Role of prostanoid EP3 receptor synergism in femoral arteries from rats with streptozotocin-induced diabetes

Wan Wan Ahmad, Robert Jones, Roger Wadsworth, Brian Furman. Strathclyde Institute of Pharmacy and Biomedical Sciences, Glasgow, United Kingdom.

During progression of streptozotocin (STZ)-induced diabetes, maximum contraction to the thromboxane (TP) agonist U-46619 in de-endothelialized rat femoral artery was reduced while the sensitivity was increased (Shi et al, 2007). In this context, weak contraction of rat femoral artery by PGE2 is accompanied by marked enhancement of responses to strong agonists such as U-46619, phenylephrine and K+ (Hung et al, 2006). The role of this EP3 system was investigated using a selective EP3 receptor antagonist L-798106 (Clarke et al., 2006).

Type-1 diabetes of 4 weeks duration was induced with streptozotocin (STZ; 60 mgkg-1 i.p.) in male 10-12 week-old Sprague-Dawley rats. De-endothelialized rings were suspended in a Mulvaney myograph. Changes in isometric tension were expressed as a percentage of the 60 mM KCl response.

Contractile responses to phenylephrine were similar in vehicle and STZ preparations: Emax 75.4 + 2.3, 88.8 ± 2.6 %; pEC50 7.55 + 0.08, 7.40 + 0.77. In both cases, L-798106 (1 µM) significantly reduced the maximal response of phenylephrine (vehicle: 52.3 + 9.9%; STZ: 48.0 + 2.1 %) and shifted the curve to the right (pEC50 6.87 + 0.06; 6.21 + 0.09). BMS-180291 (100 nM), a potent and selective TP receptor antagonist did not affect these profiles. The COX-inhibitors indomethacin (1 - 10 µM) and flurbiprofen (1 - 10 µM) did not modify the phenylephrine log concentration-response curve.

In conclusion, we were surprised to see no significant pharmacological differences between the vessels from control and 4-week STZ-diabetic rats; perhaps a longer diabetic state is required. In both treatment situations, α1-adrenoceptor-induced contraction may be enhanced by an endogenous EP3 agonist. However, the COX-inhibitor data suggest either an involvement of a non-COX biosynthetic pathway or a co-role for prostacyclin acting as a functional antagonist.

Clarke DL et al. (2004) Br J Pharmacol 141: 600–609.
Hung GH et al. (2006) Prost Leukot Essent Fatty Acids 74: 401-415.
Shi Y et al. (2007) Br J Pharmacol 150: 624-632.

We thank GlaxoSmithKline and Bristol-Myers Squibb for gifts of L-798106 and BMS-180291 respectively.