KRN-2391

Background  Adenosine triphosphate (ATP)‐sensitive potassium channels (KATP) are important modulators of vascular tone. Preliminary data from our laboratory suggests that KATP channels are expressed in the fetoplacental vasculature where addition of pinacidil, a specific KATP opener, promotes relaxation. We aimed to assess the effects of KRN2391 and KRN4884 on the fetoplacental vasculature, which are putative KATP channel openers.Materials and methods  Functional activity of KATP channels was assessed in chorionic plate arteries and veins using wire myography. Cromakalim‐, KRN2391‐ and KRN4884‐induced relaxations were assessed in the presence and absence of agonist‐induced pretone. Cromakalim, an established KATP channel opener, acted as control.Results  KRN2391 evoked significantly greater relaxation of chorionic plate arteries and veins than either KRN4884 or cromakalim. KRN2391‐induced relaxation of precontracted arteries and veins was reduced in the presence of inhibitiors of the nitric oxide pathway (L‐NNA or LY83583). With KRN4884, there was no contribution of nitric oxide to the induced relaxation.Conclusions  We conclude that KATP channels play an important role in controlling placental vascular tone. KRN2391 induces relaxation of human placental blood vessels by activation of KATP channels and via activation of nitric oxide‐dependent pathways.

We evaluated the effect of the adenosine triphosphate dependent K channel opener KRN2391 (N-cyano-N' -(2-nitroxyethyl)-3-pyridinecarboximidamide methanesulfonate) (Kirin Brewery Co., Gunma, Japan) on bladder overactivity induced by middle cerebral artery occlusion.

At 7 days after implantation of a bladder catheter in male Sprague-Dawley rats a cannula for intracerebroventricular administration was implanted and the left middle cerebral artery was occluded with 4-zero monofilament nylon thread. At 22 hours after the induction of cerebral ischemia saline was infused into the bladder at a constant rate (200 microl. per minute) and a cystometrogram was obtained with the rat in the conscious state. KRN2391 (5 microl.) was administered in intracerebroventricular fashion at graded doses (0.15 to 15 microg.).

Bladder capacity in conscious rats was significantly reduced after left middle cerebral artery occlusion. Intracerebroventricular administration of KRN2391 significantly increased bladder capacity in cerebral infarcted but not in sham operated rats.

These results show that a adenosine triphosphate dependent K channel opener may be useful for neurogenic bladder overactivity after cerebral infarction via action on the central nervous system.