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O Gøtzsche

Publications and source records attributed to O Gøtzsche.

25 records · Page 2Linked to original sources
PubMed1983

The adrenergic beta-receptor adenylate cyclase system in heart and lymphocytes from streptozotocin-diabetic rats. In vivo and in vitro evidence for a desensitized myocardial beta-receptor.

The myocardial beta-receptor adenylate cyclase system was investigated in short-term streptozotocin-diabetic rats. Earlier reports of a decreased sensitivity of the myocardium to isoproterenol (ISO) in these animals were elucidated by measuring the in vivo production of cAMP after ISO. A substantial decrease was seen in diabetic animals compared with controls and starved animals, and thyroxine treatment, known to sensitize the myocardium to catecholamines, did not normalize the response. The desensitization was retained in a membrane fraction in such a way that ISO was unable to increase the cAMP production while stimulation via the nucleotide-binding protein (with NaF or GTP) leads to a normal cAMP response. As the beta-adrenergic receptor number and affinity turned out to be identical in control and diabetic animals, a functional uncoupling of the myocardial beta-receptor from productive adenylate cyclase activation seems thus to exist in experimental diabetes. It is unlikely that it has anything to do with the thyroid status of the animals, but the possibility of a catecholamine-induced densensitization cannot be excluded. The phenomenon is not universal as the beta-receptor-adenylate cyclase system is normal in isolated spleen lymphocytes. Whether the described phenomenon obtained in an animal study has any relevance for the increased incidence of heart failure in human diabetes mellitus is not known at present.

Adenylyl Cyclases↗
PubMed1983

Decreased myocardial calcium uptake after isoproterenol in streptozotocin-induced diabetic rats. Studies in the in vitro perfused heart.

Myocardial calcium uptake in response to isoproterenol (ISO, 10(-4) M) was investigated in control and streptozotocin-induced diabetic rats using an in vitro heart perfusion model. An initial labeling with 45Ca added to the perfusate (with or without ISO) was followed by a cold calcium-free washout, thus clearing the myocardial interstitium of 45Ca. In this way the remaining 45Ca was an estimate of the myocardial calcium uptake during the labeling period. In control rats ISO induced a statistically significant increase in myocardial calcium uptake within the first 5 minutes, as well as from the 5th to the 15th minutes after exposure to this strong beta-receptor agonist. In contrast to this, diabetic hearts showed no increase in calcium uptake during any of these periods. The toxic effect of ISO was expressed by a leak of creatinine phosphokinase to the perfusate. In control rats the concentration of creatinine phosphokinase increased after ISO with a statistically significant correlation to the calcium uptake, whereas no enzymatic leak was seen after perfusion of the diabetic hearts. This abnormal response to strong beta-receptor stimulation in experimental diabetes is in accordance with our earlier in vivo finding of a myocardial protection against toxic doses of ISO. These results indicate a decreased catacholamine-induced calcium transport through the myocardial sarcolemma in streptozotocin-induced diabetic rats. This might hypothetically have relevance for diabetic heart disease as well as diabetic neuropathy.

Animals↗
PubMed1982

Lack of cardiotoxic effect of isoproterenol in streptozotocin diabetic rats. A morphometric study of isoproterenol induced fibrosis.

The well known cardiotoxic effect of isoproterenol (ISO) was investigated in normal and streptozotocin diabetic rats. Seven days after the subcutaneous injection of ISO (15 mg/kg) the hearts were perfusion fixed and 12 sections from each heart were stained (Masson's trichrome). ISO induced myocardial fibrosis was quantified at the light microscopic level according to established morphometric principles. Pulse rate and ST elevation were recorded by EEC (3 standard leads) before and after the ISO injection. Non-diabetic control animals showed marked fibrosis after ISO, but surprisingly the diabetic animals showed no fibrosis after ISO treatment. These findings were in accordance with an ISO induced ST elevation seen only among control animals although both groups showed the same degree of tachycardia. Insulin treatment prevented the protection against ISO and when streptozotocin was injected 24 h after the ISO a normal quantitative and qualitative appearance of the scar tissue was seen. It thus seems that streptozotocin diabetic rats are protected against the toxic effect of ISO, leaving the haemodynamic response unaffected. Which factor in the diabetic metabolism is responsible for the present phenomenon is not known, but a defect in the signal transmission from the beta-receptor to the adenylcyclase is suggested as a possible explanation.

Animals↗
PubMed1981

Irreversibility of glomerular basement membrane accumulation despite reversibility of renal hypertrophy with islet transplantation in early experimental diabetes.

A quantitative morphologic study of the glomeruli in rats after 4 wk of streptozotocin-induced diabetes showed a number of glomerular changes, as previously described. Of particular interest was the increase in the total amount of glomerular basement membrane material [from 0.94 +/- 0.13 (SD) mm3 to 1.26 +/- 0.14 mm3 per kidney]. This parameter did not change after 4 wk of normoglycemia following islet cell transplantation (1.19 +/- 0.17 mm3), nor was the total glomerular volume normalized. The contralateral kidney was weighed and used for estimating the total amounts of protein, RNA, and DNA. Four weeks of diabetes expectedly resulted in a 50% increase in kidney weight, and islet cell transplantation diminished this to 15% in excess of normal. The average cell size (protein/DNA ratio) paralleled the kidney size after diabetes and following transplantation. The average amount of RNA per cell (RNA/DNA) increased significantly after induction of diabetes and was totally normalized after transplantation. Kidney protein concentration (mg protein/mg kidney) remained constant throughout the experiment. Considering that a few weeks of diabetes provokes a large increase in basement membrane material, it is especially noteworthy that 1 mo of normoglycemia is quite insufficient to reverse the accumulation.

Animals↗
PubMed1980

The rate of synthesis and breakdown of glomerular basement membrane material at the transition 'normal to diabetes' and 'diabetes to normal'.

A considerable enlargement of the renal glomeruli is present very early after the acute onset of juvenile diabetes mellitus. In the hypertrophied glomeruli the surface area of the capillary walls, the filtration surface, is increased, and thereby also the amount of basement membrane in the capillary wall. The rate of development of this type of diabetic basement membrane accumulation has been studied in streptozotocin diabetic rats with 4- and 47-day duration of diabetes. During the first 4 days a 40% increase in the total amount of peripheral basement membrane material occurs, whereas the following period up to 47 days shows no further change. The structural changes of the glomerular capillaries seen in conjunction with the basement membrane accumulation comprise an enlargement of the filtration surface and capillary luminal volume. In another experiment, 4-week diabetic animals were transplanted with pancreatic islets. The renal structures were studied quantitatively after 4 weeks of normalization. It was found that the increased amounts of basement membrane material were still present.

Animals↗