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 ²⁺ -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 ²⁺ (inwardly rectifying K ⁺ channels), 4-AP (voltage-dependent K ⁺ channels), and paxilline (large conductance Ca ²⁺ -activated K ⁺ channels) did not affect linagliptin-induced vasodilation. Furthermore, the L-type Ca ²⁺ channel inhibitor, nifedipine, and the sarcoplasmic/endoplasmic reticulum Ca ²⁺ -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 ²⁺ influx, or SERCA pump.
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