Cardiovascular effects of a novel, potent and selective phosphodiesterase 5 inhibitor, DMPPO: <i>in vitro</i> and <i>in vivo</i> characterization

Delpy, Eric; Gouville, Anne-Charlotte Le Monnier de

doi:10.1111/j.1476-5381.1996.tb15548.x

Cited by 17 publications

(14 citation statements)

References 38 publications

(28 reference statements)

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“…Our unanticipated finding of no significant interaction between these two agents on FMD and blood pressure suggests that responses to these agents are attributable to independent mechanisms of action. The effects of sildenafil are almost certainly attributable to potentiation of cGMP signalling, as PDE5 inhibitors induce vasodilation only in the presence of NO [35,36]. Accordingly, our present findings suggest that the acute effects of ramipril on FMD are not attributable to augmentation of cGMP signalling in vascular smooth muscle.…”

Section: Possible Mechanismscontrasting

confidence: 40%

Inhibition of angiotensin-converting enzyme and phosphodiesterase type 5 improves endothelial function in heart failure

et al. 2005

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ACE (angiotensin-converting enzyme) inhibitors and PDE5 (phosphodiesterase type 5) inhibitors have each been reported to improve endothelial function in cardiovascular disease patients, but the comparative and combined effects of these two classes have not been studied previously. We sought to characterize the acute effects of ramipril alone, sildenafil alone, or their combination on endothelial function in patients with CHF (chronic heart failure). CHF subjects (n=64) were randomized to receive placebo, 10 mg of ramipril alone, 50 mg of sildenafil alone or a combination of ramipril and sildenafil in a double-blind manner. FMD (flow-mediated dilation) of the brachial artery was determined by high-resolution ultrasound imaging before and at 1, 2 and 4 h after administration of the study drug. Ramipril alone increased FMD at 4 h compared with placebo (+2.3+/-1.3%, P=0.02). Sildenafil alone increased FMD at 1, 2 and 4 h compared with placebo (+3.9+/-1.4, +4.6+/-1.8 and +3.7+/-1.3% respectively, all P<0.02). Sildenafil in combination with ramipril increased FMD at 1, 2 and 4 h when compared with placebo (+3.5+/-1.5, +4.5+/-1.8 and +4.8+/-1.3% respectively, all P<0.03). Ramipril and sildenafil both acutely improved FMD in patients with CHF, with additive effects evident at 4 h during combination therapy. Therefore further work to characterize chronic effects of combined ACE and PDE5 inhibition on endothelial function are warranted.

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Section: Possible Mechanismscontrasting

confidence: 40%

Inhibition of angiotensin-converting enzyme and phosphodiesterase type 5 improves endothelial function in heart failure

et al. 2005

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“…Similar dose-response curves were obtained in separate aortic rings from BDL and sham-operated rats that were preincubated with DMPPO (0.1 M), a selective inhibitor of PDE5 (7), to examine the role of PDE5 in these responses. In this study, 0.1 M DMPPO was used to specifically and maximally inhibit PDE5 without acting on other PDE isozymes such as PDE3 and PDE4 implicated in vasorelaxation (9,18). In separate studies, the relaxant effect of DMPPO itself and of the non-endothelium-dependent vasodilator diazoxide was investigated in aortic rings with intact endothelium, and a concentration-response curve was obtained.…”

Section: In Vitro Studiesmentioning

confidence: 99%

Effect of phosphodiesterase 5 inhibitor on alteration in vascular smooth muscle sensitivity and renal function in rats with liver cirrhosis

Tahseldar-Roumieh¹,

Ghali-Ghoul²,

Lugnier³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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. Effect of phosphodiesterase 5 inhibitor on alteration in vascular smooth muscle sensitivity and renal function in rats with liver cirrhosis. Am J Physiol Heart Circ Physiol 290: H481-H488, 2006; doi:10.1152/ajpheart.00507.2005.-Previous studies suggested that increased activity of phosphodiesterase (PDE)5 in the kidneys of cirrhotic rats contributes to sodium retention. This study examined the role of PDE5 in the changes in vascular reactivity, hemodynamics, and sodium excretion in rats with liver cirrhosis. Four weeks after bile duct ligation (BDL) or sham operation (SO), in vitro reactivity of aortic rings to various agents and in vivo effects of a PDE5-selective inhibitor [1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)pyrazolo-[3,4d]-pyrimidin-4-(5H)-one, DMPPO] were studied. The vasodilator responses to nitroglycerin and S-nitroso-N-acetyl-penicillamine (SNAP) in phenylephrine-precontracted rings without endothelium were attenuated in BDL compared with SO rats. Pretreatment with DMPPO (0.1 M) enhanced these responses and eliminated the differences between the two groups. Vasodilation to DMPPO itself was also less in BDL rats. The responses to phenylephrine were attenuated in endothelium-rich aorta from BDL relative to SO rats, but they were similar in endotheliumdenuded aorta and remained similar despite preincubation with SNAP (0.1 M) alone or with SNAP and DMPPO. In vivo, BDL rats were vasodilated relative to SO rats; DMPPO (5 mg/kg iv) decreased arterial pressure and vascular resistance in both groups equally and caused significant increase in sodium excretion in BDL rats only. In conclusion, the results are in accordance with a possible increase in PDE5 activity in aorta and kidney of cirrhotic rats that results in reduced responses to NO donors and contributes to the increase in sodium retention. PDE5 inhibitors may ameliorate sodium retention in cirrhosis but may worsen vasodilation. Examining the effect of PDE5 inhibitors after chronic administration will be more revealing.hemodynamics; nitric oxide; vasodilation; sodium retention; guanosine 3Ј,5Ј-cyclic monophosphate CIRRHOSIS OF THE LIVER is associated with development of sodium retention by the kidney, renal vasoconstriction, and peripheral vasodilation especially in the splanchnic vasculature, leading to a hyperdynamic circulation (26). The pathogenesis of these findings has been the subject of numerous studies. Much evidence has been provided to support a role of NO in the genesis of splanchnic vasodilation (32). In addition, several studies have suggested that NO overproduction accounts for the decreased sensitivity of the mesenteric vasculature to vasoconstrictors (2, 3). However, some studies failed to support a role for NO in cirrhosis-induced vasodilation (12, 27), and it was recently shown that mice with a targeted deletion of endothelial nitric oxide synthase (eNOS) still developed the hyperdynamic circulation and peripheral vasodilation characteristic of portal hypertension (13), which suggested that other factors contributed ...

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“…We have recently shown (Delpy & le Monnier de Gouville, 1996) that PDE 5 inhibitors could represent a new class of therapeutic agents useful in the treatment of cardiovascular disorders such as essential hypertension. We have demonstrated in the present study that augmenting cyclic GMP levels by a PDE 5 inhibitor could also be an interesting strategy to potentiate the vasodilator effects of adenylate cyclase activators such as endogenous catecholamines and prostacyclin.…”

Section: Effect Offorskolin On Rat Aortic Ringsmentioning

confidence: 99%

“…Therefore, selective inhibition of this enzyme will increase intracellular cyclic GMP. We recently described a potent and selective PDE 5 inhibitor, 1,3dimethyl-6-(2-propoxy-5-methanesulphonylamidophenyl) pyrazolo [3,4-d] pyrimidin-4-(SH)-one (DMPPO), which lowers blood pressure in different rat models and potentiates the relaxant effects of cyclic GMP-elevating agents in rat aortic rings (Delpy & le Monnier de Gouville, 1996).…”

Section: Introductionmentioning

confidence: 99%

Effects of cyclic GMP elevation on isoprenaline‐induced increase in cyclic AMP and relaxation in rat aortic smooth muscle: role of phosphodiesterase 3

Delpy¹,

Coste²,

Gouville³

1996

British J Pharmacology

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1In rat aortic rings precontracted with phenylephrine, the P-adrenoceptor agonist isoprenaline (10 nM to 30 gM) produces greater relaxant effects in preparations with endothelium than in endotheliumdenuded preparations. The aim of this study was to determine the mechanisms involved in this effect and in particular investigate the possibility of a synergistic action between adenosine 3': 5'-cyclic monophosphate (cyclic AMP) and guanosine 3': 5'-cyclic monophosphate (cyclic GMP). 2 Isoprenaline-induced relaxation of rat aortic rings precontracted with phenylephrine was greatly reduced by the nitric oxide (NO) synthase inhibitor N--nitro-L-arginine methyl ester (L-NAME, 300 giM) or the soluble guanylate cyclase inhibitors methylene blue (10 gM) or lH-[l,2,4]oxadiazolo[4,3-a]quinoxalin-l-one (ODQ, 10 giM) but unaffected by indomethacin (10 uM), a cyclo-oxygenase inhibitor.Similarly, in intact rings, the concentration-response curve of forskolin (10 nM to 1 jiM) was shifted to the right upon endothelium removal or treatment with methylene blue. 3 In endothelium-denuded rat aortic rings, isoprenaline-induced relaxation was potentiated by the guanylate cyclase activators atrial natriuretic factor (ANF, 1 to 10 nM) and sodium nitroprusside (SNP, 1 to 10 nM), and to a greater extent in the presence of the cyclic GMP-specific phosphodiesterase (PDE 5) inhibitor, 1,3dimethyl-6-(2-propoxy-5-methane sulphonylamidophenyl) pyrazolo [3,4-d] pyrimidin-4-(5H)-one (DMPPO, 30 nM). Relaxation induced by isoprenaline was also potentiated by the cyclic GMP-inhibited PDE (PDE 3) inhibitor cilostamide (100 nM). 4 Intracellular cyclic nucleotide levels were measured either in rat cultured aortic smooth muscle cells or in de-endothelialized aortic rings. In both types of preparation, isoprenaline (5 nM and 10 jiM) increased cyclic AMP levels and this effect was potentiated by cilostamide (10 pM), by rolipram, a cyclic AMP-specific PDE (PDE 4) inhibitor (10 jM) and by cyclic GMP-elevating agents (50 nM ANF or 30 nM SNP plus 100 nM DMPPO). In isoprenaline-stimulated conditions, the increase in cyclic AMP induced by rolipram was further potentiated by cilostamide and by cyclic GMP-elevating agents. Cilostamide and cyclic GMP-elevating agents did not potentiate each other, suggesting a similar mechanism of action. 5 We conclude that in vascular smooth muscle (VSM) cells an increase in cyclic GMP levels may inhibit PDE 3 and, thereby, cyclic AMP catabolism. Under physiological conditions of constitutive NO release, and to a greater extent in the presence of the PDE 5 inhibitor DMPPO, cyclic GMP should act synergistically with adenylate cyclase activators to relax VSM.

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Cardiovascular effects of a novel, potent and selective phosphodiesterase 5 inhibitor, DMPPO: in vitro and in vivo characterization

Cited by 17 publications

References 38 publications

Inhibition of angiotensin-converting enzyme and phosphodiesterase type 5 improves endothelial function in heart failure

Inhibition of angiotensin-converting enzyme and phosphodiesterase type 5 improves endothelial function in heart failure

Effect of phosphodiesterase 5 inhibitor on alteration in vascular smooth muscle sensitivity and renal function in rats with liver cirrhosis

Effects of cyclic GMP elevation on isoprenaline‐induced increase in cyclic AMP and relaxation in rat aortic smooth muscle: role of phosphodiesterase 3

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