Isoenzymes of cyclic nucleotide phosphodiesterase in the human aorta: characterization and the effects of E4021.
In extracts of the human aorta, five isoenzymes of cyclic nucleotide phosphodiesterase, namely, phosphodiesterase I, phosphodiesterase II, phosphodiesterase III, phosphodiesterase IV and phosphodiesterase V, were identified exclusively in the cytosolic fraction, and no phosphodiesterase activity was detected in the particulate fraction. Phosphodiesterase V and phosphodiesterase I were the major cGMP-hydrolyzing enzymes in the human aorta. A novel vasorelaxant, sodium 1-[6-chloro-4-(3,4-methylenedioxybenzyl)aminoquinazolin-2-yl ]piperidine-4- carboxylate sesquihydrate (E4021), relaxed prostaglandin F2 alpha-precontracted strips of human pulmonary artery with an ED50 value of 0.5 microM. E4021 potently and highly selectively inhibited the activity of phosphodiesterase V from human aorta with a Ki value of 2.4 nM. These results suggest that there is a unique distribution of phosphodiesterase isoenzymes in the human aorta and that inhibitors of phosphodiesterase V might be useful as a new type of vasodilator in the treatment of clinical disorders.
First Department of Internal Medicine, Mie University School of Medicine, Japan.
M
M
Miyahara
M
M
Ito
H
H
Itoh
T
T
Shiraishi
N
N
Isaka
T
T
Konishi
T
T
Nakano
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D001011:Aorta / Q000187:drug effects / Q000201:enzymology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000302:isolation & purification / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D015237:Dinoprost / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D009119:Muscle Contraction / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D013347:Subcellular Fractions / Q000201:enzymology; D014665:Vasodilator Agents / Q000494:pharmacology*
C091517:E 4021; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D010880:Piperidines; D011799:Quinazolines; D014665:Vasodilator Agents; D015237:Dinoprost; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D015106:3',5'-Cyclic-GMP Phosphodiesterases