Rabbit corpus cavernosum smooth muscle shows a different phosphodiesterase profile than human corpus cavernosum.
OBJECTIVE
Cyclic nucleotide phosphodiesterases (PDEs) are important regulators of cAMP/cGMP secondary messenger systems. Fluctuations in the level of cyclic nucleotides control the smooth muscle tone of corpus cavernosum. It had been shown that milrinone, a PDE3 inhibitor, was as potent as sildenafil, a PDE5 inhibitor, in relaxing human corpus cavernosum. However, milrinone is much less effective in relaxing rabbit corpus cavernosum than sildenafil. PDEs in rabbit corpus cavernosum were characterized and organ bath experiments were carried out in an attempt to search for the biochemical basis of this species difference.


METHODS
In a biochemical study, PDE isozymes from rabbit corpus cavernosum were isolated by FPLC and characterized by PDE assay. In organ bath experiments, rabbit corpus cavernous tissue strips were precontracted and increasing doses of various inhibitors were added.


RESULTS
The major PDE in rabbit corpus cavernosum is PDE5. There are small amounts of PDE2 and PDE1. PDE3, which contributes significantly to the total PDE activity in human corpus cavernosum, is apparently lacking in rabbit corpus cavernosum. Organ bath experiments with isotype-specific inhibitors confirm this conclusion.


CONCLUSIONS
The distribution of PDE isozymes in corpus cavernosum is different in human and in rabbit. This could be the biochemical basis for the differential effects of milrinone in relaxing rabbit and human corpus cavernosum. Our study emphasizes the importance of a more complete understanding of the tissue distribution of targeted proteins in an animal model before applying the results to humans.
Qiu
Y
Y
Department of Reproductive Therapeutics, R.W. Johnson Pharmaceutical Research Institute, Raritan, NJ 08869, USA.
Kraft
P
P
Lombardi
E
E
Clancy
J
J
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000302:isolation & purification; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D000242:Cyclic AMP / Q000502:physiology; D006152:Cyclic GMP / Q000502:physiology; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004195:Disease Models, Animal; D005092:Exonucleases / Q000037:antagonists & inhibitors / Q000302:isolation & purification; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000145:classification / Q000302:isolation & purification; D008297:Male; D020105:Milrinone / Q000494:pharmacology; D009129:Muscle Tonus / Q000502:physiology; D009130:Muscle, Smooth / Q000201:enzymology*; D010413:Penis / Q000201:enzymology*; D043264:Phosphodiesterase I; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000145:classification* / Q000302:isolation & purification / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology; D011687:Purines; D011817:Rabbits; D015290:Second Messenger Systems / Q000502:physiology; D000068677:Sildenafil Citrate; D013045:Species Specificity; D013450:Sulfones
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D000242:Cyclic AMP; D005092:Exonucleases; C022650:spleen exonuclease; D010727:Phosphoric Diester Hydrolases; D043264:Phosphodiesterase I; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; D006152:Cyclic GMP; D020105:Milrinone