Effect of metformin treatment on isolated cardiac function and blood pressure in diabetic and hypertensive rats

The general purpose of this thesis was to examine the effect of chronic metformin treatment on isolated cardiac function in rats made diabetic with STZ and secondly to explore the effect of metformin treatment on the hyperinsulinemic status of two rodent models of hypertension, the spontaneously hypertensive rat and the fructose-induced hypertensive rat. In the first set of experiments, the effects of oral metformin administration were studied in isolated perfused working hearts from control and diabetic rats. Control (C) and streptozotocin (STZ) diabetic (D) rats were treated for 8 weeks with metformin hydrochloride. Treatment was initiated at 350 mg/kg/day and was gradually increased to a dose of 650 mg/kg/day which was maintained over a six week period. Isolated heart performance was assessed under conditions of increasing preload in order to evaluate the performance of each heart to "stress". Hearts from untreated D rats exhibited a depressed response to increases in left atrial filling pressure from 17.5 to 22.5 cm H₂O in terms of left ventricular developed pressure (LVDP), ventricular contractility (+dP/dt) and ventricular relaxation (-dP/dt) when compared to age matched controls. The diabetic hearts also exhibited a delayed halftime to relaxation (T₁/₂R) at filling pressures from 15 to 22.5 cm H₂O. The function curves were performed at a constant heart rate of 300 beats/minute. These responses were restored to control values in D rats treated with metformin. Metformin treatment did not affect these ventricular indices in the C rats. Metformin reduced plasma glucose levels in the diabetic rats from 24.3 mM to 14.4 mM without any increase in the plasma insulin level. The D group had higher triglyceride levels than age matched untreated C rats and metformin administration in the D rat reduced triglyceride levels to control values but had no effect in C rats. In conclusion, metformin administration improved cardiac performance in STZ-diabetic rats under conditions of increasing preload. The second series of experiments aimed at exploring the relationship between elevated insulin levels and experimental hypertension using metformin as the experimental intervention. In particular, the effect of chronic metformin treatment was studied in a genetic and acquired model of hyperinsulinemia and hypertension; the Spontaneously hypertensive rat (SHR) and the fructose-induced hypertensive rat. SHR and their genetic normotensive controls, the Wistar-Kyoto (WKY) rat, were procured at 5 weeks (when hypertension is not manifest in the SHR). The rats were divided into four groups: SHR untreated, SHR metformin-treated, WKY untreated and WKY metformin-treated. Baseline measurements of plasma insulin, plasma glucose and systolic blood pressure were performed from week 9 to 13. At week 16 insulin implants were surgically implanted in the treated animals to evaluate the effect of artificially raising plasma insulin and systolic blood pressure were measured. The SHR exhibited full blown systolic hypertension by 9 weeks of age which persisted throughout the experiment. Paralleling the elevation in systolic blood pressure, the SHR exhibited sustained hyperinsulinemia by 9 weeks of age. Metformin treatment of the SHR prevented the rise in plasma insulin when compared to untreated SHR. The treatment also attenuated the systolic blood pressure by approximately 30-35 mm Hg. Metformin administration did not change the plasma glucose level in any group. Raising the plasma insulin level in the treated groups via insulin implants caused an elevation in the plasma insulin level in the SHR-treated group which was accompanied by an increase in systolic blood pressure. The next step was to explore if the insulin-blood pressure relationship in the fructose-induced hypertensive rat, where hypertension is not genetically determined but is induced by feeding rats a fructose-enriched diet. Sprague Dawley rats were divided into four groups: control untreated, control metformin-treated, fructose treated and fructose-fed metformin-treated. A baseline reading of plasma insulin, plasma glucose and systolic blood pressure was performed at week 6 following which chronic metformin treatment was initiated in the treated groups at the same dose as discussed in the previous experiment. At week 7, the animals in the fructose groups were started on a fructose-enriched diet. Weekly measurements of plasma insulin, plasma glucose and systolic blood pressure were performed from week seven to eleven. The fructose-fed untreated rats exhibited an elevated plasma insulin level by week 9 as compared to control rats. This hyperinsulinemia was sustained over the experimental period. the fructose-fed untreated rats also exhibited an elevation in systolic blood pressure of about 20-25 mm Hg. As seen in the previous study, metformin treatment did not change the plasma glucose levels in any group. Treatment of Sprague Dawley rats with metformin prior to starting fructose, prevented the rise in plasma insulin when compared to fructose-fed untreated rats. This was also accompanied by a complete prevention in the rise of systolic blood pressure seen in the fructose fed untreated rats. The fact that a specific drug intervention (metformin) caused a decrease in the plasma insulin level and systolic blood pressure, provides strong support to the notion that elevated insulin levels contribute at least in part to the development of hypertension in these two rodent models of hypertension. Further studies addressing this issue need to be carried out to clearly establish a cause-effect relationship of insulin and hypertension.

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