Krn2391: Dual Action On Rat Pulmonary Artery And No Loss Of Potency In Pulmonary Hypertension

Abstract

1. The pulmonary vasorelaxant properties of KRN2391 (N-cyano-N'-(2-nitroxyethyl)-3-pyridinecarboximidamide) were examined in isolated ring preparations of main (MPA) and intralobar (IPA) pulmonary artery from control and pulmonary hypertensive rats (exposure to hypoxia, 10% oxygen, for 1 week). 2. On both MPA and IPA, pulmonary vasorelaxant responses were inhibited by methylene blue (10 micromol/L) or glibenclamide (1 or 10 micromol/L). Thus, KRN2391 has the properties of both a nitric oxide (NO) donor and a K(ATP) channel opener on rat pulmonary arteries. 3. KRN2391 was more potent and gave a greater maximum relaxation on MPA (-log EC(50) 6.47; maximum 92% reversal of induced contraction) than on IPA (-log EC(50) 6.09; maximum 58% reversal of induced contraction). Comparable differences between MPA and IPA were seen for SIN-1 (NO donor) and levcromakalim (K(ATP) channel opener). 4. KRN2391 was equipotent in MPA from control and pulmonary hypertensive rats but, when glibenclamide (10 micromol/L) was present, KRN2391 was six-fold less potent in preparations from pulmonary hypertensive than control rats. An eight-fold reduction in potency was seen for SIN-1 (no glibenclamide) in arteries from pulmonary hypertensive rats, confirming previous findings with other NO donors. 5. It is concluded that the dual mechanism of action of KRN2391 accounts for the finding that this drug is equally potent in pulmonary arteries from pulmonary hypertensive and control rats. In the context of pulmonary hypertension, this property of the drug could give it an advantage over drugs that act solely as NO donors because these decline in potency, at least in animal models of this disease.

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

“…Cromakalim, a well-characterized selective K ATP channel opener that has been exploited pharmacologically to induce hyperpolarization and thus vasodilatation in conditions such as pulmonary hypoxia [2], has yet to be assessed in human placental blood vessels. KRN2391 is a putative K ATP channel opener that has been suggested to produce significant relaxation of rat [15] and human [16] systemic arterial preparations. 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.…”