Date of Award
Master of Science in Pharmacology and Toxicology
Pharmacology and Toxicology
Robert L. Rodgers
Ornithine decarboxylase (ODC) is the first and rate-limiting enzyme in the synthesis of polyamines, which play a regulatory role in nucleic acid and protein synthesis. The enzyme may be involved in normal and abnormal growth of the myocardium, in the relationship between mechanical stress and protein synthesis, and in the development of left ventricular hypertrophy (LVH). Results from this and other laboratories suggest that experimental diabetes has a more profound effect on mechanical function and cellular growth of hypertrophic heart muscle than it does on nonhypertrophic tissue. Diabetes is associated with reduced serum levels of both insulin and thyroid hormone. Both of these hormones are demonstrated regulators of ODC activity. Despite this, relatively little is known about the effects of diabetes on cardiac ODC activity and polyamine synthesis in the presence or absence of LVH. Therefore, we have hypothesized that: 1) ODC activity of hypertrophic left ventricle in spontaneously hypertensive rat (SHR) is higher than that of nonhypertrophic left ventricle in the normotensive rat strains, Wistar Kyoto (WKY) and Sprague Dawley (SD); 2) Untreated diabetes will reduce left ventricular ODC activity of SHR and of nonhypertensive rats, but its effects on the former will be greater in magnitude; 3) The effects of diabetes on left ventricular ODC activity, of either SHR or normotensive rats, will be preventable with insulin treatment, and at least partially preventable by thyroid hormone treatment, in vivo. Diabetes was induced in SHR and WKY by Streptozotocin (STZ) at 15 weeks of age. Subgroups were treated with insulin or triiodothyronine (T3). After 8 weeks of treatment, left and right ventricles were assayed for ODC activity, by measuring the rate of evolution of 14co2 from (1- 14c) L-ornithine. The results show that left ventricular ODC activity of nondiabetic SHR was not significantly different from that of either the WKY or SD normotensive rats. Streptozotocin-induced diabetes reduced left ventricular ODC activity to about the same extent in the hypertrophic SHR and in the nonhypertrophic WKY, depressing Vmax without affecting the apparent Km of the enzyme in both strains. However, experimental diabetes had no effect on right ventricular ODC activity in either the SHR or WKY strains. Both insulin and T3 treatment were partially effective in preventing the reductions in ODC activity caused by diabetes. The results show that the depression in ODC activity caused by untreated diabetes 1) Is selective for the left ventricle perhaps because of its relatively greater workload; 2) Is not selective for the hypertrophic ventricle in the SHR strain; and 3) May be related, in part, to the effects of the hypothyroidism which attends diabetes. These results do not support a causal relationship between left ventricular ODC activity and the maintenance of hypertrophy, nor do they support a predisposition of left ventricular hypertrophy to influences of diabetes on ODC activity (Hypotheses 1 and 2). The results do support a participation of attendant hypothyroidism in the effects of diabetes on left ventricular ODC activity (Hypothesis 3).
Christe, Michael E., "MYOCARDIAL ORNITHINE DECARBOXYLASE OF HYPERTENSIVE AND DIABETIC RATS: EFFECTS OF INSULIN AND TRIIODOTHYRONINE TREATMENT" (1989). Open Access Master's Theses. Paper 240.