Vasodilator effect of carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl in the coronary circulation: in vivo and in vitro studies.
2-Phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) derivatives, new radical forms of nitric oxide (NO) antagonists, are reported to react with NO and generate NO2 and 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl (PTI) derivatives. We found that carboxy-PTI, a water-soluble derivative of PTI, showed a potent vasodilator effect in the canine coronary artery system. In anesthetized dogs, intracoronary infusion of carboxy-PTI significantly increased the coronary flow in a dose-dependent manner without altering systemic hemodynamic variables. This coronary flow increasing effect of carboxy-PTI was not influenced by pretreatment with either NG-nitro-L-arginine methyl ester or 8-phenyltheophylline or autonomic blockade. However, the flow increasing effect of carboxy-PTI was abolished by reducing carboxy-PTI with ascorbic acid to a non-radical form of carboxy-PTI, indicating that carboxy-PTI shows its effect only in a radical form. In isolated canine coronary arterial rings, carboxy-PTI caused endothelium-independent relaxation. This relaxation response was significantly attenuated by pretreatment with methylene blue, an inhibitor of soluble guanylate cyclase. Thus, carboxy-PTI has an endothelium-independent coronary vasodilator effect in both large conduit arteries and small resistance vessels. The results of the in vitro experiment suggested that the activation of soluble guanylate cyclase of the vascular smooth muscle cell may be involved, at least in part, in the vasodilator mechanism of carboxy-PTI in large conduit arteries.
Tsunoda
R
R
Division of Cardiology, Kumamoto University School of Medicine, Japan.
Okumura
K
K
Ishizaka
H
H
Matsunaga
T
T
Tabuchi
T
T
Yasue
H
H
Akaike
T
T
Sato
K
K
Maeda
H
H
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001565:Benzoates; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects*; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D005609:Free Radicals; D006162:Guanylate Cyclase / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D066298:In Vitro Techniques; D007261:Infusions, Intra-Arterial; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D009585:Nitrogen Dioxide / Q000378:metabolism; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology*
D001565:Benzoates; D003497:Cyclic N-Oxides; D005609:Free Radicals; D007093:Imidazoles; D014665:Vasodilator Agents; C079393:1,3-dihydroxy-4,4,5,5-tetramethyl-2-(4-carboxyphenyl)tetrahydroimidazole; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D009569:Nitric Oxide; D001120:Arginine; D013806:Theophylline; C028322:8-phenyltheophylline; D006162:Guanylate Cyclase; D009585:Nitrogen Dioxide; D008751:Methylene Blue; D019331:NG-Nitroarginine Methyl Ester