Effects of KRN4884, a Novel K+ Channel Opener, on Ionic Currents in Rabbit Femoral Arterial Myocytes

Abstract

Abstract. Effects of KRN4884 (5-amino-N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine), a novel K + channel opener, on ionic currents were examined in rabbit femoral arterial myocytes (RFAMs). Under whole-cell clamp conditions where cells were superfused with 5.9 mM K + bathing solution, KRN4884 elicited an outward current at -30 mV. KRN4884-induced current had a reversal potential of -78 mV and was abolished by application of glibenclamide (glib). KRN4884 was approximately 43 times more potent than levcromakalim in activating an ATP-sensitive K + current (I K-ATP ). On the other hand, KRN4884 affected neither voltage-dependent Ca 2+ nor delayed rectifier K + channel currents. In the inside-out patch clamp configuration where cells were superfused with the symmetrical 140 mM K + solution, KRN4884 activated 47 pS K + channels in the presence of adenosine diphosphate. Similar 47 pS K + channels, which were reversibly inhibited by glib, were recorded under outside-out patch conditions. Using RT-PCR analysis, we found that inward rectifier K channel 6.1 (Kir6.1) and sulfonylurea 2B (SUR2B) transcripts were predominantly expressed in rabbit femoral artery. These results indicate that KRN4884 potently activates I K-ATP in RFAMs. The KRN4884-sensitive 47 pS K + channel activity underlying I K-ATP is a vascular type K ATP channel consisting of Kir6.1 and SUR2B and has similar characteristics to those of ATP-sensitive K + channels activated by K + channel openers in other types of smooth muscles.

Relaxation of human placental arteries and veins by ATP‐sensitive potassium channel openers

“…Animal studies have shown variable relaxation to KRN4884 depending on the animal and location of the vessels examined. Some groups report that KRN4884 is equipotent to cromakalim [31], whereas others found KRN4884 to be up to 43 times more potent than levocromakalim on ionic currents in rat femoral artery myocytes [20]. Furthermore, it has been reported that KRN4884 is a longer-lasting antihypertensive in spontaneously hypertensive rats compared to laevocromakalim [19,31].…”

“…KRN2391 has also been suggested to have dual modes of action; a K ATP channel opener and an organic nitrate [17,18] and, thus, may provide a more potent tool for placental vascular relaxation. Another Kirin compound, KRN4884, has also been reported to act as a K ATP channel opener, directly activating the channels and by decreasing the sensitivity of the channels to ATP [19][20][21][22]. However, there is no data in the literature detailing its effects on the nitric oxide pathway.…”

Reciprocal Relationship between Ca²⁺ Signaling and Ca²⁺-Gated Ion Channels as a Potential Target for Drug Discovery

“…124) In contrast, the BK channel has consistently been an attractive drug target for the treatment of diseases due to smooth muscle hypercontractility, including hypertension, overactive bladder, incontinence, asthma, chronic obstructive pulmonary disease, and threatened premature labor. [138][139][140] Similar to ATP-sensitive K + channel openers, such as nicorandil, 141) minoxidil, 142) (levo) cromakalim 143,144) KRN2391, 145) and KRN4884, 146) the development of BK channel openers targeting these diseases has been extensively challenged, but not yet successful in clinical trials. 138,147) The main undesired effects of BK channel openers are facial flushing, migraine, and postural hypotension.…”