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UBC Theses and Dissertations

Effect of hypertension on the development of diabetic cardiomyopathy Mathis, David R.


The general objective of this thesis was to examine whether or not hypertension exacerbated the development of diabetic cardiomyopathy. Previous reports in the literature support the idea that hypertension and diabetes have an additive effect and impair cardiac performance to a greater extent than does diabetes alone. However, recent evidence suggests that the rodent model of hypertension used in these studies (the Spontaneously Hypertensive Rat (SHR)) is more sensitive to the diabetogenic effects of streptozotocin (STZ) than other strains. Because the same dose of STZ was used for both hypertensive and control rats, the possibility exists that the increased cardiac dysfunction reported in the diabetic-SHR was due to a more severe diabetic condition. To study this possibility, the dose of STZ was titrated so that an equivalent level of diabetes could be induced in both SHR and Wistar control rats, thereby allowing for the examination of the influence of hypertension on the progression of diabetic cardiomyopathy. In SHR Study #1, both SHR and Wistar rats received a dose of 45 mg/kg STZ and were maintained for twelve weeks of diabetes before cardiac function was studied using the isolated working heart technique. The induction of diabetes depressed weight gain in the SHR while in the Wistar-diabetic (WD) group weight gain was not significantly attenuated. Food and fluid consumption were elevated in both diabetic groups, but was significantly higher in the SHR-diabetic (SD) animals. These data, coupled with the fact that over 70% of SHR became diabetic compared to only 40% of the Wistar rats, indicated that the SHR were more sensitive to the diabetogenic effects of STZ. Cardiac contractile function was analyzed in terms of left ventricular developed pressure (LVDP), rate of contraction (+dP/dt), and rate of relaxation (-dP/dt) when the rats were twenty weeks of age. At the higher left atrial filling pressures, the SD had depressed cardiac function. However, the same dose of STZ in the WD group resulted in no impairment of cardiac performance. Two main conclusions were made from this study. The first was that SHR were more susceptible to the diabetogenic effects of STZ because, even at a low dose, STZ induced diabetes in the majority of SHR. In the Wistar rat, the same dose results in diabetes in only a small percentage of animals. The study also confirmed that a dose of 45 mg/kg in the SHR results in the development of cardiac dysfunction. In SHR Study #2 and SHR Study #3, the objective was to examine the effect of hypertension on the progression of diabetic cardiomyopathy. To that end, SHR were injected with 45 mg/kg STZ either before (8 weeks of age) or after (12 weeks of age) the development of hypertension and compared to normotensive Wistar rats made diabetic with 55 mg/kg STZ. In both studies, the induction of diabetes resulted in depressed weight gain and increased food and fluid consumption. For the rats injected at eight weeks of age, an oral glucose tolerance test (OGTT) demonstrated that the SD rats were significantly less diabetic than the WD rats, yet the degree of cardiac dysfunction was equivalent in both strains. Injecting the SHR at twelve weeks of age increased the severity of the diabetic condition compared the rats injected at eight weeks of age. This was demonstrated by a greater glucose area under the curve (AUC), lower insulin AUC and elevated plasma lipid levels in the rats injected at the older age. Surprisingly, the heart function of the SD rats was not significantly different from the non-diabetic SHR control rats. Injecting the WD at the older age also increased the diabetic condition, but opposite to the SD animals, still impaired cardiac performance. The development of LV hypertrophy at the time of STZ injection may have prevented or compensated for the damaging effects of diabetes on the myocardium, thereby enabling the heart to perform normally.

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