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. 1986 Aug;78(2):448–455. doi: 10.1172/JCI112596

Verapamil favorably influences hepatic microvascular exchange and function in rats with cirrhosis of the liver.

J Reichen, M Le
PMCID: PMC423578  PMID: 3734100

Abstract

The effect of the calcium channel blocking agent, verapamil, on microcirculatory patterns and hepatic function was investigated in the perfused liver of cirrhotic rats. Compared with controls, cirrhotic livers had higher vascular resistance, increased intrahepatic shunting, and smaller extravascular albumin space and larger extravascular sucrose space, as determined by a multiple-indicator dilution technique. Hepatic function, estimated by determining propranolol and antipyrine extraction, was markedly reduced in cirrhotic livers. Portal pressure was then reduced 25% either pharmacologically by verapamil or hydrodynamically by lowering inflow. Verapamil decreased vascular resistance by 22%. This was associated with a 38% reduction in intrahepatic shunting and a 62% increase in extravascular albumin space. Hydrodynamically lowering pressure had no or adverse effects. The verapamil-induced improvement in microcirculatory characteristics was associated with a significant improvement in oxygen consumption (+21%) and antipyrine clearance (+20%). We conclude that the microvascular distortions of liver cirrhosis in the rat are partially reversible by vasodilators like verapamil.

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Selected References

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  1. BRODIE B. B., AXELROD J. The fate of antipyrine in man. J Pharmacol Exp Ther. 1950 Jan;98(1):97–104. [PubMed] [Google Scholar]
  2. Barbare J. C., Poupon R., Jaillon P., Bories P., Aussanaire M., Darnis F., Michel H., Cheymol G. The influence of vasoactive agents on metabolic activity of the liver in cirrhosis: a study of the effects of posterior pituitary extract, vasopressin, and somatostatin. Hepatology. 1984 Jan-Feb;4(1):59–62. doi: 10.1002/hep.1840040110. [DOI] [PubMed] [Google Scholar]
  3. Berry W. R., Kirshenbaum G., Hoilien C., Le M., Reichen J. Taurolithocholate increases heme catabolism and alters the clearance of antipyrine in the rat. Gastroenterology. 1985 Feb;88(2):397–402. doi: 10.1016/0016-5085(85)90498-6. [DOI] [PubMed] [Google Scholar]
  4. Bianchi F. B., Biagini G., Ballardini G., Cenacchi G., Faccani A., Pisi E., Laschi R., Liotta L., Garbisa S. Basement membrane production by hepatocytes in chronic liver disease. Hepatology. 1984 Nov-Dec;4(6):1167–1172. doi: 10.1002/hep.1840040612. [DOI] [PubMed] [Google Scholar]
  5. Branch R. A., James J. A., Read A. E. The clearance of antipyrine and indocyanine green in normal subjects and in patients with chronic lever disease. Clin Pharmacol Ther. 1976 Jul;20(1):81–89. doi: 10.1002/cpt197620181. [DOI] [PubMed] [Google Scholar]
  6. Branch R. A., Shand D. G., Wilkinson G. R., Nies A. S. Increased clearance of antipyrine and d-propranolol after phenobarbital treatment in the monkey. Relative contributions of enzyme induction and increased hepatic blood flow. J Clin Invest. 1974 Apr;53(4):1101–1107. doi: 10.1172/JCI107647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Burroughs A. K., Jenkins W. J., Sherlock S., Dunk A., Walt R. P., Osuafor T. O., Mackie S., Dick R. Controlled trial of propranolol for the prevention of recurrent variceal hemorrhage in patients with cirrhosis. N Engl J Med. 1983 Dec 22;309(25):1539–1542. doi: 10.1056/NEJM198312223092502. [DOI] [PubMed] [Google Scholar]
  8. Chang S. L., Nelson S. D., Levy R. H. Correlation between antipyrine clearance and cytochrome P-450 level after phenobarbital induction in rat. Drug Metab Dispos. 1984 Jan-Feb;12(1):139–141. [PubMed] [Google Scholar]
  9. Conn H. O. Propranolol in portal hypertension: problems in paradise? Hepatology. 1984 May-Jun;4(3):560–564. doi: 10.1002/hep.1840040333. [DOI] [PubMed] [Google Scholar]
  10. Evans G. H., Wilkinson G. R., Shand D. G. The disposition of propranolol. IV. A dominant role for tissue uptake in the dose-dependent extraction of propranolol by the perfused rat liver. J Pharmacol Exp Ther. 1973 Sep;186(3):447–454. [PubMed] [Google Scholar]
  11. Fraser R., Bowler L. M., Day W. A., Dobbs B., Johnson H. D., Lee D. High perfusion pressure damages the sieving ability of sinusoidal endothelium in rat livers. Br J Exp Pathol. 1980 Apr;61(2):222–228. [PMC free article] [PubMed] [Google Scholar]
  12. Freeman J. G., Barton J. R., Record C. O. Effect of isosorbide dinitrate, verapamil, and labetalol on portal pressure in cirrhosis. Br Med J (Clin Res Ed) 1985 Aug 31;291(6495):561–562. doi: 10.1136/bmj.291.6495.561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. GORESKY C. A. A linear method for determining liver sinusoidal and extravascular volumes. Am J Physiol. 1963 Apr;204:626–640. doi: 10.1152/ajplegacy.1963.204.4.626. [DOI] [PubMed] [Google Scholar]
  14. Goresky C. A., Ziegler W. H., Bach G. G. Capillary exchange modeling. Barrier-limited and flow-limited distribution. Circ Res. 1970 Nov;27(5):739–764. doi: 10.1161/01.res.27.5.739. [DOI] [PubMed] [Google Scholar]
  15. Greenway C. V., Seaman K. L., Innes I. R. Norepinephrine on venous compliance and unstressed volume in cat liver. Am J Physiol. 1985 Apr;248(4 Pt 2):H468–H476. doi: 10.1152/ajpheart.1985.248.4.H468. [DOI] [PubMed] [Google Scholar]
  16. Groszmann R. J., Kravetz D., Bosch J., Glickman M., Bruix J., Bredfeldt J., Conn H. O., Rodes J., Storer E. H. Nitroglycerin improves the hemodynamic response to vasopressin in portal hypertension. Hepatology. 1982 Nov-Dec;2(6):757–762. doi: 10.1002/hep.1840020602. [DOI] [PubMed] [Google Scholar]
  17. Groszmann R. J., Vorobioff J., Riley E. Splanchnic hemodynamics in portal-hypertensive rats: measurement with gamma-labeled microspheres. Am J Physiol. 1982 Feb;242(2):G156–G160. doi: 10.1152/ajpgi.1982.242.2.G156. [DOI] [PubMed] [Google Scholar]
  18. Hahn E., Wick G., Pencev D., Timpl R. Distribution of basement membrane proteins in normal and fibrotic human liver: collagen type IV, laminin, and fibronectin. Gut. 1980 Jan;21(1):63–71. doi: 10.1136/gut.21.1.63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hamann S. R., Blouin R. A., McAllister R. G., Jr Clinical pharmacokinetics of verapamil. Clin Pharmacokinet. 1984 Jan-Feb;9(1):26–41. doi: 10.2165/00003088-198409010-00002. [DOI] [PubMed] [Google Scholar]
  20. Huet P. M., Goresky C. A., Villeneuve J. P., Marleau D., Lough J. O. Assessment of liver microcirculation in human cirrhosis. J Clin Invest. 1982 Dec;70(6):1234–1244. doi: 10.1172/JCI110722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Huet P. M., Villeneuve J. P. Determinants of drug disposition in patients with cirrhosis. Hepatology. 1983 Nov-Dec;3(6):913–918. doi: 10.1002/hep.1840030604. [DOI] [PubMed] [Google Scholar]
  22. Jetley M., Weston A. H. Some effects of sodium nitroprusside, methoxyverapamil (D600) and nifedipine on rat portal vein. Br J Pharmacol. 1980 Feb;68(2):311–319. doi: 10.1111/j.1476-5381.1980.tb10420.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Karaki H., Weiss G. B. Calcium channels in smooth muscle. Gastroenterology. 1984 Oct;87(4):960–970. [PubMed] [Google Scholar]
  24. Kiel J. W., Pitts V., Benoit J. N., Granger D. N., Shepherd A. P. Reduced vascular sensitivity to norepinephrine in portal-hypertensive rats. Am J Physiol. 1985 Feb;248(2 Pt 1):G192–G195. doi: 10.1152/ajpgi.1985.248.2.G192. [DOI] [PubMed] [Google Scholar]
  25. Kroeger R. J., Groszmann R. J. Increased portal venous resistance hinders portal pressure reduction during the administration of beta-adrenergic blocking agents in a portal hypertensive model. Hepatology. 1985 Jan-Feb;5(1):97–101. doi: 10.1002/hep.1840050120. [DOI] [PubMed] [Google Scholar]
  26. Larrey D., Lebrec D., Bercoff E., Pessayre D. Propranolol does not further decrease the clearance of antipyrine in patients with alcoholic cirrhosis. Clin Sci (Lond) 1983 Aug;65(2):203–205. doi: 10.1042/cs0650203. [DOI] [PubMed] [Google Scholar]
  27. Lebrec D., Poynard T., Bernuau J., Bercoff E., Nouel O., Capron J. P., Poupon R., Bouvry M., Rueff B., Benhamou J. P. A randomized controlled study of propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a final report. Hepatology. 1984 May-Jun;4(3):355–358. doi: 10.1002/hep.1840040301. [DOI] [PubMed] [Google Scholar]
  28. Lebrec D., Poynard T., Hillon P., Benhamou J. P. Propranolol for prevention of recurrent gastrointestinal bleeding in patients with cirrhosis: a controlled study. N Engl J Med. 1981 Dec 3;305(23):1371–1374. doi: 10.1056/NEJM198112033052302. [DOI] [PubMed] [Google Scholar]
  29. Loda M., Clowes G. H., Jr, Nespoli A., Bigatello L., Birkett D. H., Menzoian J. O. Encephalopathy, oxygen consumption, visceral amino acid clearance, and mortality in cirrhotic surgical patients. Am J Surg. 1984 Apr;147(4):542–550. doi: 10.1016/0002-9610(84)90019-9. [DOI] [PubMed] [Google Scholar]
  30. MEIER P., ZIERLER K. L. On the theory of the indicator-dilution method for measurement of blood flow and volume. J Appl Physiol. 1954 Jun;6(12):731–744. doi: 10.1152/jappl.1954.6.12.731. [DOI] [PubMed] [Google Scholar]
  31. Mak K. M., Lieber C. S. Alterations in endothelial fenestrations in liver sinusoids of baboons fed alcohol: a scanning electron microscopic study. Hepatology. 1984 May-Jun;4(3):386–391. doi: 10.1002/hep.1840040306. [DOI] [PubMed] [Google Scholar]
  32. McLean E. K., McLean A. E., Sutton P. M. Instant cirrhosis. An improved method for producing cirrhosis of the liver in rats by simultaneous administration of carbon tetrachloride and phenobarbitone. Br J Exp Pathol. 1969 Oct;50(5):502–506. [PMC free article] [PubMed] [Google Scholar]
  33. Meredith P. A., Elliott H. L., Pasanisi F., Kelman A. W., Sumner D. J., Reid J. L. Verapamil pharmacokinetics and apparent hepatic and renal blood flow. Br J Clin Pharmacol. 1985 Aug;20(2):101–106. doi: 10.1111/j.1365-2125.1985.tb05038.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Mols P., Hallemans R., Van Kuyk M., Melot C., Lejeune P., Ham H., Vertongen F., Naeije R. Hemodynamic effects of vasopressin, alone and in combination with nitroprusside, in patients with liver cirrhosis and portal hypertension. Ann Surg. 1984 Feb;199(2):176–181. doi: 10.1097/00000658-198402000-00008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Norris D. K., Bradford H. F. On the specificity of verapamil as a calcium channel-blocker. Biochem Pharmacol. 1985 Jun 1;34(11):1953–1956. doi: 10.1016/0006-2952(85)90314-4. [DOI] [PubMed] [Google Scholar]
  36. Ong H., du Souich P., Marchand C. In vivo study of propranolol and metabolite(s) disposition in rat liver. Drug Metab Dispos. 1981 Nov-Dec;9(6):529–534. [PubMed] [Google Scholar]
  37. POPPER H., ELIAS H., PETTY D. E. Vascular pattern of the cirrhotic liver. Am J Clin Pathol. 1952 Aug;22(8):717–729. doi: 10.1093/ajcp/22.8.717. [DOI] [PubMed] [Google Scholar]
  38. Pessayre D., Lebrec D., Descatoire V., Peignoux M., Benhamou J. P. Mechanism for reduced drug clearance in patients with cirrhosis. Gastroenterology. 1978 Mar;74(3):566–571. [PubMed] [Google Scholar]
  39. Pérez Tamayo R. Is cirrhosis of the liver experimentally produced by CCl4 and adequate model of human cirrhosis? Hepatology. 1983 Jan-Feb;3(1):112–120. doi: 10.1002/hep.1840030118. [DOI] [PubMed] [Google Scholar]
  40. Rappaport A. M. Hepatic blood flow: morphologic aspects and physiologic regulation. Int Rev Physiol. 1980;21:1–63. [PubMed] [Google Scholar]
  41. Rappaport A. M., MacPhee P. J., Fisher M. M., Phillips M. J. The scarring of the liver acini (Cirrhosis). Tridimensional and microcirculatory considerations. Virchows Arch A Pathol Anat Histopathol. 1983;402(2):107–137. doi: 10.1007/BF00695054. [DOI] [PubMed] [Google Scholar]
  42. Reichen J., Le M. Taurocholate, but not taurodehydrocholate, increases biliary permeability to sucrose. Am J Physiol. 1983 Nov;245(5 Pt 1):G651–G655. doi: 10.1152/ajpgi.1983.245.5.G651. [DOI] [PubMed] [Google Scholar]
  43. Reichen J., Paumgartner G. Uptake of bile acids by perfused rat liver. Am J Physiol. 1976 Sep;231(3):734–742. doi: 10.1152/ajplegacy.1976.231.3.734. [DOI] [PubMed] [Google Scholar]
  44. Reilly F. D., Dimlich R. V., Cilento E. V., McCuskey R. S. Hepatic microvascular regulatory mechanisms. III. Aminergic mechanisms as related to mast cells. Int J Microcirc Clin Exp. 1983;2(1):61–73. [PubMed] [Google Scholar]
  45. Rowland M., Benet L. Z., Graham G. G. Clearance concepts in pharmacokinetics. J Pharmacokinet Biopharm. 1973 Apr;1(2):123–136. doi: 10.1007/BF01059626. [DOI] [PubMed] [Google Scholar]
  46. SCHAFFNER F., POPER H. Capillarization of hepatic sinusoids in man. Gastroenterology. 1963 Mar;44:239–242. [PubMed] [Google Scholar]
  47. Shand D. G., Nuckolls E. M., Oates J. A. Plasma propranolol levels in adults with observations in four children. Clin Pharmacol Ther. 1970 Jan-Feb;11(1):112–120. doi: 10.1002/cpt1970111112. [DOI] [PubMed] [Google Scholar]
  48. Varin F., Huet P. M. Hepatic microcirculation in the perfused cirrhotic rat liver. J Clin Invest. 1985 Nov;76(5):1904–1912. doi: 10.1172/JCI112186. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Villeneuve J. P., Wood A. J., Shand D. G., Rogers L., Branch R. A. Impaired drug metabolism in experimental cirrhosis in the rat. Biochem Pharmacol. 1978;27(22):2577–2581. doi: 10.1016/0006-2952(78)90330-1. [DOI] [PubMed] [Google Scholar]
  50. Vorobioff J., Bredfeldt J. E., Groszmann R. J. Increased blood flow through the portal system in cirrhotic rats. Gastroenterology. 1984 Nov;87(5):1120–1126. [PubMed] [Google Scholar]
  51. Wood A. J., Villeneuve J. P., Branch R. A., Rogers L. W., Shand D. G. Intact hepatocyte theory of impaired drug metabolism in experimental cirrhosis in the rat. Gastroenterology. 1979 Jun;76(6):1358–1362. [PubMed] [Google Scholar]

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