Accumulating clinical evidence indicates that
impaired glucose tolerance is a common phenomenon in
essential hypertension. Although recent evidence underscores the role of
heme-oxygenase (HO) in diabetes, its effects on
insulin sensitivity and
glucose metabolism in spontaneously hypertensive rat (SHR), a model of
essential hypertension with characteristics of
metabolic syndrome including
insulin resistance/impaired
glucose metabolism remains largely unclear. Here we report the effects of the HO inducer,
hemin, and the HO blocker,
chromium-mesoporphyrin on
insulin sensitivity and
glucose metabolism in SHRs. Adult SHRs were severely hypertensive but normoglycemic.
Hemin therapy lowered blood pressure, increased plasma
insulin, decreased glycemia, and enhanced
insulin sensitivity by improving
glucose tolerance (ip
glucose tolerance test) and
insulin tolerance (ip
insulin tolerance test) but reduced
insulin resistance (homeostasis model assessment index). These effects were accompanied by increased gastrocnemius muscle HO-1, HO activity, cGMP, cAMP alongside
antioxidants including
bilirubin,
ferritin,
superoxide dismutase,
catalase, and the total
antioxidant capacity, whereas oxidative/inflammatory mediators like
8-isoprostane,
nuclear-factor-kappaB, activating-protein-1, activating-protein-2, c-Jun-NH2-terminal-kinase, and
heme were abated. Furthermore,
hemin reduced
proteinuria/
albuminuria and enhanced the depressed levels of
adiponectin,
AMP-activated protein-kinase, and
glucose transporter-4 in SHRs, suggesting that although SHRs are normoglycemic,
insulin signaling and renal function may be impaired. Contrarily, the HO inhibitor
chromium-mesoporphyrin exacerbated oxidative stress, aggravated
insulin resistance,
glucose tolerance,
insulin tolerance and nephropathy.
Hemin also enhanced HO signaling in Wistar Kyoto and Sprague Dawley rats and increased
insulin sensitivity albeit less intensely than in SHRs, suggesting greater selectivity of HO in SHRs with dysfunctional
insulin signaling. These results suggest that perturbations of
insulin signaling may be a forerunner to
hyperglycemia in
essential hypertension. By concomitantly potentiating
insulin-sensitizing agents, suppressing
insulin/
glucose intolerance, and abating oxidative stress, HO inducers may prevent metabolic and cardiovascular complications in
essential hypertension.