The vasodilatory effect of the antidiabetic drug linagliptin via inhibition of Rho-associated protein kinase in aortic smooth muscle.

AIMS

The vasodilatory effects of the anti-diabetic drug, linagliptin in phenylephrine-precontracted aortic rings were investigated.

MATERIALS AND METHODS

Male New Zealand White rabbits were used in the experiment and its arterial tone was measured by using myogragh system.

KEY FINDINGS

Linagliptin induced vasodilation in a concentration-dependent manner. The vasodilatory effect of linagliptin was not affected by the absence of the endothelium, or by pretreatment with a nitric oxide synthase inhibitor (L-NAME) or a small-conductance Ca-activated K channel inhibitor (apamin). Moreover, application of the adenylyl cyclase inhibitor SQ22536, protein kinase A (PKA) inhibitor KT5720, guanylyl cyclase inhibitor ODQ, or protein kinase G (PKG) inhibitor KT5823 did not alter the vasodilatory effect of linagliptin. However, inhibition of Rho-associated protein kinase by Y-27632 significantly attenuated linagliptin-induced vasodilation. Ion channel involvement in the vasodilatory effect of linagliptin was also investigated. Pretreatment with the vascular K channel inhibitors glibenclamide (ATP-sensitive K channels), Ba (inwardly rectifying K channels), 4-AP (voltage-dependent K channels), and paxilline (large conductance Ca-activated K channels) did not affect linagliptin-induced vasodilation. Furthermore, the L-type Ca channel inhibitor, nifedipine, and the sarcoplasmic/endoplasmic reticulum Ca-ATPase (SERCA) pump inhibitor, thapsigargin, did not change the vasodilatory effect of linagliptin.

SIGNIFICANCE

We suggests that linagliptin-induced vasodilation was mediated by the inhibition of Rho-associated kinase, but not with the endothelium, cAMP-PKA or cGMP-PKG-dependent signaling pathways, K channels, Ca influx, or SERCA pump.