Selective inhibition of cyclic nucleotide phosphodiesterases of human, bovine and rat aorta

Lugnier, Claire; Schoeffter, Philippe; Bec, Alain Le; Strouthou, E.; Stoclet, Jean‐Claude

doi:10.1016/0006-2952(86)90333-3

Cited by 284 publications

(169 citation statements)

References 24 publications

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“…This e ect was fully reversed by ODQ con®rming that YC-1 exerts its e ects through activation of soluble guanylyl cyclase (sGC; Ko et al, 1994;Wu et al, 1995). The relaxing e ects of YC-1 were potentiated by zaprinast, a selective inhibitor of type V (cyclic GMP speci®c) phosphodiesterase (Lugnier et al, 1986) and antagonized by Rp-8-Br-cGMPS, an inhibitor of cyclic GMP-dependent protein kinase (Zhou et al, 1994). Both ®ndings demonstrate the key role of cyclic GMP in mediating the e ects of YC-1.…”

Section: Discussionmentioning

confidence: 99%

“…The relaxant e ect of YC-1 was reversed by the application of ODQ (30 mM), an inhibitor of soluble guanylyl cyclase (sGC; Garthwaite et al, 1995;Figure 1a). Zaprinast (10 mM), a selective inhibitor of type V (cyclic GMP speci®c) phosphodiesterase (Lugnier et al, 1986), potentiated the relaxant e ects of YC-1 (Figure 1b). Rp-8-Br-cGMPs, a cyclic GMP analogue that inhibits protein kinase G (Zhuo et al, 1994), antagonized the relaxant e ects of YC-1 (Figure 1b).…”

Section: E Ects Of Yc-1 On Aortic Tensionmentioning

confidence: 98%

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Activation of soluble guanylyl cyclase by YC‐1 in aortic smooth muscle but not in ventricular myocardium from rat

Wegener

Gath

Förstermann

et al. 1997

British J Pharmacology

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1 The e ects of YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole), an activator of soluble guanylyl cyclase, on tension, levels of cyclic GMP and cyclic AMP, and cardiac L-type Ca 2+ -current (I Ca(L) ) were investigated in aortic smooth muscle and ventricular heart muscle from rat. 2 YC-1 (0.1 ± 30 mM) induced a concentration-dependent relaxation in aortic rings precontracted with phenylephrine (3 mM). The relaxant e ects of YC-1 were reversed by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (30 mM; ODQ), potentiated by zaprinast (10 mM) and antagonized by Rp-8-BrcGMPS (100 mM). 3 In ventricular heart muscle strips, YC-1 (30 mM) exhibited no e ects on force of contraction (F c ) in the absence or presence of either zaprinast (10 mM) or 3-isobutyl-1-methylxanthine (30 mM). F c was slightly increased by YC-1 (30 mM) in the presence of isoprenaline (100 nM), but this e ect was not in¯uenced by ODQ (30 mM). 4 Cardiac I Ca(L) was not signi®cantly a ected by YC-1 (30 mM), either in the absence or presence of isoprenaline (30 nM). 5 In aortic rings, cyclic GMP levels were increased almost 3 fold by YC-1 (30 mM); this e ect was abolished by ODQ (30 mM). In isolated ventricular cardiomyocytes, cyclic GMP levels were not a ected by YC-1 (30 mM) but almost doubled by activation of particular guanylyl cyclase with atriopeptin II (100 nM). 6 YC-1 (30 mM) did not increase cyclic AMP levels either in aortic rings or in ventricular cardiomyocytes. In contrast, isoprenaline (3 mM) increased cyclic AMP levels about two fold in both tissues. In cardiomyocytes, the e ect of isoprenaline (3 mM) was slightly enhanced by YC-1 (30 mM). 7 It is concluded that relaxation of smooth muscle preparations by YC-1 is mediated mainly by activation of soluble guanylyl cyclase and subsequent increase in cyclic GMP levels. The failure of YC-1 to a ect cardiac F c , levels of cyclic GMP, and I Ca(L) suggests that soluble guanylyl cyclase is not in¯uenced by YC-1 in rat heart muscle or only barely present in this tissue.

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Section: Discussionmentioning

confidence: 99%

Section: E Ects Of Yc-1 On Aortic Tensionmentioning

confidence: 98%

Activation of soluble guanylyl cyclase by YC‐1 in aortic smooth muscle but not in ventricular myocardium from rat

Wegener

Gath

Förstermann

et al. 1997

British J Pharmacology

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“…Cytosolic cyclic nucleotide phosphodiesterase activities were isolated from the media layer of bovine aorta by a modification of the methods of Lugnier et al (1986). Briefly, the tissue was homogenized in 10 vol (w/v) isotonic buffer A (25 mM sodium phosphate pH 6.6, 250 mM saccharose, 2 mM magnesium acetate (MgAc), 1 mM dithiothreitol, 5 mM EGTA, 2000 u ml' aprotinin, 10,lg ml-' soya bean trypsin inhibitor and 10 yg ml-' leupeptin) using an Ultra-turrax (six times, 10 s) and a glass pestle homogenizer, and then centrifuged at 105,000 g for 60 min.…”

Section: Phosphodiesterase Inhibitionmentioning

confidence: 99%

“…Each fraction was tested for PDE activity. Since DEAE-Sephacel did not allow the separation of CaM-PDE from cGMP-PDE, as did DEAE-Trisacryl chromatography (Lugnier et al, 1986) a further higher performance liquid chromatography (h.p.l.c.) repurification was carried out.…”

Section: Phosphodiesterase Inhibitionmentioning

confidence: 99%

“…J. Pharmacol. (1993 We have examined the inhibitory effect of antioquine on the following cytosolic molecular forms of PDE isolated from bovine aorta: a PDE form called CaM-PDE, which preferentially hydrolyzes guanosine 3':5'-cyclic monophosphate (cyclic GMP) and is activated by calmodulin (CaM); a cyclic GMP selective form (cGMP-PDE) insensitive to the stimulatory effect of CaM; and two PDE forms, one belonging to the cyclic GMP-inhibited family (CGI-PDE, type III) and the other a rolipram-sensitive form (cAMP-PDE, type IV) (Lugnier et al, 1986;Ivorra et al, 1992b), which specifically hydrolyze adenosine 3':5'-cyclic monophosphate (cyclic AMP) with a low Km and not stimulated by the addition of Ca2+-CaM.…”

Section: Introductionmentioning

confidence: 99%

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Investigations of the dual contractile/relaxant properties showed by antioquine in rat aorta

Ivorra

Lugnier²,

Catret

et al. 1993

British J Pharmacology

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1 In the present study we assessed the activity of antioquine, a bisbenzyltetrahydroisoquinoline alkaloid isolated from Pseudoxandra sclerocarpa, by examining its effects on 3 Paradoxically, at the highest concentration tested (300 gM) antioquine induced a contractile response of similar magnitude in the presence and absence of extracellular calcium, at 37°C. This activity was greatly attenuated at 25°C. Antioquine-induced contractions were not inhibited by prazosin (0.1 JIM), nifedipine (1 gM) or diltiazem (100 gM). On the contrary, prazosin and nifedipine slightly increased the contractions in the presence of extracellular calcium. Papaverine (100 jiM) partially inhibited the contractile response to antioquine both in the presence and absence of extracellular calcium. 4 At 25°C, in Ca2+-free solution, antioquine (300 jiM) did not modify the contractile response (phasic and tonic) evoked by noradrenaline, but increased the phasic contraction induced by caffeine. At 37°C, the contraction elicited by antioquine made it impossible to observe the noradrenaline-induced one. Antioquine showed affinity for the [3H]-prazosin binding site and for the [3H]-(+)-cis-diltiazembinding site of the Ca2+-channel receptor complex, but had no effect at the dihydropyridine binding site in rat cerebral cortex.6 Antioquine weakly inhibited some PDE forms isolated from bovine aorta: a CaM-PDE (PDE I) which preferentially hydrolyzes cyclic GMP and is activated by calmodulin, and a rolipram-sensitive cyclic AMP-PDE (PDE IV) which hydrolyzed cyclic AMP. Antioquine did not exert any inhibitory effect on the other forms of PDE, a cyclic GMP selective form (PDE V) and a low Km cyclic AMP-PDE that is inhibited by cyclic GMP (CGI-PDE, PDE III). 7 The present work provides evidence that antioquine has properties both as a calcium entry blocker (possibly through the benzothiazepine recognition site in the calcium channel) and as a contractile agent.Its mechanism of action as a contractile agent is not related to Ca2+-entry and is hypothetically similar to that of calyculin-A or okadaic acid. The possible involvement of a-adrenoceptors in this paradoxical effect cannot be excluded. The rigidity of the molecule provides an interesting model for analyzing this contractile mechanism and the intracellular processes involved.

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Analog Design

Wermuth¹

2010

Burger's Medicinal Chemistry and Drug Discovery

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Analog design is usually defined as the modification of a drug molecule or of any bioactive compound in order to prepare a new molecule showing chemical and biological similarity with the original model compound. Excellent descriptions of the various possibilities of bioisosteric replacement are found in Cannon's chapter “Analog Design” published in the previous edition of this book. As a rule, it is expected that the analog exhibits some improvements over the original drug molecule, but sometimes financial motivations are predominant and justify the decision to prepare an analog in order to share market parts. Analog design is a fruitful procedure, easy to practice, and very popularly employed in pharmaceutical research from the beginning. Particularly, from the second half of the twentieth century, the production of very sophisticated molecules such as steroids, prostaglandins, anticancer drugs, and antibiotics became available and considerable advances could be made in medicinal chemistry. Analog design represents two‐third of all small molecule sales. Among the 29 new drugs launched in 2000, 24 were copies.

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Selective inhibition of cyclic nucleotide phosphodiesterases of human, bovine and rat aorta

Cited by 284 publications

References 24 publications

Activation of soluble guanylyl cyclase by YC‐1 in aortic smooth muscle but not in ventricular myocardium from rat

Activation of soluble guanylyl cyclase by YC‐1 in aortic smooth muscle but not in ventricular myocardium from rat

Investigations of the dual contractile/relaxant properties showed by antioquine in rat aorta

Analog Design

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