| Summary: | 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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