Patients with
central obesity have impaired
insulin-stimulated vasodilation and increased ET-1 (
endothelin 1) vasoconstriction, which may contribute to
insulin resistance and vascular damage.
Apelin enhances
insulin sensitivity and
glucose disposal but also acts as a
nitric oxide (NO)-dependent
vasodilator and a counter-regulator of AT1 (
angiotensin [Ang] II type 1) receptor-induced vasoconstriction. We, therefore, examined the effects of exogenous (Pyr1)
apelin on NO-mediated vasodilation and Ang II- or ET-1-dependent
vasoconstrictor tone in obese patients. In the absence of
hyperinsulinemia, forearm blood flow responses to graded doses of
acetylcholine and
sodium nitroprusside were not different during saline or
apelin administration (both P>0.05). During
intra-arterial infusion of
regular insulin, however,
apelin enhanced the vasodilation induced by both
acetylcholine and
nitroprusside (both P<0.05). Interestingly, the
vasodilator effect of concurrent blockade of AT1 (
telmisartan) and AT2 (PD 123,319) receptors was blunted by
apelin (3±5% versus 32±9%; P<0.05). Similarly, during
apelin administration, blockade of ETA receptors (BQ-123) resulted in lower
vasodilator response than during saline (23±10% versus 65±12%; P<0.05).
NO synthase inhibition by
L-NMMA (l-N-monometylarginine) during the concurrent blockade of either Ang II or ETA receptors resulted in similar vasoconstriction in the absence or presence of
apelin (P>0.05). In conclusion, in patients with
central obesity,
apelin has favorable effects not only to improve
insulin-stimulated endothelium-dependent and endothelium-independent
vasodilator responses but also to blunt Ang II- and ET-1-dependent vasoconstriction by a mechanism not involving NO. Taken together, our results suggest that targeting the
apelin system might favorably impact some hemodynamic abnormalities of
insulin-resistant states like
obesity.