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Insulin resistance and hypertension: the hemodynamic and metabolic effects of deuterium oxide, enalapril, and metformin Maxwell, Sharon


Elevated blood pressure has been recognized as a marker for disease since the early I 800s. It is commonly divided into two categories: primary hypertension and secondary hypertension. Primary hypertension is defined as hypertension where inheritable and/or environmental factors are unknown whereas, secondary hypertension is defined as hypertension caused by a known congenital or acquired disease. Primary hypertension is discussed in this paper. In an attempt to better understand the pathophysiology of hypertension, a common syndrome in patients was described called Syndrome X. Patients with this syndrome have resistance to insulin-stimulated glucose uptake, glucose intolerance, hyperinsulinemia, increased very-low-density lipoprotein triglyceride, decreased high-density lipoprotein cholesterol, and hypertension. In an attempt to better understand the relationship between elevated insulin concentrations (hyperinsulinemia) and elevated blood pressure, experiments were designed using spontaneously hypertensive rats (SHR) as a genetic model of hypertension. Agents which lower blood pressure (deuterium oxide and enalapril) and an agent which lowers plasma glucose concentrations were used to try to elucidate the relationship between insulin resistance and hypertension. If insulin resistance and hypertension are causally related one would expect that by pharmacologically altering one of the abnormalities a similar direction and magnitude of effect would occur in the other. Two experiments were performed. The first experiment examined the effects of 10% 020 and 50 mg/L enalapril on hemodynamic and metabolic factors in the SHR. The second experiment examined a dose range (10, 30, 100, and 300 mg/kg/day) of metformin in SHR and its effects on hemodynamic and metabolic factors. In both experiments body weight, systolic blood pressure, insulin, glucose and triglyceride concentrations in plasma, water intake, and urine volume were recorded weekly. At the end of each experiment direct blood pressures were recorded from the iliac artery. In the D20 and enalapril experiment, enalapril significantly lowered the systolic pressure compared to the control and 10% D20 groups. There was no significant difference in the insulin (mU/L) or glucose (mmol/L) concentrations between the three groups and the insulin:glucose ratio (mU/mmoL) was not significantly different between the groups. These results suggest that there is no effect on insulin or glucose concentrations when the blood pressure is lowered in the SHR. In the metformin experiment, metformin did not significantly lower the systolic blood pressure during the treatment period. There was also no significant difference in fasting plasma insulin and glucose concentrations. The insulin:glucose ratio also showed no significant difference between the groups. Conclusions: 1. Ten % D20 decreases fasting plasma glucose concentrations, thus possible causing a decrease in insulin resistance. 2. Despite this, chronic 10% D20 has no effect on blood pressure or fasting plasma insulin concentration in the SHR. 3. This suggests that insulin resistance does not cause increased blood pressure. 4. Enalapril decreases blood pressure but has no effects on glucose and insulin concentrations in the SHR, confirming that high blood pressure does not cause insulin resistance. 5. Enalapril causes a large increase in urine volume and water in the SHR. 6. Chronic metformin (10 to 300 mg/kg/day) has no effect on insulin and glucose concentrations or blood pressure in SHR. 7. The SHR may not be an appropriate model for studying the link between hypertension and insulin resistance.

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