolic imaging of cardiac bioenergetics in transgenic mice.

Recent advances in transgenic technology have made the mouse a particularly interesting small animal in cardiovascular research. Increasingly sophisticated experimental methods and tools are needed for detailed characterization of cardiovascular physiology and biochemistry in the mice. The objective of this study was to develop a method for noninvasive evaluation of cardiac energy metabolism in the mouse. Cardiac gated (31)P magnetic resonance spectroscopy using Image Selected in Vivo Spectroscopy (ISIS) method was applied in old mice overexpressing bovine growth hormone (bGH) (n = 5) and control mice (n = 5). The localized volumes of interest were 128 and 112 microL, respectively. Phosphocreatine-to-ATP ratio was 1.5 +/- 0.13 in the bGH mice and 2.1 +/- 0.04 in the control group (P < 0.01). The study demonstrates the feasibility of application of volume-selective (31)P MRS for evaluation of cardiac energy metabolism in the mouse under maintained physiological conditions.

Animals↗
PubMed2000

Postprandial resynthesis of myofibrillar proteins is translationally rather than transcriptionally regulated in human skeletal muscle.

Feeding stimulates protein synthesis in skeletal muscles, although the regulatory mechanisms are incompletely understood. The aim of this study was to determine whether this could be detected at the gene transcription level for postprandial stimulation of the synthesis of muscle proteins. Healthy male volunteers were investigated after an overnight fast. Open muscle biopsies were performed in the starved state and 3 h after meal intake, consisting of 0.15 gN/kg, 12 kcal/kg. Blood samples were drawn every 15 to 30 min for 5 h. Myosin mRNA and insulin growth factor-I (IGF-I) mRNA were measured by solution hybridization assay in homogenized muscle specimens. After food intake, plasma glucose concentrations increased from 5.0 +/- 0.1 to 7.3 +/- 0.3 (P < or = 0.001), and insulin concentration rose from 3.8 +/- 0.5 mU/L before to 75.3 +/- 11.4 15 min after the meal (P < or = 0.001). Plasma concentration of free fatty acids declined after food intake (P < or = 0.001). Plasma concentrations of amino acids increased from basal values (2864 +/- 128 microM) to 4419 +/- 262 microM (P < or = 0.05) 90 min after meal ingestion. Myosin mRNA concentration in the biopsied muscle tissue was higher during starvation and was reduced by 20% after food intake: 10.8 +/- 1.3 amol mRNA/microgram DNA in the starved state and 8.5 +/- 1.3 amol mRNA/microgram DNA after food intake (P < or = 0.05). Feeding did not alter IGF-I mRNA concentrations in muscle: 0.51 +/- 0.05 and 0.55 +/- 0.06 amol/microgram DNA in the starved and fed state, respectively (P < or = 0.48). Improved protein balance by stimulation of protein synthesis has been related to increased plasma amino acids. Interestingly, in the short term, this was not related to increases in gene transcription of either myofibrillar proteins (myosin) or muscle IGF-I. Thus, postprandial stimulation of protein synthesis appears not to be regulated by increased gene transcription but by increased translation using the increased concentrations of amino acids. In contrast, as far as the 2X myosin mRNA level is concerned, this is enhanced during starvation, which facilitates rapid recovery once the availability of substrate is resumed.

Adult↗
PubMed2000

Semi-starvation alters myofibrillar mRNA concentrations to expedite rapid recovery of muscle protein stores following feeding.

BACKGROUND: Protein synthesis in skeletal muscle is reduced following starvation and restored by feeding. The mediators and mechanisms are incompletely understood. The aim of this study was to evaluate whether prolongation of undernutrition induced changes in muscle gene expression at the level of mRNA and protein. MATERIALS AND METHODS: The changes in myosin heavy-chain 2X mRNA in adult partially starved (50% of ad libitum standard rodent chow intake for 4 or 7 days) C57BL mice or subsequently refed mice were studied. Ad libitum-fed mice were used as controls. Protein synthesis, total RNA and myosin heavy-chain 2X mRNA concentrations were determined. Plasma concentrations of amino acids were measured by high-performance liquid chromatography. RESULTS: Partial starvation of 4 and 7 days reduced bodyweight by 15.6 +/- 1% and 17.1 +/- 2.1% (P < or = 0.05) vs. ad libitum fed controls. Protein synthesis was reduced by 32 +/- 9% and protein content by 20 +/- 4% (P < or = 0.05) following 7 days of partial starvation. Plasma amino acid concentrations were increased (6297 +/- 853) in refed animals vs. ad libitum-fed controls (3057 +/- 141, P < or = 0.05). Total RNA concentration (micrograms RNA micrograms(-1) DNA) in skeletal muscle was unchanged. Myosin heavy-chain 2X mRNA concentration did not change following 4 days of partial starvation but increased by 24 +/- 5% (P < or = 0.05) following 7 days of partial starvation, hence suggesting that expression of myosin mRNA was nutritionally altered. CONCLUSION: Postprandial stimulation of protein synthesis following starvation may thus be a combination of increased mRNA availability and increased translation. This effect may be activated by peak concentrations of amino acids in plasma following feeding.

Amino Acids↗
PubMed2000

IGF-I/IGFBP-3 binary complex modulates sepsis-induced inhibition of protein synthesis in skeletal muscle.

The present study evaluated the ability of insulin-like growth factor I (IGF-I) complexed with IGF binding protein-3 (IGFBP-3) to modulate the sepsis-induced inhibition of protein synthesis in gastrocnemius. Beginning 16 h after the induction of sepsis, either the binary complex or saline was injected twice daily via a tail vein, with measurements made 3 and 5 days later. By day 3, sepsis had reduced plasma IGF-I concentrations approximately 50% in saline-treated rats. Administration of the binary complex provided exogenous IGF-I to compensate for the sepsis-induced diminished plasma IGF-I. Sepsis decreased rates of protein synthesis in gastrocnemius relative to controls by limiting translational efficiency. Treatment of septic rats with the binary complex for 5 days attenuated the sepsis-induced inhibition of protein synthesis and restored translational efficiency to control values. Assessment of potential mechanisms regulating translational efficiency showed that neither the sepsis-induced change in gastrocnemius content of eukaryotic initiation factor 2B (eIF2B), the amount of eIF4E associated with 4E binding protein-1 (4E-BP1), nor the phosphorylation state of 4E-BP1 or eIF4E were altered by the binary complex. Overall, the results are consistent with the hypothesis that decreases in plasma IGF-I are partially responsible for enhanced muscle catabolism during sepsis.

Animals↗
PubMed2000

The growth hormone secretagogue hexarelin improves cardiac function in rats after experimental myocardial infarction.

Several studies have shown that GH can enhance cardiac performance in rats after experimental myocardial infarction and in humans with congestive heart failure. In the present study, the hemodynamic effects of hexarelin (Hex), an analog of GH-releasing peptide-6 and a potent GH secretagogue, were compared with the effects of GH. Four weeks after ligation of the left coronary artery male rats were treated sc twice daily with hexarelin [10 microg/kg x day (Hex10) or 100 microg/kg x day (Hex100)], recombinant human GH (2.5 mg/kg x day), or 0.9% NaCl for 2 weeks. Transthoracic echocardiography was performed before and after the treatment period. GH, but not Hex, increased body weight gain. GH and Hex100 decreased total peripheral resistance (P < 0.05) and increased stroke volume (P < 0.05 and P < 0.01, respectively) and stroke volume index (P = 0.06 and P < 0.01, respectively) vs. NaCl. Cardiac output was increased by GH and Hex100 (P < 0.05), and cardiac index was increased by Hex100 with a borderline significance for GH (P = 0.06). In conclusion, Hex improves cardiac function and decreases peripheral resistance to a similar extent as exogenous GH in rats postmyocardial infarction. The mechanisms of these effects are unclear; they could be mediated by GH or a direct effect of Hex on the cardiovascular system.

Animals↗
PubMed2000

Pretreatment with growth hormone-releasing peptide-2 directly protects against the diastolic dysfunction of myocardial stunning in an isolated, blood-perfused rabbit heart model.

Brief coronary occlusion followed by reperfusion leads to reversible myocardial dysfunction (stunning) which can induce irreversible damage of other organ systems. We studied the effects of pretreatment with recombinant human GH (rhGH) and the GH-secretagogue GHRP-2 on myocardial stunning in a blood-perfused isolated rabbit heart model. In a first set of experiments, effects of bolus rhGH administration (3.5 mg/kg) (n = 5) into the aortic root of unpretreated animals were compared with those of saline (n = 6). In a second set, animals were pretreated for 14 days with SC rhGH 3.5 mg/kg x day (n = 9) or 160 microg/kg x day GHRP-2 (n = 8) in two divided doses. Body weight and plasma concentrations of rhGH, rabbit GH (rGH) and IGF-I were determined before and at the end of 14 days pretreatment. Hearts were excised and submitted to 15 min ischemia followed by 80 min reperfusion, after which postischemic recovery was compared with nonischemic hearts mounted into the same system. At study end, all hearts were snap-frozen to examine markers of apoptosis. Circulating levels of rabbit GH (rGH) remained identical in all animals. Pretreatment with rhGH for 14 days induced a 142 +/- 116% rise of serum IGF-I vs. 8 +/- 15% with GHRP-2 (P < 0.001) and increased body weight with 6.8 +/- 2.5% vs. 3.4 +/- 3.3% with GHRP-2 (P = 0.01). A bolus injection of rhGH did not alter myocardial function compared with saline allowing data from these experiments to be pooled into one ischemic control group for further analysis of the effect of pretreatment. No difference in postischemic recovery of left ventricular systolic function among the unpretreated, rhGH pretreated and GHRP-2 pretreated hearts was apparent. At the end of reperfusion, a 3-fold higher end-diastolic pressure (EDP) persisted in the unpretreated and rhGH pretreated hearts compared with the nonischemic hearts. In the GHRP-2 pretreated hearts, EDP decreased to half the pressure observed in unpretreated and rhGH pretreated hearts (all P < or = 0.02), a level which was indistinguishable from that in the non-ischemic hearts, suggesting full postischemic recovery of diastolic function. There were no signs of increased apoptosis in the experimental groups. In conclusion, 14 days pretreatment with GHRP-2, but not rhGH, protected selectively against the diastolic dysfunction of myocardial stunning in this model. This observation may open perspectives for GH-secretagogues as cardioprotective agents.

Animals↗
PubMed2000

Growth hormone improves bioenergetics and decreases catecholamines in postinfarct rat hearts.

The aims of this study were to examine, in vivo, the effects of GH treatment on myocardial energy metabolism, function, morphology, and neurohormonal status in rats during the early postinfarct remodeling phase. Myocardial infarction (MI) was induced in male Sprague Dawley rats. Three different groups were studied: MI rats treated with saline (n = 7), MI rats treated with GH (MI + GH; n = 11; 3 mg/kg x day), and sham-operated rats (sham; n = 8). All rats were investigated with 31P magnetic resonance spectroscopy and echocardiography at 3 days after MI and 3 weeks later. After 3 weeks treatment with GH, the phosphocreatine/ATP ratio increased significantly, compared with the control group (MI = 1.69 +/- 0.09 vs. MI + GH = 2.42 +/- 0.05, P < 0.001; sham = 2.34 +/- 0.08). Treatment with GH significantly attenuated an increase in left ventricular end systolic volume and end diastolic volume. A decrease in ejection fraction was prevented in GH-treated rats (P < 0.05 vs. MI). Myocardial and plasma noradrenaline levels were significantly lower in MI rats treated with GH. These effects were accompanied by normalization of plasma brain natriuretic peptide levels (sham = 124.1 +/- 8.4; MI = 203.9 +/- 34.7; MI + GH = 118.3 +/- 8.4 ng/ml; P < 0.05 vs. MI). In conclusion, GH improves myocardial energy reserve, preserves left ventricular function, and attenuates pathologic postinfarct remodeling in the absence of induction of left ventricular hypertrophy in postinfarct rats. The marked decrease in myocardial content of noradrenaline, after GH treatment, may protect myocardium from adverse effects of catecholamines during postinfarct remodeling.

Animals↗
PubMed2000

Impairment of cardiac function and bioenergetics in adult transgenic mice overexpressing the bovine growth hormone gene.

Cardiovascular abnormalities represent the major cause of death in patients with acromegaly. We evaluated cardiac structure, function, and energy status in adult transgenic mice overexpressing bovine GH (bGH) gene. Female transgenic mice expressing bGH gene (n = 11) 8 months old and aged matched controls (n = 11) were used. They were studied with two-dimensional guided M-mode and Doppler echocardiography. The animals (n = 6) for each group were examined with 31P magnetic resonance spectroscopy to determine the cardiac energy status. Transgenic mice had a significantly higher body weight (BW), 53.2+/-2.4 vs. 34.6+/-3.7 g (P < 0.0001) and hypertrophy of left ventricle (LV) compared with normal controls: LV mass/BW 5.6+/-1.6 vs. 2.7+/-0.2 mg/g, P < 0.01. Several indexes of systolic function were depressed in transgenic animals compared with controls mice such as shortening fraction 25+/-3.0% vs. 39.9+/-3.1%; ejection fraction, 57+/-9 vs. 77+/-5; mean velocity of circumferential shortening, 4.5+/-0.8 vs. 7.0+/-1.1 circ/sec, p < 0.01. Creatine phosphate-to-ATP ratio was significantly lower in bGH overexpressing mice (1.3+/-0.08 vs. 2.1+/-0.23 in controls, P < 0.05). Ultrastructural examination of the hearts from transgenic mice revealed substantial changes of mitochondria. This study provides new insight into possible mechanisms behind the deteriorating effects of long exposure to high level of GH on heart function.

Acromegaly↗
PubMed1999

Interaction between the renin-angiotensin system and insulin-like growth factor I in aorto-caval fistula-induced cardiac hypertrophy in rats.

The effects of angiotensin converting enzyme inhibition and angiotensin II receptor blockade on the development of cardiac hypertrophy and myocardial insulin-like growth factor I (IGF-I) in volume overload were studied in male Wistar rats with aorto-caval fistulas (ACF). Rats were treated with ramipril (RAM, 3 mg kg(-1) day(-1)) for 4-20 days or losartan (LOS, 10 mg kg(-1) day(-1)) for 2-7 days. Myocardial IGF-I and IGF-I receptor (IGF-I-R) mRNA were determined by solution hybridization. ACF caused hypertrophy of left (LV) and right ventricles (RV). Hypertrophy appeared on day 2 and reached maximal values of +60% in LV and +75% in RV at day 12. Systolic blood pressure was initially reduced 15% but recovered by day 12. RAM abolished the recovery of blood pressure. Furthermore, RAM attenuated RV hypertrophy by 17% on day 7 and on day 20, RV weights were close to values found in controls. Beginning on day 9, RAM reduced LV weight back to control levels in parallel to blood pressure. In contrast, LOS affected neither RV nor LV hypertrophy. RV IGF-I mRNA increased 60-100% on day 7 alone in RV in ACF. RAM potentiated the increase in RV IGF-I to +400% and induced an increase in RV IGF-I-R mRNA on day 7 (+90%) in ACF. LOS did not affect RV IGF-I. Development of cardiac hypertrophy in ACF seemed independent of angiotensin II. RV hypertrophy was associated with activation of IGF-I independent of the renin-angiotensin system. IGF-I was further potentiated when development of hypertrophy was attenuated, possibly indicative of a greater urge for compensational growth in a relatively thinner and more volume-distended chamber.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Possible protective role of growth hormone in hypoxia-ischemia in neonatal rats.

Perinatal asphyxia still constitutes a clinical hazard associated with considerable neurologic morbidity. Several growth factors, including insulin-like growth factor-I (IGF-I), have been reported to have a neuroprotective effect in experimental models of hypoxic ischemia (HI). In the present study, we have applied solution hybridization for quantification of the time course for mRNA expression of IGF-I, IGF-I receptor, and growth hormone (GH) receptor after HI in 7-d-old rats. There was a significant increase in IGF-I mRNA in the damaged hemisphere 72 h (1.19 +/- 0.28 vs 0.48 +/- 0.02 amol/microg DNA, p < 0.05) and 14 d (0.61 +/- 0.18 vs 0.19 +/- 0.05 amol/microg DNA, p < 0.05) after HI. In the contralateral hemisphere, both IGF-I and GH receptor mRNA had increased by 14 d after the insult (0.36 +/- 0.042 vs 0.13 +/- 0.011, p < 0.05, and 0.31 +/- 0.013 vs 0.11 +/- 0.004 amol/microg DNA, p < 0.001, respectively). There were no changes in IGF-I receptor mRNA throughout the study period. We have also evaluated the neuroprotective effect of GH after HI in neonatal rats. GH administered s.c. after HI in daily doses of 50 and 100 mg/kg provided a moderate neuroprotection of 20%. These results suggest a role for the GH/IGF-I axis in the neurochemical process leading to HI brain injury.

Animals↗
PubMed1999

Differential regulation of IGF-I, its receptor and GH receptor mRNAs in the right ventricle and caval vein in volume-loaded genetically hypertensive and normotensive rats.

It has been suggested, mainly by in vitro findings, that cardiovascular tissue in the spontaneously hypertensive rat (SHR) should be more prone to proliferate/hypertrophy than that of the Wistar-Kyoto rat (WKY). The present study tests the hypothesis that the tissue of the low-pressure compartment in SHR, being structurally similar to that of the WKY, shows an increased growth response due to activation of the GH-IGF-I system. An aortocaval fistula (ACF) was induced in 64 SHR and WKY male rats and 44 rats served as controls. They were all followed for 1, 2, 4 and 7 days after surgery. In separate groups of SHR (n=4) and WKY (n=3), central venous pressure was measured by telemetry recordings prior to opening of the fistula and for up to 16 h post-surgery. Systolic blood pressure was measured during the week post-surgery. The right ventricular (RV) and the caval vein IGF-I mRNA and RV IGF-I receptor and GH receptor mRNAs were quantitated by means of solution hybridisation assay. In rats with ACF the systolic blood pressure decreased, approximately 29% in SHR and 16% in WKY between 1 and 7 days post-surgery (P<0.05, n=5-6 in each group). SHR with ACF showed a transient elevation in central venous pressure vs WKY. Within the week following fistula induction both strains showed a similar, pronounced increase in RV hypertrophy. SHR with ACF showed a smaller, or even blunted, overall response with respect to activation of the GH-IGF-I system compared with WKY, the latter showing clear-cut elevation of gene expressions. Two days after shunt opening in SHR, RV and caval vein IGF-I mRNA increased by 57% and 108% (P<0.05 for both, n=5-6 in each group) respectively, and these expressions were then turned off, whereas RV GH receptor and IGF-I receptor mRNA expression remained unaffected compared with WKY rats. WKY rats showed on average a later and a greater response of GH-IGF-I system mRNA expression vs SHR. The present in vivo study suggests that the SHR requires less activation of the GH-IGF-I system for creating a given adaptive structural growth response.

Animals↗
PubMed1998

[Study and treatment of heart failure require new approaches. Natriuretic peptides can be safe and simple diagnostic and outcome measures].

Analysis of plasma natriuretic peptides and related propeptide fragments may be a cost-effective aid to diagnostic evaluation and treatment follow-up in cases of heart failure. In diagnostic potential such variables may constitute first-line measures of high negative predictive value, allowing further examination, e.g. by echocardiography, in cases where values are above the respective cut-off levels. However, in many cases evaluation of published reports is rendered difficult by their omission of information on such pre-analytical variables as blood sampling and storage, and drug therapy. Moreover, different analytical methods may yield widely divergent results. Thus, before such assays are introduced in general use, their long-term validity needs to be ensured, for instance by consistency in calibration, and measurements need to be made in representative series of unselected patients for the determination of appropriate cut-off levels.

Amino Acid Sequence↗
PubMed1998

Inhibited expression of insulin-like growth factor I mRNA and attenuated cardiac hypertrophy in volume overloaded hearts treated with difluoromethylornithine.

The present study examined whether the previously reported hypertrophy and increased expression of insulin-like growth factor I (IGF-I) mRNA in the volume-overloaded right ventricle was dependent on an intact production of polyamines. Volume overload was created in normotensive Wistar rats by means of an aorto-caval fistula. Difluoromethylornithine (DFMO) 2%, which is a specific, irreversible blocker of ornithine decarboxylase, was administered in the drinking water to intervention groups and one sham group, respectively, 24 h prior to surgery and for up to 26 days. DFMO blocked transiently the early over-expression of right ventricular IGF-I mRNA and attenuated the rapid development of both right and left ventricular hypertrophy during volume overload. Expression of IGF-I mRNA in the right ventricle in the early phase of volume overload appears to be dependent on activation of ornithine decarboxylase, whereas other pathways are involved in the later phase of cardiac structural adaptation. Thus, these findings link together early and late growth responses potentially important for compensatory cardiac hypertrophy.

Angiotensin II↗
PubMed1998

A placebo-controlled study of growth hormone in patients with congestive heart failure.

AIM: Experimental data in heart failure models and an open trial of seven patients with idiopathic dilated cardiomyopathy have suggested beneficial effects of growth hormone on cardiac function. The aim of the present study was to evaluate growth hormone effects on cardiac function in a placebo-controlled study. METHODS: Twenty two patients with congestive heart failure of different aetiologies in NYHA II and III and an echocardiographic ejection fraction <0.45 were studied in a 3 month double-blind placebo-controlled study with growth hormone added to optimal heart failure therapy. Patients received either placebo (n=11) or recombinant human growth hormone (n=11) in an initial dose of 0.1 IU x kg(-1) week(-1) for 1 week, and thereafter 0.25 IU x kg(-1) week(-1) for the rest of the treatment period. Cardiac function was assessed by equilibrium radionuclide angiography and Doppler echocardiography. Functional capacity was evaluated by computerized bicycle exercise electrocardiography. RESULTS: Recombinant human growth hormone had no significant effect on systolic or diastolic cardiac function, exercise capacity or neuroendocrine activation. In addition, there was no overall improvement in functional class or dyspnoea grade. Insulin-like growth factor-I significantly increased demonstrating that the growth hormone had an endocrine effect. CONCLUSION: This is the first double-blind and placebo-controlled study of the administration, over 3 months, of recombinant human growth hormone in patients with congestive heart failure of different aetiologies. The treatment was safe and without serious side effects. However, no beneficial effects on cardiac function or structure could be detected.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Growth hormone improves cardiac function in rats with experimental myocardial infarction.

Accumulating evidence suggests from experimental and clinical studies beneficial effects of growth hormone (GH) on contractility, although concomitant cardiac hypertrophy, generally considered to be a cardiovascular risk factor, has also been reported. In the present study, we combine a rat model with impaired cardiac performance after myocardial infarction (MI) with echocardiographic evaluation of GH effects on cardiac structure and function. We have used a rat model with ligation of the left coronary artery in normal, growing male rats resulting in subsequent impaired cardiac performance. After 6 weeks' recovery, blind transthoracic echocardiography was performed to determine infarction size, cardiac geometry and performance. Rats with no signs of myocardial infarction were excluded from the study. After randomization, the rats were treated with daily s.c. injections of saline (n = 8) or recombinant human growth hormone (rhGH) (n = 6) at a dose of approximately 1 mg kg-1 body weight for 1 week. A new blind echocardiography examination was performed after treatment demonstrating a 13% increase in ejection fraction (EF) and a 50% increase in cardiac index in GH-treated rats compared with control rats (P < 0.01). Moreover, GH caused a significant decrease in end-systolic volume. There were no significant changes in left ventricular (LV) or interventricular wall thickness, LV dimensions, heart rate or diastolic function. No effects were seen on LV weight, cardiac insulin-like growth factor (IGF) I, IGF-I receptor and GH receptor mRNA content. GH in a physiological dose improves systolic function in an experimental model of heart failure without signs of hypertrophy, suggesting a potential role as a therapeutic agent in the treatment of heart failure and merits further investigation.

Animals↗