Abstract
Purpose
We investigated the effects of tolvaptan, a vasopressin V2-receptor antagonist, on diuretic response and systemic and renal hemodynamic characteristics in conscious dogs with congestive heart failure (CHF). We also compared these effects with those of furosemide, a loop diuretic.
Methods
CHF was induced by rapid right-ventricular pacing at 260 beats/min for at least 3 weeks, and maintained with a pacing rate of 220–240 beats/min. CHF dogs were orally given tolvaptan (10 mg/kg), furosemide (10 mg/kg) and vehicle in random order during the stable CHF state. Urine excretion, systemic and renal hemodynamic parameters, and plasma hormone levels were measured over 6-hour periods after drug administration.
Results
Tolvaptan induced aquaresis with an increase in free water clearance, resulting in a significant increase in serum sodium concentrations and a decrease in cumulative water balance. Tolvaptan also decreased pulmonary capillary wedge pressure without affecting systemic vascular resistance, glomerular filtration rate or renal blood flow. Tolvaptan tended to increase plasma arginine vasopressin concentrations but did not affect plasma renin activity. In contrast, furosemide induced clear saluresis with increased electrolyte excretion, resulting in decreased pulmonary capillary wedge pressure. However, furosemide also decreased serum potassium concentration and increased plasma arginine vasopressin concentrations and plasma renin activity.
Conclusion
Tolvaptan elicited a potent aquaretic response and reduced the cardiac preload without unfavorable effects on systemic or renal hemodynamics, the renin–angiotensin–aldosterone system, or the sympathetic nervous system in CHF dogs. Thus, tolvaptan may offer a novel approach to remove excess water congestion from patients with CHF.
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References
McInnes G. Diuretics. In: Dukes M, editor. Meyler’s side effects of drugs. Amsterdam: Elsevier Science B.V; 1996. p. 558–82.
Cooper HA, Dries DL, Davis CE, Shen YL, Domanski MJ. Diuretics and risk of arrhythmic death in patients with left ventricular dysfunction. Circulation. 1999;100:1311–5.
Domanski M, Norman J, Pitt B, Haigney M, Hanlon S, Peyster E. Diuretic use, progressive heart failure, and death in patients in the Studies Of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol. 2003;42:705–8.
Lee WH, Packer M. Prognostic importance of serum sodium concentration and its modification by converting-enzyme inhibition in patients with severe chronic heart failure. Circulation. 1986;73:257–67.
Francis GS, Siegel RM, Goldsmith SR, Olivari MT, Levine TB, Cohn JN. Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure. Activation of the neurohumoral axis. Ann Intern Med. 1985;103:1–6.
Anand IS, Kalra GS, Harris P, et al. Diuretics as initial and sole treatment in chronic cardiac failure. Cardioscience. 1991;2:273–8.
Colucci W. Pathophysiology of heart failure. In: Brounwald E, editor. Heart Disease. Philadelphia: WB Saunders Co.; 1997. p. 394–420.
Kondo K, Ogawa H, Yamashita H, et al. 7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoyl-amino)benzoyl ]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061): a potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist. Bioorg Med Chem. 1999;7:1743–54.
Yamamura Y, Nakamura S, Itoh S, et al. OPC-41061, a highly potent human vasopressin V2-receptor antagonist: pharmacological profile and aquaretic effect by single and multiple oral dosing in rats. J Pharmacol Exp Ther. 1998;287:860–7.
Hirano T, Yamamura Y, Nakamura S, Onogawa T, Mori T. Effects of the V2-receptor antagonist OPC-41061 and the loop diuretic furosemide alone and in combination in rats. J Pharmacol Exp Ther. 2000;292:288–94.
Gheorghiade M, Niazi I, Ouyang J, et al. Vasopressin V2-receptor blockade with tolvaptan in patients with chronic heart failure: results from a double-blind, randomized trial. Circulation. 2003;107:2690–6.
Gheorghiade M, Gattis WA, O’Connor CM, et al. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial. JAMA. 2004;291:1963–71.
Costello-Boerrigter LC, Smith WB, Boerrigter G, et al. Vasopressin-2-receptor antagonism augments water excretion without changes in renal hemodynamics or sodium and potassium excretion in human heart failure. Am J Physiol Renal Physiol. 2006;290:F273–8.
Brun C. Thiosulfate determination in kidney function tests; a simple method for the determination of thiosulfate in blood and urine. J Lab Clin Med. 1950;35:152–4.
Davidson WD, Sackner MA. Simplification of the anthrone method for the determination of inulin in clearance studies. J Lab Clin Med. 1963;62:351–6.
Armstrong PW, Stopps TP, Ford SE, de Bold AJ. Rapid ventricular pacing in the dog: pathophysiological studies of heart failure. Circulation. 1986;74:1075–84.
Riegger AJ, Liebau G. The renin-angiotensin-aldosterone system, antidiuretic hormone and sympathetic nerve activity in an experimental model of congestive heart failure. Clin Sci. 1982;62:465–9.
Kearney MT, Fox KA, Lee AJ, et al. Predicting death due to progressive heart failure in patients with mild-to-moderate chronic heart failure. J Am Coll Cardiol. 2002;40:1801–8.
Giebisch G. Renal potassium transport: mechanisms and regulation. Am J Physiol Renal Physiol. 1998;274:F817–33.
Amorim JB, Malnic G. V1 receptors in luminal action of vasopressin on distal K+ secretion. Am J Physiol Renal Physiol. 2000;278:F809–16.
Steiness E, Olesen KH. Cardiac arrhythmias induced by hypokalaemia and potassium loss during maintenance digoxin therapy. Br Heart J. 1976;38:167–72.
Robertson GL. Thirst and vasopressin function in normal and disordered states of water balance. J Lab Clin Med. 1983;101:351–71.
Dunn FL, Brennan TJ, Nelson AE, Robertson GL. The role of blood osmolality and volume in regulating vasopressin secretion in the rat. J Clin Invest. 1973;52:3212–9.
Wang BC, Sundet WD, Hakumaki MO, Geer PG, Goetz KL. Cardiac receptor influences on the plasma osmolality-plasma vasopressin relationship. Am J Physiol. 1984;246:H360–8.
Keeton TK, Campbell WB. The pharmacologic alteration of renin release. Pharmacol Rev. 1980;32:81–227.
Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. Am J Cardiol. 1999;83:1A–38.
Udelson JE, Orlandi C, Ouyang J, et al. Acute hemodynamic effects of tolvaptan, a vasopressin V2 receptor blocker, in patients with symptomatic heart failure and systolic dysfunction: an international, multicenter, randomized, placebo-controlled trial. J Am Coll Cardiol. 2008;52:1540–5.
Naitoh M, Suzuki H, Murakami M, et al. Effects of oral AVP receptor antagonists OPC-21268 and OPC-31260 on congestive heart failure in conscious dogs. Am J Physiol. 1994;267:H2245–54.
Burrell LM, Phillips PA, Risvanis J, Chan RK, Aldred KL, Johnston CI. Long-term effects of nonpeptide vasopressin V2 antagonist OPC-31260 in heart failure in the rat. Am J Physiol. 1998;275:H176–82.
Takeuchi M, Lee JD, Shimizu H, Ueda T. Effects of long-term oral treatment with selective vasopressin V2 receptor antagonist (OPC-31260) on adriamycin-induced heart failure in rats. Int J Cardiol. 2006;108:231–6.
Acknowledgments
The authors thank Mr. S Kinoshita for his excellent technical assistance and Dr. Y Liu for his assistance in preparing this manuscript.
Disclosures
None of the authors have any conflicts of interest associated with this study.
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Onogawa, T., Sakamoto, Y., Nakamura, S. et al. Effects of Tolvaptan on Systemic and Renal Hemodynamic Function in Dogs with Congestive Heart Failure. Cardiovasc Drugs Ther 25 (Suppl 1), 67–76 (2011). https://doi.org/10.1007/s10557-011-6350-4
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DOI: https://doi.org/10.1007/s10557-011-6350-4