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. 1995 Feb;95(2):658–668. doi: 10.1172/JCI117711

Hemodynamic and neurohumoral effects of various grades of selective adenosine transport inhibition in humans. Implications for its future role in cardioprotection.

G A Rongen 1, P Smits 1, K Ver Donck 1, J J Willemsen 1, R A De Abreu 1, H Van Belle 1, T Thien 1
PMCID: PMC295532  PMID: 7860749

Abstract

In 12 healthy male volunteers (27-53 yr), a placebo-controlled randomized double blind cross-over trial was performed to study the effect of the intravenous injection of 0.25, 0.5, 1, 2, 4, and 6 mg draflazine (a selective nucleoside transport inhibitor) on hemodynamic and neurohumoral parameters and ex vivo nucleoside transport inhibition. We hypothesized that an intravenous draflazine dosage without effect on hemodynamic and neurohumoral parameters would still be able to augment the forearm vasodilator response to intraarterially infused adenosine. Heart rate (electrocardiography), systolic blood pressure (Dinamap 1846 SX; Critikon, Portanje Electronica BV, Utrecht, The Netherlands) plasma norepinephrine and epinephrine increased dose-dependently and could almost totally be abolished by caffeine pretreatment indicating the involvement of adenosine receptors. Draflazine did not affect forearm blood flow (venous occlusion plethysmography). Intravenous injection of 0.5 mg draflazine did not affect any of the measured hemodynamic parameters but still induced a significant ex vivo nucleoside-transport inhibition of 31.5 +/- 4.1% (P < 0.05 vs placebo). In a subgroup of 10 subjects the brachial artery was cannulated to infuse adenosine (0.15, 0.5, 1.5, 5, 15, and 50 micrograms/100 ml forearm per min) before and after intravenous injection of 0.5 mg draflazine. Forearm blood flow amounted 1.9 +/- 0.3 ml/100 ml forearm per min for placebo and 1.8 +/- 0.2, 2.0 +/- 0.3, 3.8 +/- 0.9, 6.3 +/- 1.2, 11.3 +/- 2.2, and 19.3 +/- 3.9 ml/100 ml forearm per min for the six incremental adenosine dosages, respectively. After the intravenous draflazine infusion, these values were 1.6 +/- 0.2 ml/100 ml forearm per min for placebo and 2.1 +/- 0.3, 3.3 +/- 0.6, 5.8 +/- 1.1, 6.9 +/- 1.4, 14.4 +/- 2.9, and 23.5 +/- 4.0 ml/100 ml forearm per min, respectively (Friedman ANOVA: P < 0.05 before vs after draflazine infusion). In conclusion, a 30-50% inhibition of adenosine transport significantly augments the forearm vasodilator response to adenosine without significant systemic effects. These results suggest that draflazine is a feasible tool to potentiate adenosine-mediated cardioprotection in man.

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Selected References

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  1. Arend L. J., Haramati A., Thompson C. I., Spielman W. S. Adenosine-induced decrease in renin release: dissociation from hemodynamic effects. Am J Physiol. 1984 Sep;247(3 Pt 2):F447–F452. doi: 10.1152/ajprenal.1984.247.3.F447. [DOI] [PubMed] [Google Scholar]
  2. Belardinelli L., Linden J., Berne R. M. The cardiac effects of adenosine. Prog Cardiovasc Dis. 1989 Jul-Aug;32(1):73–97. doi: 10.1016/0033-0620(89)90015-7. [DOI] [PubMed] [Google Scholar]
  3. Biaggioni I. Contrasting excitatory and inhibitory effects of adenosine in blood pressure regulation. Hypertension. 1992 Oct;20(4):457–465. doi: 10.1161/01.hyp.20.4.457. [DOI] [PubMed] [Google Scholar]
  4. Biaggioni I., Killian T. J., Mosqueda-Garcia R., Robertson R. M., Robertson D. Adenosine increases sympathetic nerve traffic in humans. Circulation. 1991 May;83(5):1668–1675. doi: 10.1161/01.cir.83.5.1668. [DOI] [PubMed] [Google Scholar]
  5. Biaggioni I., Olafsson B., Robertson R. M., Hollister A. S., Robertson D. Cardiovascular and respiratory effects of adenosine in conscious man. Evidence for chemoreceptor activation. Circ Res. 1987 Dec;61(6):779–786. doi: 10.1161/01.res.61.6.779. [DOI] [PubMed] [Google Scholar]
  6. Biaggioni I., Onrot J., Hollister A. S., Robertson D. Cardiovascular effects of adenosine infusion in man and their modulation by dipyridamole. Life Sci. 1986 Dec 8;39(23):2229–2236. doi: 10.1016/0024-3205(86)90401-7. [DOI] [PubMed] [Google Scholar]
  7. Biaggioni I., Paul S., Puckett A., Arzubiaga C. Caffeine and theophylline as adenosine receptor antagonists in humans. J Pharmacol Exp Ther. 1991 Aug;258(2):588–593. [PubMed] [Google Scholar]
  8. Blass K. E., Block H. U., Förster W., Pönicke K. Dipyridamole: a potent stimulator of prostacyclin (PGI2) biosynthesis. Br J Pharmacol. 1980 Jan;68(1):71–73. doi: 10.1111/j.1476-5381.1980.tb10700.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bush A., Busst C. M., Clarke B., Barnes P. J. Effect of infused adenosine on cardiac output and systemic resistance in normal subjects. Br J Clin Pharmacol. 1989 Feb;27(2):165–171. doi: 10.1111/j.1365-2125.1989.tb05347.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cohen M. V., Downey J. M. Ischaemic preconditioning: can the protection be bottled? Lancet. 1993 Jul 3;342(8862):6–6. doi: 10.1016/0140-6736(93)91878-p. [DOI] [PubMed] [Google Scholar]
  11. Conradson T. B., Clarke B., Dixon C. M., Dalton R. N., Barnes P. J. Effects of adenosine on autonomic control of heart rate in man. Acta Physiol Scand. 1987 Dec;131(4):525–531. doi: 10.1111/j.1748-1716.1987.tb08272.x. [DOI] [PubMed] [Google Scholar]
  12. Conradson T. B., Dixon C. M., Clarke B., Barnes P. J. Cardiovascular effects of infused adenosine in man: potentiation by dipyridamole. Acta Physiol Scand. 1987 Mar;129(3):387–391. doi: 10.1111/j.1748-1716.1987.tb08082.x. [DOI] [PubMed] [Google Scholar]
  13. Costa F., Biaggioni I. Role of adenosine in the sympathetic activation produced by isometric exercise in humans. J Clin Invest. 1994 Apr;93(4):1654–1660. doi: 10.1172/JCI117147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. De Abreu R. A., Van Baal J. M., De Bruyn C. H., Bakkeren J. A., Schretlen E. D. High-performance liquid chromatographic determination of purine and pyrimidine bases, ribonucleosides, deoxyribonucleosides and cyclic ribonucleotides in biological fluids. J Chromatogr. 1982 Apr 16;229(1):67–75. doi: 10.1016/s0378-4347(00)86037-5. [DOI] [PubMed] [Google Scholar]
  15. Deutsch E., Berger M., Kussmaul W. G., Hirshfeld J. W., Jr, Herrmann H. C., Laskey W. K. Adaptation to ischemia during percutaneous transluminal coronary angioplasty. Clinical, hemodynamic, and metabolic features. Circulation. 1990 Dec;82(6):2044–2051. doi: 10.1161/01.cir.82.6.2044. [DOI] [PubMed] [Google Scholar]
  16. Dibner-Dunlap M. E., Kinugawa T., Thames M. D. Activation of cardiac sympathetic afferents: effects of exogenous adenosine and adenosine analogues. Am J Physiol. 1993 Jul;265(1 Pt 2):H395–H400. doi: 10.1152/ajpheart.1993.265.1.H395. [DOI] [PubMed] [Google Scholar]
  17. Edlund A., Sollevi A., Linde B. Haemodynamic and metabolic effects of infused adenosine in man. Clin Sci (Lond) 1990 Aug;79(2):131–138. doi: 10.1042/cs0790131. [DOI] [PubMed] [Google Scholar]
  18. Feldman M. D., Ayers C. R., Lehman M. R., Taylor H. E., Gordon V. L., Sabia P. J., Ras D., Skalak T. C., Linden J. Improved detection of ischemia-induced increases in coronary sinus adenosine in patients with coronary artery disease. Clin Chem. 1992 Feb;38(2):256–262. [PubMed] [Google Scholar]
  19. Forman M. B., Velasco C. E., Jackson E. K. Adenosine attenuates reperfusion injury following regional myocardial ischaemia. Cardiovasc Res. 1993 Jan;27(1):9–17. doi: 10.1093/cvr/27.1.9. [DOI] [PubMed] [Google Scholar]
  20. Fredholm B. B., Lindgren E. Inhibition of soluble 5'-nucleotidase from rat brain by different xanthine derivatives. Biochem Pharmacol. 1983 Sep 15;32(18):2832–2834. doi: 10.1016/0006-2952(83)90103-x. [DOI] [PubMed] [Google Scholar]
  21. Fukunaga A. F., Flacke W. E., Bloor B. C. Hypotensive effects of adenosine and adenosine triphosphate compared with sodium nitroprusside. Anesth Analg. 1982 Mar;61(3):273–278. [PubMed] [Google Scholar]
  22. Fuller R. W., Maxwell D. L., Conradson T. B., Dixon C. M., Barnes P. J. Circulatory and respiratory effects of infused adenosine in conscious man. Br J Clin Pharmacol. 1987 Sep;24(3):309–317. doi: 10.1111/j.1365-2125.1987.tb03174.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. German D. C., Kredich N. M. A radioenzymatic assay for plasma adenosine. Anal Biochem. 1984 Nov 1;142(2):536–541. doi: 10.1016/0003-2697(84)90503-7. [DOI] [PubMed] [Google Scholar]
  24. German D. C., Kredich N. M., Bjornsson T. D. Oral dipyridamole increases plasma adenosine levels in human beings. Clin Pharmacol Ther. 1989 Jan;45(1):80–84. doi: 10.1038/clpt.1989.12. [DOI] [PubMed] [Google Scholar]
  25. Katholi R. E., Whitlow P. L., Hageman G. R., Woods W. T. Intrarenal adenosine produces hypertension by activating the sympathetic nervous system via the renal nerves in the dog. J Hypertens. 1984 Aug;2(4):349–359. [PubMed] [Google Scholar]
  26. Kroll K., Kelm M. K., Bürrig K. F., Schrader J. Transendothelial transport and metabolism of adenosine and inosine in the intact rat aorta. Circ Res. 1989 Jun;64(6):1147–1157. doi: 10.1161/01.res.64.6.1147. [DOI] [PubMed] [Google Scholar]
  27. Kubo T., Su C. Effects of adenosine on [3H]norepinephrine release from perfused mesenteric arteries of SHR and renal hypertensive rats. Eur J Pharmacol. 1983 Feb 18;87(2-3):349–352. doi: 10.1016/0014-2999(83)90352-7. [DOI] [PubMed] [Google Scholar]
  28. Kurtz A., Della Bruna R., Pfeilschifter J., Bauer C. Role of cGMP as second messenger of adenosine in the inhibition of renin release. Kidney Int. 1988 Apr;33(4):798–803. doi: 10.1038/ki.1988.70. [DOI] [PubMed] [Google Scholar]
  29. Lappe R. W., Sheldon J. H., Cox B. F. Selective adenosine-2 agonist produces both direct and reflex tachycardia in normotensive rats. J Cardiovasc Pharmacol. 1992 Mar;19(3):460–463. doi: 10.1097/00005344-199203000-00025. [DOI] [PubMed] [Google Scholar]
  30. Lucarini A. R., Picano E., Marini C., Favilla S., Salvetti A., Distante A. Activation of sympathetic tone during dipyridamole test. Chest. 1992 Aug;102(2):444–447. doi: 10.1378/chest.102.2.444. [DOI] [PubMed] [Google Scholar]
  31. Masuda M., Demeulemeester A., Chen C. C., Hendrikx M., Van Belle H., Flameng W. Cardioprotective effects of nucleoside transport inhibition in rabbit hearts. Ann Thorac Surg. 1991 Dec;52(6):1300–1305. doi: 10.1016/0003-4975(91)90017-k. [DOI] [PubMed] [Google Scholar]
  32. Maxwell D. L., Fuller R. W., Conradson T. B., Dixon C. M., Aber V., Hughes J. M., Barnes P. J. Contrasting effects of two xanthines, theophylline and enprofylline, on the cardio-respiratory stimulation of infused adenosine in man. Acta Physiol Scand. 1987 Nov;131(3):459–465. doi: 10.1111/j.1748-1716.1987.tb08262.x. [DOI] [PubMed] [Google Scholar]
  33. McElroy F. A., Philip R. B. Relative potencies of dipyridamole and related agents as inhibitors of cyclic nucleotide phosphodiesterases: possible explanation of mechansim of inhibition of platelet function. Life Sci. 1975 Nov 1;17(9):1479–1493. doi: 10.1016/0024-3205(75)90170-8. [DOI] [PubMed] [Google Scholar]
  34. Miura T., Ogawa T., Iwamoto T., Shimamoto K., Iimura O. Dipyridamole potentiates the myocardial infarct size-limiting effect of ischemic preconditioning. Circulation. 1992 Sep;86(3):979–985. doi: 10.1161/01.cir.86.3.979. [DOI] [PubMed] [Google Scholar]
  35. Mohrman D. E., Heller L. J. Transcapillary adenosine transport in isolated guinea pig and rat hearts. Am J Physiol. 1990 Sep;259(3 Pt 2):H772–H783. doi: 10.1152/ajpheart.1990.259.3.H772. [DOI] [PubMed] [Google Scholar]
  36. Mosqueda-Garcia R., Tseng C. J., Biaggioni I., Robertson R. M., Robertson D. Effects of caffeine on baroreflex activity in humans. Clin Pharmacol Ther. 1990 Nov;48(5):568–574. doi: 10.1038/clpt.1990.193. [DOI] [PubMed] [Google Scholar]
  37. Mullane K. Myocardial preconditioning. Part of the adenosine revival. Circulation. 1992 Feb;85(2):845–847. doi: 10.1161/01.cir.85.2.845. [DOI] [PubMed] [Google Scholar]
  38. Murry C. E., Jennings R. B., Reimer K. A. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986 Nov;74(5):1124–1136. doi: 10.1161/01.cir.74.5.1124. [DOI] [PubMed] [Google Scholar]
  39. Norton E. D., Jackson E. K., Turner M. B., Virmani R., Forman M. B. The effects of intravenous infusions of selective adenosine A1-receptor and A2-receptor agonists on myocardial reperfusion injury. Am Heart J. 1992 Feb;123(2):332–338. doi: 10.1016/0002-8703(92)90643-a. [DOI] [PubMed] [Google Scholar]
  40. Olsson R. A., Pearson J. D. Cardiovascular purinoceptors. Physiol Rev. 1990 Jul;70(3):761–845. doi: 10.1152/physrev.1990.70.3.761. [DOI] [PubMed] [Google Scholar]
  41. Ralevic V., Burnstock G. Roles of P2-purinoceptors in the cardiovascular system. Circulation. 1991 Jul;84(1):1–14. doi: 10.1161/01.cir.84.1.1. [DOI] [PubMed] [Google Scholar]
  42. Rardon D. P., Kovacs R. J., Bailey J. C. Adenosine and prostacyclin independent electrophysiological effects of dipyridamole in guinea-pig papillary muscles and canine cardiac Purkinje fibers. J Pharmacol Exp Ther. 1984 Oct;231(1):206–213. [PubMed] [Google Scholar]
  43. Reid P. G., Watt A. H., Routledge P. A., Smith A. P. Intravenous infusion of adenosine but not inosine stimulates respiration in man. Br J Clin Pharmacol. 1987 Mar;23(3):331–338. doi: 10.1111/j.1365-2125.1987.tb03053.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Robertson D., Wade D., Workman R., Woosley R. L., Oates J. A. Tolerance to the humoral and hemodynamic effects of caffeine in man. J Clin Invest. 1981 Apr;67(4):1111–1117. doi: 10.1172/JCI110124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Smits P., Boekema P., De Abreu R., Thien T., van 't Laar A. Evidence for an antagonism between caffeine and adenosine in the human cardiovascular system. J Cardiovasc Pharmacol. 1987 Aug;10(2):136–143. doi: 10.1097/00005344-198708000-00002. [DOI] [PubMed] [Google Scholar]
  46. Smits P., Hoffmann H., Thien T., Houben H., van't Laar A. Hemodynamic and humoral effects of coffee after beta 1-selective and nonselective beta-blockade. Clin Pharmacol Ther. 1983 Aug;34(2):153–158. doi: 10.1038/clpt.1983.145. [DOI] [PubMed] [Google Scholar]
  47. Smits P., Lenders J. W., Thien T. Caffeine and theophylline attenuate adenosine-induced vasodilation in humans. Clin Pharmacol Ther. 1990 Oct;48(4):410–418. doi: 10.1038/clpt.1990.169. [DOI] [PubMed] [Google Scholar]
  48. Smits P., Lenders J. W., Willemsen J. J., Thien T. Adenosine attenuates the response to sympathetic stimuli in humans. Hypertension. 1991 Aug;18(2):216–223. doi: 10.1161/01.hyp.18.2.216. [DOI] [PubMed] [Google Scholar]
  49. Smits P., Schouten J., Thien T. Respiratory stimulant effects of adenosine in man after caffeine and enprofylline. Br J Clin Pharmacol. 1987 Dec;24(6):816–819. doi: 10.1111/j.1365-2125.1987.tb03251.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Smits P., Straatman C., Pijpers E., Thien T. Dose-dependent inhibition of the hemodynamic response to dipyridamole by caffeine. Clin Pharmacol Ther. 1991 Nov;50(5 Pt 1):529–537. doi: 10.1038/clpt.1991.178. [DOI] [PubMed] [Google Scholar]
  51. Smits P., Thien T., van't Laar A. Circulatory effects of coffee in relation to the pharmacokinetics of caffeine. Am J Cardiol. 1985 Dec 1;56(15):958–963. doi: 10.1016/0002-9149(85)90412-6. [DOI] [PubMed] [Google Scholar]
  52. Sollevi A., Lagerkranser M., Irestedt L., Gordon E., Lindquist C. Controlled hypotension with adenosine in cerebral aneurysm surgery. Anesthesiology. 1984 Oct;61(4):400–405. doi: 10.1097/00000542-198410000-00007. [DOI] [PubMed] [Google Scholar]
  53. Sollevi A., Ostergren J., Fagrell B., Hjemdahl P. Theophylline antagonizes cardiovascular responses to dipyridamole in man without affecting increases in plasma adenosine. Acta Physiol Scand. 1984 Jun;121(2):165–171. doi: 10.1111/j.1748-1716.1984.tb07443.x. [DOI] [PubMed] [Google Scholar]
  54. Stringer K. A., Branconi J. M., Abadier R., Wilton J. H., Royal S. H. Disposition of oral dipyridamole in patients undergoing thallium 201 myocardial imaging. Pharmacotherapy. 1992;12(2):83–87. [PubMed] [Google Scholar]
  55. Taddei S., Arzilli F., Arrighi P., Salvetti A. Dipyridamole decreases circulating renin-angiotensin system activity in hypertensive patients. Am J Hypertens. 1992 Jan;5(1):29–31. doi: 10.1093/ajh/5.1.29. [DOI] [PubMed] [Google Scholar]
  56. Taddei S., Virdis A., Favilla S., Salvetti A. Adenosine activates a vascular renin-angiotensin system in hypertensive subjects. Hypertension. 1992 Jun;19(6 Pt 2):672–675. doi: 10.1161/01.hyp.19.6.672. [DOI] [PubMed] [Google Scholar]
  57. Thornton J. D., Liu G. S., Olsson R. A., Downey J. M. Intravenous pretreatment with A1-selective adenosine analogues protects the heart against infarction. Circulation. 1992 Feb;85(2):659–665. doi: 10.1161/01.cir.85.2.659. [DOI] [PubMed] [Google Scholar]
  58. Toombs C. F., McGee S., Johnston W. E., Vinten-Johansen J. Myocardial protective effects of adenosine. Infarct size reduction with pretreatment and continued receptor stimulation during ischemia. Circulation. 1992 Sep;86(3):986–994. doi: 10.1161/01.cir.86.3.986. [DOI] [PubMed] [Google Scholar]
  59. Van Belle H. Nucleoside transport inhibition: a therapeutic approach to cardioprotection via adenosine? Cardiovasc Res. 1993 Jan;27(1):68–76. doi: 10.1093/cvr/27.1.68. [DOI] [PubMed] [Google Scholar]
  60. Van Belle H., Verheyen W., Ver Donck K., Janssen P. A., Robertson J. I. Prevention of catecholamine-induced cardiac damage and death with a nucleoside transport inhibitor. J Cardiovasc Pharmacol. 1992 Aug;20(2):173–178. doi: 10.1097/00005344-199208000-00001. [DOI] [PubMed] [Google Scholar]
  61. Wainwright C. L., Parratt J. R., Van Belle H. The antiarrhythmic effects of the nucleoside transporter inhibitor, R75231, in anaesthetized pigs. Br J Pharmacol. 1993 Jun;109(2):592–599. doi: 10.1111/j.1476-5381.1993.tb13612.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Watt A. H., Reid P. G., Stephens M. R., Routledge P. A. Adenosine-induced respiratory stimulation in man depends on site of infusion. Evidence for an action on the carotid body? Br J Clin Pharmacol. 1987 Apr;23(4):486–490. doi: 10.1111/j.1365-2125.1987.tb03081.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Yellon D. M., Alkhulaifi A. M., Pugsley W. B. Preconditioning the human myocardium. Lancet. 1993 Jul 31;342(8866):276–277. doi: 10.1016/0140-6736(93)91819-8. [DOI] [PubMed] [Google Scholar]
  64. Zhao Z. Q., McGee S., Nakanishi K., Toombs C. F., Johnston W. E., Ashar M. S., Vinten-Johansen J. Receptor-mediated cardioprotective effects of endogenous adenosine are exerted primarily during reperfusion after coronary occlusion in the rabbit. Circulation. 1993 Aug;88(2):709–719. doi: 10.1161/01.cir.88.2.709. [DOI] [PubMed] [Google Scholar]
  65. van der Hoorn F. A., Boomsma F., Man in 't Veld A. J., Schalekamp M. A. Determination of catecholamines in human plasma by high-performance liquid chromatography: comparison between a new method with fluorescence detection and an established method with electrochemical detection. J Chromatogr. 1989 Jan 27;487(1):17–28. doi: 10.1016/s0378-4347(00)83003-0. [DOI] [PubMed] [Google Scholar]
  66. von Borstel R. W., Wurtman R. J., Conlay L. A. Chronic caffeine consumption potentiates the hypotensive action of circulating adenosine. Life Sci. 1983 Mar 7;32(10):1151–1158. doi: 10.1016/0024-3205(83)90121-2. [DOI] [PubMed] [Google Scholar]

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