COX Inhibitor Indomethacin Attenuates Phenylephrine Induced Vasoconstriction: Differences in OLETF and LETO Vascular Response

Abstract

Endothelial cell dysfunction contributes to the progression of vascular disease in type 2 diabetes (T2D). This is believed to be mediated by altered endothelial responsiveness to relaxing and/or constricting factors. We tested the hypotheses that constriction with α1-receptor agonist phenylephrine (PE) is altered by interaction with inhibitors including: cyclooxygenase (COX) inhibitor indomethacin (INDO), nitric oxide synthase inhibitor L-NAME, and their combination (LNAME+INDO) causing a loss of tone, i.e. relaxation. We used a rat model of T2D, the hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF) n=10, and their non-diabetic, normophagic control, Long-Evans Tokushima Otsuka (LETO) n=9. At 32 weeks old rats were euthanized, sequential rings of the abdominal aorta harvested, and function measured by fine wire myography. Vascular response was first confirmed with 80mM potassium chloride (KCl). After washout, inhibitors incubated with vessels for 20 minutes prior to PE with continuous recording. KCl response was not different between OLETF and LETO vessels (P=ns). In OLETF rats, PE-induced constriction diminished in INDO treated vessels compared with untreated, LNAME, and LNAME+INDO (P<0.05). In LETO rats, constriction diminished in INDO and LNAME+INDO vessels compared to both untreated and LNAME (P<0.05). We report a novel interaction for COX inhibition and PE dependent vasoconstriction. This relationship appears to effect T2D model OLETF vasculature differently than LETO controls and is an important consideration for future vascular studies. Support: HL036088 (MHL) and VHA-CDA2 1299-03 (RSR)