The vascular effects of
JTV-506 ((-)-(3S,4R)-2.2-bis(methoxymethyl)- 4-[(1,6-dihydro-l-methyl-6-oxo-3-pyridazinyl)amino]-3-hydroxychroman+ ++-6- carbonitrile hemihydrate, CAS 170148-29-5), a new
potassium channel opener, was evaluated in isolated coronary arteries and anesthetized dogs.
JTV-506 (1 nmol/l-3 mumol/l) produced a concentration-dependent relaxation in porcine isolated epicardial large coronary arteries precontracted with KCl (30 mmol/l),
phenylephrine (3 mumol/l),
histamine (3 mumol/l),
serotonin (5-HT; 300 nmol/l),
prostaglandin F2 alpha (
PGF2 alpha; 10 mumol/l),
U-46619 (100 nmol/l),
endothelin-1 (ET-1; 30 nmol/l) and Bay K-8644 (100 nmol/l).
JTV-506 was 2.5-8.5 and 13.3-81.5 times more potent than
levcromakalim (CAS 94535-50-9) and
nicorandil (CAS 65141-46-0), respectively, but was less potent than
nifedipine (CAS 21829-25-4).
JTV-506 and
levcromakalim produced almost a complete relaxation in arteries precontracted with various kinds of
vasoconstrictor, except for KCl. In contrast,
nifedipine produced about 80-90% relaxation in arteries, precontracted with
PGF2 alpha,
U-46619 and ET-1. Thus, this
potassium channel opener can be characterized as an agonist-nonselective
vasorelaxant. The relaxing effects of
JTV-506 and
levcromakalim on coronary arteries precontracted with 30 mmol/l KCl was competitively antagonized by 3 mumol/l
glibenclamide, an
ATP-sensitive
potassium (
KATP) channel blocker. In canine isolated epicardial large coronary arteries, 10 mumol/l
JTV-506, 10 mumol/l
levcromakalim, 100 mumol/l
nicorandil and 0.1 mumol/l
nifedipine eliminated 10 mmol/l 3,4-diaminopyridine-induced rhythmic contractions. In anesthetized dogs, when administered directly into the coronary artery,
JTV-506 induced dose-dependent increases in coronary arterial diameter and coronary blood flow. These results suggest that
JTV-506 elicits coronary vasorelaxation through activation of the
KATP channel. It is expected that
JTV-506 might be useful in the treatment of
coronary vasospasm in
angina pectoris.