Effects of Tolvaptan on Systemic and Renal Hemodynamic Function in Dogs with Congestive Heart Failure

Abstract

Purpose We investigated the effects of tolvaptan, a vasopressin V 2 -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-angiotensinaldosterone 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.

Effects of Tolvaptan With or Without the Pre-Administration of Renin-Angiotensin System Blockers in Hospitalized Patients With Acute Decompensated Heart Failure

“…[7][8][9] In addition, tolvaptan did not exert its effect by activating the renin-angiotensin system, 19) whereas furosemide increased plasma arginine vasopressin concentrations in addition to plasma renin activity. 20) The combination of a loop diuretic and tolvaptan may also have a synergistic diuretic effect. Therefore, the increase in UV after the use of tolvaptan in the non-ARB/ ACE-I group was significantly higher than that in the ARB/ ACE-I group.…”

Therapeutic Potential of Vasopressin-Receptor Antagonists in Heart Failure

“…In a similar dog model, 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. Furthermore, it decreased pulmonary capillary wedge pressure without affecting systemic vascular resistance, glomerular filtration rate, or renal blood flow and did not affect plasma renin activity (25). Thus, the V 2 -receptor antagonists may offer a novel approach to remove excess water congestion in patients with heart failure.…”

Immediate Administration of Tolvaptan Prevents the Exacerbation of Acute Kidney Injury and Improves the Mid-Term Prognosis of Patients With Severely Decompensated Acute Heart Failure

“…17 In contrast, tolvaptan acts as a diuretic without activating the RAAS system. 18 Moreover, it can also increase renal blood flow, decrease renal vascular resistance and improve the GFR in patients with HF. 19 It was also reported to be an optimally effective diuretic for patients with CKD.…”