β-Adrenoceptor-mediated vasodilatation is impaired in superior mesenteric arteries from Zucker diabetic rats: effect of inhibition of ERK-MAP kinase activation

Chukwuemeka Uhiara, Steve Alexander, Richard Roberts

University of Nottingham, Nottingham, UK

β-Adrenoceptor-mediated vasodilatation has been shown to be impaired in peripheral veins of patients with type 2 diabetes (Harada et al., 1999). A similar impairment of β-adrenoceptor function has been demonstrated in the coronary artery from the Zucker diabetic rat, a model of type 2 diabetes (Grisk et al., 2007). Our previous studies have demonstrated that inhibition of ERK-MAP kinase activation enhances β-adrenoceptor vasodilatation (Uhiara et al., 2008). Therefore it was of interest to determine whether β-adrenoceptor function is impaired in superior mesenteric arteries from the Zucker diabetic rat and whether this impaired response is affected by inhibition of ERK activation.

Superior mesenteric arteries from male Zucker diabetic rats (340-380g, killed by cervical dislocation) were dissected and mounted in a 4-channel myograph (Danish Myotechnology Ltd.) containing Krebs-Henseleit solution gassed with O2:CO2 (95:5) at 37°C. Tension (0.5 g wt.) was applied to the arteries, which relaxed down to a resting tension of 0.15-0.3 g wt. Superior mesenteric arteries from age-matched male Wistar rats (280-300g) were used for comparison. Tissues were pre-incubated for 45 min with the inhibitor of ERK activation, PD98059, or vehicle (0.1-0.26% DMSO v/v) and then contracted with U46619, a thromboxane receptor agonist, before relaxations were induced using cumulative concentrations of isoprenaline. Comparisons between data sets (expressed as mean ± s.e.mean) were assessed using one-way ANOVA followed by a Tukey post-hoc test.

Isoprenaline (1x10-9 M – 3x10-6 M) induced a concentration-dependent vasodilatation of the superior mesenteric artery from both Zucker diabetic and Wistar rats. Responses to 3 μM isoprenaline were significantly reduced in arteries from diabetic rats (18 ± 4 % relaxation in Zucker diabetic rats (n=6) compared to 85 ± 14 % relaxation in Wistar rats (n=4); p<0.001, Tukey’s multiple comparisons test). Pre-incubation with PD98059 (50 μM) partially restored the impaired relaxation to isoprenaline in Zucker diabetic rats, the response to 3 μM isoprenaline being 50 ± 7 % relaxation (p<0.05 v Zucker diabetic rats), although it failed to reach the level of relaxation observed in Wistar rats (p<0.05).

These data indicate that β-AR-mediated vasodilatation is impaired in superior mesenteric arteries from Zucker diabetic rats compared to Wistar rats. Inhibition of ERK activation by pre-incubation with PD98059 enhanced the relaxation, although the responses were still lower than those obtained in Wistar rats. These data suggest that the impairment of β-adrenoceptor relaxations in the superior mesenteric arteries may be related to altered ERK activity. Future studies will determine whether basal levels of ERK activity are elevated in superior mesenteric arteries from this model of type 2 diabetes.

Grisk et al., (2007). Pfluger’s Arch., 454,1011–1021.

Harada et al., (1999). Br. J. Pharmacol., 47, 427-431.

Uhiara et al., (2008) this meeting.