Inhibition of bovine brain calmodulin-dependent cGMP phosphodiesterase by peptide and non-peptide angiotensin receptor ligands.
Inhibition of a purified 60 KDa bovine brain calmodulin-dependent cGMP phosphodiesterase (PDE) was investigated for a number of peptides and non-peptides which are known to bind to angiotensin (ANG) receptors. The peptide antagonists sarilesin and sarmesin had KI = 120 and greater than 200 microM respectively, and the peptide agonists ANG II and ANG III had KI = greater than 200 and 45 microM respectively. Non-peptide ANG receptor antagonists related to DuP 753 exhibited KI values in the same range. For both peptide and non-peptide antagonists, inhibitory activities in the PDE assay reflected the order of antagonist potencies at ANG receptors in the rat isolated uterus assay and binding affinities at ANG receptors in rat uterine membranes, suggesting that molecular recognition factors are similar for both ANG receptors and cGMP PDE. The vasodilatory and blood pressure lowering effects of compounds related to DuP 753 may be due in part to inhibition of cGMP PDE. The differential effects of ANG II and ANG III at target tissues may relate in part to the marked differences in cGMP PDE inhibition associated with these two peptides hormones.
Sharma
R K
RK
Department of Medical Biochemistry, University of Calgary, Alberta, Canada.
Smith
J R
JR
Moore
G J
GJ
D015059:1-Sarcosine-8-Isoleucine Angiotensin II / Q000494:pharmacology*; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000805:Angiotensin III / Q000378:metabolism / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001921:Brain / Q000201:enzymology*; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D005260:Female; D007700:Kinetics; D015394:Molecular Structure; D010727:Phosphoric Diester Hydrolases; D051381:Rats; D011945:Receptors, Angiotensin / Q000378:metabolism*; D014599:Uterus / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D000805:Angiotensin III; C040420:angiotensin II, Sar(1)-Me-Tyr(4)-; D015059:1-Sarcosine-8-Isoleucine Angiotensin II; D010727:Phosphoric Diester Hydrolases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1