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Insulin and hypertension : a pharmacological perspective

University of British Columbia

Although considerable data lend support to the association between insulin resistance, hyperinsulinemia and hypertension, the precise nature of this relationship remains elusive. In the present study, we examined the proposition that these metabolic defects contribute causally to the development of high blood pressure. Essentially, if these metabolic abnormalities were responsible for an increase in blood pressure, then drugs that improve these metabolic defects should also attenuate hypertension. We, therefore, examined the effects of three drugs (that are known to enhance insulin action) on insulin sensitivity, plasma insulin levels and blood pressure in two established models of experimental hypertension: (a) the spontaneously hypertensive rat and (b) the fructosehypertensive rat, where hypertension is induced in normotensive rats by feeding them a high fructose diet. The drug interventions were: (a) vanadyl sulfate, the (+lV) form of the trace element vanadium (b) bis(maltolato)oxovanadium(IV) (BMOV), an organic vanadium complex and (C) pioglitazone, a thiazolidinedione derivative that enhances peripheral insulin action. In separate studies, 6 week old spontaneously hypertensive rats (SHR) and their Wistar Kyoto (WKY) controls were started on chronic oral treatment with vanadyl sulfate (0.4-0.6 mmol/kg/day), BMOV (0.35-0.45 mmol/kg/day) or pioglitazone (0.01 -0.02 mmol/kg/day). All 3 drugs caused a sustained decrease in plasma insulin concentration in the hyperinsulinemic SHR without causing any change in the WKY. Surprisingly, all the drugs caused a marked decrease in systolic blood pressure in the SHR without causing any change in the WKY. Restoration of plasma insulin levels in the drug-treated SHR to levels that existed in the untreated SHR reversed the effect/s of the drugs on blood pressure. Low dose euglycemic insulin clamps (14 pmol/kg/min) conducted in conscious, fasted rats revealed that insulin sensitivity, expressed as steady state glucose clearance per unit of plasma insulin, was higher in the untreated SHR as compared to the untreated WKY. Although BMOV further enhanced insulin sensitivity in the SHR, pioglitazone had no effect on insulin sensitivity in the SHR or WKY. Fructose feeding induced hyperinsulinemia and increased blood pressure in normotensive Sprague Dawley rats. Vanadyl sulfate (0.4-0.6 mmol/kg/day) prevented the rise in plasma insulin and blood pressure in the fructose-fed rats. Again, restoration of plasma insulin concentration in the fructose-vanadyl treated rats to pie-treatment levels reversed the effects of vanadyl sulfate on blood pressure. Low dose insulin clamps demonstrated that insulin sensitivity was reduced in the fructose-fed rats. Vanadyl caused a marked enhancement in insulin sensitivity in the fructose-fed rats without any change in the control group. In conclusion: (i) SHR are not insulin-resistant but rather are more insulinsensitive than the WKY (ii) SHR are hyperinsulinemic and drug interventions that decrease hyperinsulinemia also attenuate hypertension in the SHR (iii) The effect of the drugs on blood pressure can be reversed by restoring plasma insulin levels in the drug-treated SHR to those observed in their untreated counterparts (iv) The antihypertensive effects of pioglitazone in the SHR are independent of its effects on insulin sensitivity, which suggests that hyperinsulinemia may be unrelated to insulin resistance in the SHR (v) Vanadyl sulfate completely prevents fructose induced insulin resistance, hyperinsulinemia and hypertension. These data indicate that either hyperinsulinemia may contribute to the development of high blood pressure in both the SHR and the fructose-hypertensive rats or that the underlying mechanism is closely related to the expression of both these disorders.

Thesis/Dissertation

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2009-04-15

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http://hdl.handle.net/2429/7201

Pharmacology

University of British Columbia

UBCV

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