Summary
The efficacy of felodipine, a dihydropyridine calcium entry blocker to restore renal function was investigated in Wiggers model of haemorrhagic shock. Mongrel dogs were anaesthetized with sodium pentobarbital and subjected to haemorrhagic shock by allowing the animals to bleed into a reservoir. After maintaining the hypotensive state (mean blood pressure 40–45 mm Hg) for a period of 150 min, the blood was reinfused and the recovery of the various parameters were monitored for an additional 120 min. These studies were conducted in three different groups of dogs: (A) Solvent control, (B) Felodipine 0.01 μmol/kg i. v., administered 10 min prior to reinfusion of the blood, and (C) Felodipine 0.01 μmol/kg i. v., administered prior to haemorrhage. In all the three groups arterial blood pressure returned to similar basal levels following reinfusion. Felodipine administration prior to haemorrhage or before reinfusion (Group B and C) resulted in a 80–95% recovery in the renal blood flow, 60–65% in the glomerular filtration rate, 15–300% in the urine volume and 80–100% in the urinary sodium and potassium excretions. In the vehicle-treated control group, despite a 45% recovery in the renal blood flow, renal function was not restored following reinfusion.
The observations made in these studies suggest that felodipine, an arteriolar dilator which also possesses natriuretic properties, could be clinically useful in the treatment of renal failure in haemorrhagic shock. Prevention of cellular calcium overload during ischaemia and reperfusion by this dihydropyridine derivative, may account for its ability to preserve vascular as well as tubular function.
Similar content being viewed by others
References
Bellamy RF, Pedersen DC, Guzman LR (1984) Organ blood flow and cause of death following massive hemorrhage. Circ Shock 14:113–127
Bolt GR, Saxena PR (1984) Acute systemic and regional hemodynamic effects of felodipine, a new calcium antagonist in conscious renal hypertensive rabbits. J Cardiovasc Pharmacol 6:707–712
Burke TJ, Arnold PE, Gordon JA, Bulger RE, Dobyan DC, Schrier RW (1984) Protective effect of intrarenal calcium membrane blockers before or after renal ischemia. Functional, morphological and mitochondrial studies. J Clin Invest 74:1830–1841
Chaudry IH (1983) Cellular mechanisms of shock and ischemia and their correction. Am J Physiol 245:117–122
Chellingsworth MC, Kendall MJ (1988) Effects of nifedipine, verapamil and diltiazem on renal function. Br J Clin Pharmacol 25:599–602
Cheung JY, Bonventre JV, Malis CD, Leaf A (1986) Calcium and ischemic injury. N Engl J Med 314:1670–1676
Conger JD, Robinette JB, Guggenheim SJ (1981) Effects of acetylcholine on the early phase of irreversible norepinephrineinduced renal failure. Kidney Int 19:399–409
Cronin RE, Erickson AM, Torrente AD, McDonald KM, Schrier RW (1978) Norepinephrine-induced acute renal failure: A reversible ischemic model of acute renal failure. Kidney Int 14:187–190
Dibona GF, Sawin LL (1984) Renal tubular site of action of felodipine. J Pharmacol Exp Ther 228:420–424
Eliahou HE, Brodman RR, Friedman EA 1973 Adrenergic blockers in ischemic acute renal failure in the rat. In: Proceedings of the conference on Acute Renal Failure, DHEW Publication No (NIH) 74-608, New York, pp 265–280
Fitstzpatrick DB, Karmazyn M (1984) Comparative effects of calcium channel blocking agents and varying extracellular calcium concentration hypoxia/reoxygenation and ischeemia/reper fusion-induced cardiac injury. J Pharmacol Exp Ther 28:761–768
Fleckenstein A, Frey M, Fleckenstein GG (1985) Myocardial and vascular damage of intracellular calcium overload. Preventive actions of calcium antagonist. Godfraind T, Vanhoutte PM, Govoni S,Paoletti R (eds) Calcium entry blockers and tissue protection. Raven Press, New York, pp 91–105
Gingrich GA, Barker GR, Lui P, Stewart SC (1985) Renal preservation following severe ischemia and prophylactic calcium channel blockade. J Urol 134:408–410
Goldfarb D, Iaina A, Serban I, Gavendo S, Kapuler S, Eliahou HE (1983) Beneficial effects of verapamil in ischemic acute renal failure in the rat. Proc Soc Exp Biol Med 172:389–392
Guarnieri C, Flamigni F, Caldarera CM (1980) Role of oxygen in the cellular damage induced by reoxygenation of hypoxic heart. J Mol Cell Cardiol 12:797–808
Hackel BD, Mikat EM, Whalen G, Reimer K, Rochlani SP (1979) Treatment of hemorrhagic shock in dogs with verapamil. Effects on survival and on cardiovascular lesions Lab Invest 41: 356–359
Hackel DB, Miakat EM, Reimer K, Whalen G (1981) Effects of verapamil on heart and circulation in hemorrhagic shock in dogs. Am J Physiol 241:12–17
Hansson R, Jonsson O, Lundstom S, Petterson S, Schersten T, Waldenstrom J (1983) Effects of free radical scavengers on renal circulation after ischemia in the rabbit. Clin Sci 65:605–610
Hansson H, Johansson S, Jonsson O, Petterson S, Schersten T, Waldenstrom J (1986) Kidney protection by pretreatment with free radical scavengers and allopurinol: Renal function at recirculation after warm ischemia in rabbits. Clin Sci 71:245–251
Hasselgren BB, Edgar B, Rönn O (1988) Dose dependent effect of felodipine on diuresis and natriuresis in healthy subjects. J Cardiovasc Pharmacol 12:134–139
Hock CE, Su J-Y, Lefer AM (1984) Salutary effects of nitrendipine, a new calcium entry blocker in hemorrhagic shock. Eur J Pharmacol 97:37–46
Humes HD, Simmons CF, Brenner BM (1980) Effect of verapamil on the hydroosmotic response to antidiuretic hormone in the toad urinary bladder. Am J Physiol 239:250–257
Jakschik BA, Marshall GR, Kourik JL, Needleman P (1974) Profile of circulating vasoactive substances in hemorrhagic shock and their pharmacologic manipulation. J Clin Invest 54: 842–852
Jandhyala BS (1985) Studies on the effects of felodipine on the vascular resistance and reactivity in pentobarbital anesthetized dogs. Naunyn-Schmiedeberg's Arch Pharmacol 329:398–403
Johnsson G, Murray G, Tweddel A, Hutton I (1983) Haemodynamic effects of a new vasodilator drug, felodipine in healthy subjects. Eur J Clin Pharmacol 24:49–53
Katz AM, Reuter H (1979) Cellular calcium and cardiac cell death. Am J Cardiol 44:188–190
Lefer AM (1982) The pathophysiologic role of myocardial depressant factor as mediator of circulatory shock. Klin Wochenschr 60:713–716
Ljung B (1984) Vascular selectivity of felodipine. Drugs 29 (Suppl 2):46–58
Malis CD, Bonventres JV (1986) Mechanism of calcium potentiation of oxygen free radical injury to renal mitochondria. A model for post-ischemic and toxic mitochondrial damage. J Biol Chem 261:14201–14208
Malis CD, Cheung JY, Leaf A, Bonventre JV (1983) Effects of verapamil in models of ischemic acute renal failure in the rat. Am J Physiol 245:735–742
Marklund SL (1988) Role of toxic effects of oxygen in reperfusion damage. J Mol Cell Cardiol 20(11):23–30
Markov AK, Oglethorpe N, Young DB, Hellens HK (1981) Irreversible hemorrhagic shock: Treatment and cardiac pathophysiology. Circ Shock 8:9–19
Norlander M, Dibona GF, Ljung B, Yao T, Thoren P (1985) Renal and cardiovascular effects of acute and chronic administration of felodipine to SHR. Eur J Pharmacol 113:25–36
Sabouni M, Hodge K, Jandhyala BS (1988) Restoration of renal and mesenteric hemodynamics by felodipine in a canine model of hemorrhagic shock. Naunyn-Schmiedeberg's Arch Pharmacol 337:465 -470
Sarnoff SJ, Case RB, Waithe PE, Issacs JP (1954) Insufficient coronary flow and myocardial failure as a complicating factor in late hemorrhagic shock. Am J Physiol 176:439–446
Schrier RW, Arnold PE, Gordon JA, Wilson DR, Burke TJ (1982) Pathogenesis and prevention of ischemia induced acute renal failure. Kidney In 23:427–429
Selkurt EE, Alexander RS, Patterson MB (1947) The role of the mesenteric circulation in the irreversibility of hemorrhagic shock. Am J Physiol 149:732–743
Shapiro JI, Cheung C, Itabashi A, Chan L, Schrier RW (1985) The effect of verapamil on renal function after warm and cold ischemia in the isolated perfused rat kidney. Transplantation 40(6):596–600
Tanner GA, Sloan KL, Sophasan S (1973) Effects of renal artery occlusion on kidney function in the rat. Kidney Int 4:377–389
Truniger BS, Rosen SM, Grandchamp A, Strebel H, Kriek HR (1971) Redistribution of renal blood flow in hemorrhagic hypotension: Role of renal nerves and circulating catecholamines. Eur J Clin Invest 1:277–280
Wait RB, White G, David JH (1983) Beneficial effects of verapamil on post ischemic renal failure. Surgery 94(2):276–281
Werle JM, Crosby RS, Wiggers CJ (1942) Observations on hemorrhagic hypotension and haemorrhagic shock. Am J Physiol 136:301–420
Wetzels JFM, Wiltink PG, Hoitsma AJ, Huysmans FM, Koene AP (1988) Diuretic and natriuretic effects of nifedipine in healthy persons. Br J Clin Pharmacol 25:547–553
Author information
Authors and Affiliations
Additional information
Send offprint requests to B. S. Jandhyala at the above address
Rights and permissions
About this article
Cite this article
Chintala, M.S., Jandhyala, B.S. Renal failure in haemorrhagic shock in dogs: Salutary effects of the calcium entry blocker felodipine. Naunyn-Schmiedeberg's Arch Pharmacol 341, 357–363 (1990). https://doi.org/10.1007/BF00180662
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00180662