Sildenafil and T-1032, phosphodiesterase type 5 inhibitors, showed a different vasorelaxant property in the isolated rat aorta.
The vasorelaxant effects of sildenafil and T-1032 [methyl-2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinoline carboxylate sulfate], two phosphodiesterase type 5 inhibitors, were examined in the isolated rat aorta. Sildenafil and T-1032, both of which have almost the same potency and selectivity regarding phosphodiesterase type 5 inhibitory activity, produced a similar, moderate, relaxation at 10(-10) to 10(-7) M (sildenafil: 66.8 +/- 13.7%; T-1032: 77.9 +/- 10.8% at 10(-7) M). However, sildenafil, but not T-1032, produced further relaxation at the higher concentrations (sildenafil: 102.0 +/- 0.6%; T-1032: 81.0 +/- 7.2% at 10(-4) M, P < 0.05). Sildenafil also produced a more potent relaxation than did T-1032 at the high concentrations (10(-5) and 10(-4) M) in endothelium-denuded aortic rings and in the presence of N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor (3 x 10(-4) M). Moreover, the high concentrations of sildenafil, but not of T-1032, caused a rightward shift of the concentration-response curve for calcium chloride in K(+)-depolarized endothelium-denuded preparations. In the ligand binding assay for the L-type Ca(2+) channels, the affinities of sildenafil at 10(-5) M for binding sites of nitrendipine and (--)-desmethoxyverapamil [(--)- D888] (35.2 +/- 3.3% and 35.8 +/- 1.9%, respectively) were higher than those of T-1032 (11.8 +/- 4.0% and -13.1 +/- 1.3%, respectively, P < 0.05). Regarding cyclic nucleotide levels, both phosphodiesterase type 5 inhibitors increased cGMP levels at 10(-6) M. However, sildenafil, but not T-1032, further increased cGMP levels at the higher concentrations (sildenafil: 15.7 +/- 2.7 pmol/mg protein; T-1032: 5.6 +/- 0.6 pmol/mg protein at 10(-4) M, P < 0.05). These results suggested that high concentrations of sildenafil had additional vasorelaxant properties through mechanisms other than phosphodiesterase type 5 inhibition. Sildenafil-induced relaxation appears to be due to inhibition of the external Ca(2+)-dependent cascade for contraction and/or to an increase in cGMP levels. In contrast, T-1032 only showed a vasorelaxant property due to phosphodiesterase type 5 inhibition. In conclusion, T-1032 appears to be a specific phosphodiesterase type 5 inhibitor compared with sildenafil and a useful compound to examine the physiological function of phosphodiesterase type 5.
Mochida
Hideki
H
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-2-50, Kawagishi, Toda, Saitama 335-8505, Japan. mochida@tanabe.co.jp
Inoue
Hirotaka
H
Takagi
Michino
M
Noto
Tsunehisa
T
Yano
Koji
K
Kikkawa
Kohei
K
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D001667:Binding, Competitive; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002122:Calcium Chloride / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D011687:Purines; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D000068677:Sildenafil Citrate; D013450:Sulfones; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D020746:Calcium Channels, L-Type; D007546:Isoquinolines; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D011725:Pyridines; D013450:Sulfones; D014665:Vasodilator Agents; D015240:Phorbol 12,13-Dibutyrate; D000068677:Sildenafil Citrate; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat; D006152:Cyclic GMP; C412889:T 1032; D002122:Calcium Chloride; D019331:NG-Nitroarginine Methyl Ester