Abstract
ObjectiveInsulin resistance, diabetes, and hypertension are considered elements of metabolic syndrome which is associated with vascular dysfunction. We investigated whether inhibition of protein kinase C (PKC) would affect vascular function in diabetic hypertensive (DH) rats.MethodsA combination of type 2 diabetes and arterial hypertension was produced in male Sprague Dawley rats by intrauterine protein deprivation (IUPD) followed by high salt diet. At the age of 32 weeks, DH rats were treated for 2 weeks with the angiotensin-converting enzyme inhibitor captopril (Capto, 30 mg/kg), PKC inhibitor ruboxistaurin (RBX, 50 mg/kg) or vehicle (n = 8 per group) and blood pressure was monitored using telemetry. At the end of experiments, femoral arteries were dissected, and vascular reactivity was evaluated with isovolumic myography.ResultsThe IUPD followed by high salt diet resulted in significant elevation of plasma glucose, plasma insulin, and blood pressure. Endothelium-dependent vascular relaxation in response to acetylcholine was blunted while vascular contraction in response to phenylephrine was enhanced in the DH rats. Neither Capto nor RBX restored endothelium-dependent vascular relaxation while both suppressed vascular contraction. Ex-vivo incubation of femoral arteries from control rats with insulin induced dose-response vasorelaxation while insulin failed to induce vasorelaxation in the DH rat arteries. In the control arteries treated with endothelial nitric oxide synthase inhibitor L-NAME, insulin induced vasoconstriction that was exacerbated in DH rats. Capto and RBX partially inhibited insulin-stimulated vascular contraction.ConclusionThese findings suggest that PKC inhibition ameliorates functional endothelial insulin resistance and smooth muscle cell hypersensitivity to insulin, but does not restore acetylcholine-activated endothelium-dependent vasodilation in DH rats.
Highlights
IntroductionType 2 diabetes, and hypertension are often clustered as part of metabolic syndrome [1]
Insulin resistance, type 2 diabetes, and hypertension are often clustered as part of metabolic syndrome [1]
Insulin, and free fatty acid (FFA) were significantly elevated in diabetic hypertensive (DH) rats (Table 1)
Summary
Type 2 diabetes, and hypertension are often clustered as part of metabolic syndrome [1]. Endothelial dysfunction is a salient and, likely a unifying feature of metabolic syndrome that translates systemic risk factors into vascular pathology [2]. It has been recently recognized, that endothelial dysfunction is far more complex than blunted endothelium-. Many questions regarding vascular effects of PKC inhibition, remain unanswered It is unclear whether PKC inhibition uniformly or differentially regulates vascular response to insulin and “classical” vasoreactive substances (e.g., acetylcholine and epinephrine). Vascular insulin resistance has been primarily studied in models of metabolic syndrome driven by genetic defects that may potentially skew the results and jeopardize clinical translation
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