Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors

Beavo, Joseph A.; Reifsnyder, David H.

doi:10.1016/0165-6147(90)90066-h

Cited by 824 publications

(474 citation statements)

References 16 publications

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“…Both sildena®l and zaprinast, two inhibitors of PDE 5 (Beavo & Reifsnyder, 1990;Boolell et al, 1996;Ballard et al, 1998), increased SNP-stimulated cyclic GMP accumulation but only sildena®l inhibited neurogenic contractions. Noradrenaline-induced contractions were not modi®ed by sildena®l thus suggesting that the inhibition of neurogenic contractions was due to a prejunctional e ect.…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of neuroeffector transmission in human vas deferens by sildenafil

Medina

Segarra

Torondel

et al. 2000

British J Pharmacology

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Sildena®l (0.1 ± 30 mM), a cyclic GMP phosphodiesterase 5 (PDE 5) inhibitor, induced inhibition of electrically evoked contractions of ring segments of human vas deferens from 34 vasectomies. Zaprinast (0.1 ± 100 mM), another PDE 5 inhibitor, and the nitric oxide (NO) donor sodium nitroprusside (SNP) (0.1 ± 100 mM) had no e ect on neurogenic contractions. The inhibition induced by sildena®l was not modi®ed by the inhibitor of guanylate cyclase 1H-[1,2,4]oxadiazolo [4,3-a] quinoxaline-1-one (ODQ) (1 ± 30 mM) but it was abolished by the K + channel blockers tetraethylammonium (TEA, 1 mM), iberiotoxin (0.1 mM) and charybdotoxin (0.1 mM). Sildena®l, zaprinast and SNP did not a ect the contractions induced by noradrenaline. SNP (10 mM) caused elevation of cyclic GMP levels that was potentiated by sildena®l (10 mM) and zaprinast (100 mM). ODQ (10 mM) inhibited the increase in cyclic GMP. Sildena®l inhibits adrenergic neurotransmission in human vas deferens. The inhibition is not related to accumulation of cyclic GMP but is probably due to activation of prejunctional large-conductance Ca 2+ -activated K + channels.

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Section: Resultsmentioning

confidence: 99%

“…The present work was designed to investigate the e ects of sildena®l given alone or in combination with the NO donor SNP on nerve-and noradrenaline-induced contractions in human vas deferens. The PDE 5 inhibitor zaprinast (Beavo & Reifsnyder, 1990) was included in the study for comparison.…”

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confidence: 99%

Inhibition of neuroeffector transmission in human vas deferens by sildenafil

Medina

Segarra

Torondel

et al. 2000

British J Pharmacology

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“…Cyclic GMP may also affect vascular functions via interaction with the cyclic AMP signalling pathway, due to its ability to activate protein kinase(s) A at high concentrations which is closely related in structure and function to the cyclic GMP-dependent protein kinase (Forte et al, 1992;Cornwell et al, 1994a). Moreover cyclic GMP inhibits the activity of the vascular smooth muscle phosphodiesterase III which preferentially hydrolyzes cyclic AMP (Beavo & Reifsnyder, 1990). The expression of the cyclic GMP-dependent protein kinase decreases with increasing passage of rat aortic smooth muscle cells (Cornwell et al, 1994b) whereas the activity of protein kinase(s) A is maintained in cultured vascular smooth muscle cells (Lincoln & Cornwell, 1993); hence the stimulating effect of cyclic GMP on iNOS expression (as observed here) could be due to an interaction with the cyclic AMP signalling pathway.…”

Section: Expression Of Inos Proteinmentioning

confidence: 99%

Effect of cyclic GMP‐dependent vasodilators on the expression of inducible nitric oxide synthase in vascular smooth muscle cells: role of cyclic AMP

Boese

Busse

Mülsch

et al. 1996

British J Pharmacology

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1 In the present study we examined whether interleukin-lf (IL-Ifl) increases the activity of adenylyl cyclase in vascular smooth muscle cells and determined its role in the cytokine-induced expression of the inducible nitric oxide synthase (iNOS) and activation of nuclear transcription factor-KB (NF-KB). In addition the interaction between cyclic AMP-and cyclic GMP-elevating agonists on the IL-iIf-stimulated expression of iNOS was examined.2 Exposure of vascular smooth muscle cells to IL-,IB stimulated the formation of cyclic AMP but not of cyclic GMP. The intracellular level of cyclic AMP reached a maximum within 1 h and then gradually declined over the next 5 h. This IL-l, (60 u ml-')-stimulated formation of cyclic AMP was modest (about 3 fold at 60 u ml-' for 1 h) compared to that evoked by isoprenaline (about 9 fold at 3 x 10-6 M for 2 min). 3 The IL-iI (60 u ml1 for 24 h)-stimulated accumulation of nitrite, which was taken as an index of NO production, was concentration-dependently increased by preferential inhibitors of cyclic AMP-dependent phosphodiesterases (rolipram and trequinsin). This effect was reproduced by a specific activator of the cyclic AMP-dependent protein kinase(s) A, Sp-8-CPT-cAMPS (10-4 M) but was prevented by a specific inhibitor of cyclic AMP-dependent protein kinase(s) A, Rp-8-CPT-cAMPS (10-4 M). These compounds alone [rolipram (10-6 M), trequinsin (3 x 10-6 M) and Sp-8-CPT-cAMPS (l0-4 M)] slightly but significantly increased the release of nitric oxide while Rp-8-CPT-cAMPS elicited no such effect. 4 Inducible NOS protein was expressed in IL-/IB (30 u ml-', 24 h)-stimulated smooth muscle cells as assessed by Western blot analysis. The level of iNOS protein was markedly increased in smooth muscle cells which had been exposed to IL-,IB in combination with either rolipram (3 x 10-6 M) or Sp-8-CPTcAMPS (l0-4 M) but was reduced in those exposed to IL-,IB and Rp-8-CPT-cAMPS (l0-4 M). A weak expression of iNOS protein was found in smooth muscle cells which had been exposed to either Sp-8-CPT-cAMPS or rolipram alone for 24 h while Rp-8-CPT-cAMPS elicited no such effect. 5 Exposure of smooth muscle cells to IL-lI (30 u ml-') for 30 min increased the level of NF-KB-DNA complexes in nuclear extracts as detected by electrophoretic mobility shift assay. Similar levels of NF-KB-DNA complexes were found in cells which had been exposed to IL-,IB in combination with either Sp

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“…Therefore, the combination of sildena®l plus intraurethral or intracavernosal PGE 1 , or intracavernosal forskolin or VIP, might be effective in patients with ED in whom monotherapy with these agents has failed. That papaverine and sildena®l were not synergistic in this study might be because they have similar mechanisms of action on the relaxation of cavernosal smooth muscles [20,26,27]. To ascertain why there are different synergistic effects of cAMP-mediated agents plus sildena®l, the intracellular cAMP level should be measured, and expression and functional studies of receptors of VIP and PGE 1 after treatment with forskolin, VIP and PGE 1 conducted in cavernosal smooth muscles.…”

Section: Discussionmentioning

confidence: 96%

Synergistic effects of sildenafil on relaxation of rabbit and rat cavernosal smooth muscles when combined with various vasoactive agents

Seo¹,

Kim²,

Jun³

et al. 2001

BJU International

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Objective To evaluate which vasoactive agents have synergistic effects on the cavernosal smooth muscles of rabbits and rats when the agents are combined with sildena®l. Materials and methods Relaxation responses of cavernosal smooth muscle to single agents (phentolamine, moxisylyte, sodium nitroprusside, forskolin, vasoactive intestinal peptide, VIP, papaverine and sildena®l) in the rabbit, and prostaglandin-E 1 and sildena®l in the rat, and to combinations of each agent plus sildena®l, were assessed in vitro. The response to sildena®l of the rabbit strips with and without incubation with L-arginine (1 mmol/L) for 20 min was also evaluated. The effective concentrations for a half-maximal response of single agents and combination solutions were compared. Results All single agents induced concentrationdependent relaxation of the rabbit and rat cavernosal smooth muscles. There was signi®cant synergism on rabbit cavernosal smooth muscle when the sildena®l was combined with forskolin, sodium nitroprusside, VIP or phentolamine.There was also signi®cant synergism with sildena®l plus prostaglandin-E 1 in rat cavernosal muscles. There were no synergistic effects of combinations of sildena®l plus moxisylyte, papaverine or L-arginine.Conclusions These results suggest potentially effective combined therapies of sildena®l and intraurethral or intracavernosal prostaglandin-E 1 , intracavernosal forskolin or VIP, or oral phentolamine for patients with erectile dysfunction who have no success after monotherapy with these agents.

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Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors

Cited by 824 publications

References 16 publications

Inhibition of neuroeffector transmission in human vas deferens by sildenafil

Inhibition of neuroeffector transmission in human vas deferens by sildenafil

Effect of cyclic GMP‐dependent vasodilators on the expression of inducible nitric oxide synthase in vascular smooth muscle cells: role of cyclic AMP

Synergistic effects of sildenafil on relaxation of rabbit and rat cavernosal smooth muscles when combined with various vasoactive agents

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