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Cardiovascular effects of a novel, potent and selective phosphodiesterase 5 inhibitor, DMPPO: in vitro and in vivo characterization
Author(s) -
Delpy Eric,
Gouville AnneCharlotte le Monnier
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15548.x
Subject(s) - sodium nitroprusside , in vivo , forskolin , chemistry , adenosine , phosphodiesterase , phosphodiesterase inhibitor , phenylephrine , cyclic guanosine monophosphate , guanosine , medicine , endocrinology , endothelium , pharmacology , in vitro , biochemistry , nitric oxide , biology , enzyme , microbiology and biotechnology , blood pressure
1 The aim of this study was to investigate the cardiovascular effects of a novel, potent and specific phosphodiesterase 5 (PDE 5) inhibitor, 1,3 dimethyl‐6‐(2‐propoxy‐5‐methane sulphonylamidophenyl)‐pyrazolo[3,4‐d]pyrimidin‐4‐(5H)‐one (DMPPO) in phenylephrine‐precontracted rat aortic rings and different in vivo rat preparations. 2 DMPPO elicited a concentration‐dependent relaxation of rat aortic rings with functional endothelium. DMPPO‐induced relaxation was abolished by endothelium removal or pretreatment with the soluble guanylate cyclase inhibitor, methylene blue (10 μ m ). 3 In aortic rings without endothelium, the potency (pD 2 = ‐log 10 EC 50 ) of atrial natriuretic peptide (ANP) to induce relaxation increased from 8.13 ± 0.05 in the absence of DMPPO to 8.32 ± 0.05 and 8.52 ± 0.08 in the presence of 30 nM and 100 nM DMPPO, respectively. Similarly, the potency of sodium nitroprusside (SNP) in inducing relaxation increased from 7.38 ± 0.07 in the absence of the PDE 5 inhibitor to 8.07 ± 0.11 and 8.15 ± 0.08 in the presence of 30 nM and 100 nM DMPPO, respectively. In contrast, relaxation to the adenylate cyclase activator, forskolin, was unchanged by DMPPO (100μ m ). 4 In rings without endothelium, DMPPO (100 nM) increased by 2.5 fold intracellular levels of guanosine 3′:5′‐cyclic monophosphate (cyclic GMP). Moreover, DMPPO (100 nM) potentiated the increases in cyclic GMP levels induced by ANP (30 nM) by 3 fold and SNP (30 nM) by 2.7 fold. Adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) levels were not modified by DMPPO. 5 In anaesthetized normotensive or spontaneously hypertensive rats (SHR), DMPPO (2 and 5 mg kg −1 , i.v.) lowered blood pressure without affecting heart rate. Similarly, in conscious SHR, orally administered DMPPO (5 mg kg −1 ) induced a 25 mmHg decrease in blood pressure for at least 7 h without modifying heart rate. Meanwhile, urinary cyclic GMP was increased by 50% whereas cyclic AMP remained unchanged. 6 In normotensive anaesthetized rats, sodium nitroprusside (SNP) (i.v. bolus) induced a decrease in blood pressure which rapidly returned to baseline. In DMPPO (1 mg kg −1 , i.v.)‐treated rats, the hypotensive effects of SNP (10 to 100 μg kg −1 ) were prolonged over time whereas the peak effect was unchanged. 7 In pithed rats, phenylephrine (i.v. bolus) induced dose‐dependent increases in blood pressure. Pretreatment with DMPPO (5 mg kg −1 , i.v.) partially inhibited the pressor response to phenylephrine (0.3 to 100 μg kg −1 ). 8 In conclusion, the potent and selective PDE 5 inhibitor, DMPPO, produces relaxation in isolated vessels in the presence of a cyclic GMP drive and reduces blood pressure of intact animals. Its high oral bioavailability and long duration of action should make it a useful tool to study the role of cyclic GMP in various biological systems.