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. 1992 Oct;107(2):463–470. doi: 10.1111/j.1476-5381.1992.tb12768.x

The effect of SK&F 95654, a novel phosphodiesterase inhibitor, on cardiovascular, respiratory and platelet function.

K J Murray 1, R J Eden 1, J S Dolan 1, D C Grimsditch 1, C A Stutchbury 1, B Patel 1, A Knowles 1, A Worby 1, J A Lynham 1, W J Coates 1
PMCID: PMC1907861  PMID: 1422592

Abstract

1. SK&F 95654 inhibited the guanosine 3':5'-cyclic monophosphate (cyclic GMP)-inhibited phosphodiesterase (cGI-PDE) with an IC50 value of 0.7 microM. The IC50 values were greater than 100 microM for the other four phosphodiesterase isoenzymes tested. The R-enantiomer of SK&F 95654 (IC50 = 0.35 microM) was a more potent inhibitor of cGI-PDE than was the S-enantiomer (IC50 = 5.3 microM). 2. In the guinea-pig working heart, SK&F 95654 produced a positive inotropic response without altering heart rate. 3. Oral administration of SK&F 95654 to conscious dogs caused dose-dependent increases in left ventricular dp/dtmax in the range 10-50 micrograms kg-1. These positive inotropic responses were maintained for 3 h without simultaneous changes in heart rate or blood pressure. The peak effects on left ventricular dp/dtmax were similar for orally and intravenously administered compound, indicating good oral bioavailability. 4. SK&F 95654 caused a potent inhibition of U46619-induced aggregation in both a human washed platelet suspension (WPS) (IC50 = 70 nM) and in human platelet-rich plasma (PRP) (IC50 = 60 nM), indicating that the compound shows negligible plasma binding. 5. The R-enantiomer of SK&F 95654 was twenty fold more potent as an inhibitor of platelet aggregation than was the S-enantiomer. The similarity of this ratio to that obtained on the cGI-PDE suggests that SK&F 95654 inhibits platelet aggregation via its effects on cGI-PDE. This was also indicated by studies which showed that SK&F 95654 increased adenosine 3':5'-cyclic monophosphate (cyclic AMP) levels and activated cyclic AMP-dependent protein kinase in human platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Beavo J. A., Reifsnyder D. H. Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors. Trends Pharmacol Sci. 1990 Apr;11(4):150–155. doi: 10.1016/0165-6147(90)90066-H. [DOI] [PubMed] [Google Scholar]
  2. Beier N., Harting J., Jonas R., Klockow M., Lues I., Haeusler G. The novel cardiotonic agent EMD 53 998 is a potent "calcium sensitizer". J Cardiovasc Pharmacol. 1991 Jul;18(1):17–27. doi: 10.1097/00005344-199107000-00004. [DOI] [PubMed] [Google Scholar]
  3. Brodde O. E. Beta 1- and beta 2-adrenoceptors in the human heart: properties, function, and alterations in chronic heart failure. Pharmacol Rev. 1991 Jun;43(2):203–242. [PubMed] [Google Scholar]
  4. Cargnelli G., Piovan D., Bova S., Padrini R., Ferrari M. Present and future trends in research and clinical applications of inodilators. J Cardiovasc Pharmacol. 1989;14 (Suppl 8):S124–S132. [PubMed] [Google Scholar]
  5. Curfman G. D. Inotropic therapy for heart failure--an unfulfilled promise. N Engl J Med. 1991 Nov 21;325(21):1509–1510. doi: 10.1056/NEJM199111213252111. [DOI] [PubMed] [Google Scholar]
  6. Davis A., Warrington B. H., Vinter J. G. Strategic approaches to drug design. II. Modelling studies on phosphodiesterase substrates and inhibitors. J Comput Aided Mol Des. 1987 Jul;1(2):97–119. doi: 10.1007/BF01676955. [DOI] [PubMed] [Google Scholar]
  7. DeLean A., Munson P. J., Rodbard D. Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol. 1978 Aug;235(2):E97–102. doi: 10.1152/ajpendo.1978.235.2.E97. [DOI] [PubMed] [Google Scholar]
  8. Eschenhagen T., Mende U., Nose M., Schmitz W., Scholz H., Haverich A., Hirt S., Döring V., Kalmár P., Höppner W. Increased messenger RNA level of the inhibitory G protein alpha subunit Gi alpha-2 in human end-stage heart failure. Circ Res. 1992 Apr;70(4):688–696. doi: 10.1161/01.res.70.4.688. [DOI] [PubMed] [Google Scholar]
  9. Fleming J. S., Buchanan J. O., Seiler S. M., Meanwell N. A. Antithrombotic activity of BMY-43351, a new imidazoquinoline with enhanced aqueous solubility. Thromb Res. 1991 Jul 1;63(1):145–155. doi: 10.1016/0049-3848(91)90277-4. [DOI] [PubMed] [Google Scholar]
  10. Gristwood R. W., Comer M. B., Eden R. J., Taylor E. M., Turner J. A., Wallduck M., Owen D. A. In vivo pharmacological studies with SK&F 94836, a potent inotrope/vasodilator with a sustained duration of action. Br J Pharmacol. 1988 Apr;93(4):893–901. doi: 10.1111/j.1476-5381.1988.tb11477.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hay D. W., Farmer S. G., Raeburn D., Muccitelli R. M., Wilson K. A., Fedan J. S. Differential effects of epithelium removal on the responsiveness of guinea-pig tracheal smooth muscle to bronchoconstrictors. Br J Pharmacol. 1987 Oct;92(2):381–388. doi: 10.1111/j.1476-5381.1987.tb11334.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Heaslip R. J., Buckley S. K., Sickels B. D., Grimes D. Bronchial vs. cardiovascular activities of selective phosphodiesterase inhibitors in the anesthetized beta-blocked dog. J Pharmacol Exp Ther. 1991 May;257(2):741–747. [PubMed] [Google Scholar]
  13. Holmberg S. R., Williams A. J. Phosphodiesterase inhibitors and the cardiac sarcoplasmic reticulum calcium release channel: differential effects of milrinone and enoximone. Cardiovasc Res. 1991 Jul;25(7):537–545. doi: 10.1093/cvr/25.7.537. [DOI] [PubMed] [Google Scholar]
  14. Katz A. M. Cardiomyopathy of overload. A major determinant of prognosis in congestive heart failure. N Engl J Med. 1990 Jan 11;322(2):100–110. doi: 10.1056/NEJM199001113220206. [DOI] [PubMed] [Google Scholar]
  15. Lindgren S., Andersson K. E. Effects of selective phosphodiesterase inhibitors on isolated coronary, lung and renal arteries from man and rat. Acta Physiol Scand. 1991 May;142(1):77–82. doi: 10.1111/j.1748-1716.1991.tb09130.x. [DOI] [PubMed] [Google Scholar]
  16. Merritt J. E., Hallam T. J., Brown A. M., Boyfield I., Cooper D. G., Hickey D. M., Jaxa-Chamiec A. A., Kaumann A. J., Keen M., Kelly E. Octimibate, a potent non-prostanoid inhibitor of platelet aggregation, acts via the prostacyclin receptor. Br J Pharmacol. 1991 Jan;102(1):251–259. doi: 10.1111/j.1476-5381.1991.tb12162.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Movsesian M. A., Smith C. J., Krall J., Bristow M. R., Manganiello V. C. Sarcoplasmic reticulum-associated cyclic adenosine 5'-monophosphate phosphodiesterase activity in normal and failing human hearts. J Clin Invest. 1991 Jul;88(1):15–19. doi: 10.1172/JCI115272. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Muller B., Lugnier C., Stoclet J. C. Implication of cyclic AMP in the positive inotropic effects of cyclic GMP-inhibited cyclic AMP phosphodiesterase inhibitors on guinea pig isolated left atria. J Cardiovasc Pharmacol. 1990 Mar;15(3):444–451. doi: 10.1097/00005344-199003000-00015. [DOI] [PubMed] [Google Scholar]
  19. Murray K. J., Eden R. J., England P. J., Dolan J., Grimsditch D. C., Stutchbury C. A., Patel B., Reeves M. L., Worby A., Torphy T. J. Potential use of selective phosphodiesterase inhibitors in the treatment of asthma. Agents Actions Suppl. 1991;34:27–46. [PubMed] [Google Scholar]
  20. Murray K. J., England P. J., Hallam T. J., Maguire J., Moores K., Reeves M. L., Simpson A. W., Rink T. J. The effects of siguazodan, a selective phosphodiesterase inhibitor, on human platelet function. Br J Pharmacol. 1990 Mar;99(3):612–616. doi: 10.1111/j.1476-5381.1990.tb12978.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Murray K. J., England P. J. Inhibitors of cyclic nucleotide phosphodiesterases as therapeutic agents. Biochem Soc Trans. 1992 May;20(2):460–464. doi: 10.1042/bst0200460. [DOI] [PubMed] [Google Scholar]
  22. Murray K. J., England P. J., Lynham J. A., Mills D., Schmitz-Peiffer C., Reeves M. L. Use of a synthetic dodecapeptide (malantide) to measure the cyclic AMP-dependent protein kinase activity ratio in a variety of tissues. Biochem J. 1990 May 1;267(3):703–708. doi: 10.1042/bj2670703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Reeves M. L., Leigh B. K., England P. J. The identification of a new cyclic nucleotide phosphodiesterase activity in human and guinea-pig cardiac ventricle. Implications for the mechanism of action of selective phosphodiesterase inhibitors. Biochem J. 1987 Jan 15;241(2):535–541. doi: 10.1042/bj2410535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Robertson D. W., Krushinski J. H., Beedle E. E., Wyss V., Pollock G. D., Wilson H., Kauffman R. F., Hayes J. S. Dihydropyridazinone cardiotonics: the discovery and inotropic activity of 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H -indol-2- one. J Med Chem. 1986 Oct;29(10):1832–1840. doi: 10.1021/jm00160a006. [DOI] [PubMed] [Google Scholar]
  25. Seiler S., Arnold A. J., Grove R. I., Fifer C. A., Keely S. L., Jr, Stanton H. C. Effects of anagrelide on platelet cAMP levels, cAMP-dependent protein kinase and thrombin-induced Ca++ fluxes. J Pharmacol Exp Ther. 1987 Nov;243(2):767–774. [PubMed] [Google Scholar]
  26. Seiler S., Gillespie E., Arnold A. J., Brassard C. L., Meanwell N. A., Fleming J. S. Imidazoquinoline derivatives: potent inhibitors of platelet cAMP phosphodiesterase which elevate cAMP levels and activate protein kinase in platelets. Thromb Res. 1991 Apr;62(1-2):31–42. doi: 10.1016/0049-3848(91)90666-k. [DOI] [PubMed] [Google Scholar]
  27. Silver P. J., Lepore R. E., O'Connor B., Lemp B. M., Hamel L. T., Bentley R. G., Harris A. L. Inhibition of the low Km cyclic AMP phosphodiesterase and activation of the cyclic AMP system in vascular smooth muscle by milrinone. J Pharmacol Exp Ther. 1988 Oct;247(1):34–42. [PubMed] [Google Scholar]
  28. Simpson A. W., Reeves M. L., Rink T. J. Effects of SK&F 94120, an inhibitor of cyclic nucleotide phosphodiesterase type III, on human platelets. Biochem Pharmacol. 1988 Jun 15;37(12):2315–2320. doi: 10.1016/0006-2952(88)90357-7. [DOI] [PubMed] [Google Scholar]
  29. Torphy T. J., Burman M., Huang L. B., Tucker S. S. Inhibition of the low km cyclic AMP phosphodiesterase in intact canine trachealis by SK&F 94836: mechanical and biochemical responses. J Pharmacol Exp Ther. 1988 Sep;246(3):843–850. [PubMed] [Google Scholar]
  30. Uretsky B. F., Jessup M., Konstam M. A., Dec G. W., Leier C. V., Benotti J., Murali S., Herrmann H. C., Sandberg J. A. Multicenter trial of oral enoximone in patients with moderate to moderately severe congestive heart failure. Lack of benefit compared with placebo. Enoximone Multicenter Trial Group. Circulation. 1990 Sep;82(3):774–780. doi: 10.1161/01.cir.82.3.774. [DOI] [PubMed] [Google Scholar]
  31. Weishaar R. E., Burrows S. D., Kobylarz D. C., Quade M. M., Evans D. B. Multiple molecular forms of cyclic nucleotide phosphodiesterase in cardiac and smooth muscle and in platelets. Isolation, characterization, and effects of various reference phosphodiesterase inhibitors and cardiotonic agents. Biochem Pharmacol. 1986 Mar 1;35(5):787–800. doi: 10.1016/0006-2952(86)90247-9. [DOI] [PubMed] [Google Scholar]

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