Potent aquaretic agent. A novel nonpeptide selective vasopressin 2 antagonist (OPC-31260) in men.

Abstract

Solute-free water diuretics (aquaretics) by antagonizing hydrosmotic vasopressin receptors (V2) may be useful in treating water-retaining diseases. The effects ofintravenous administration of a newly developed nonpeptide, selective V2 antagonist, OPC-31260, at doses ranging from 0.017 to 1.0 mg/kg to groups of healthy, normally hydrated men were compared with those of 0.33 mg/kg furosemide and placebo. OPC-31260 increased the hypotonic urine volume dose dependently for the first 4 h, while furosemide induced sodium diuresis for 2 h. The absolute increase in the cumulative response in the urine to the highest doses of OPC-31260 was not significantly different from that to furosemide. The higher doses of OPC-31260 rapidly lowered urine osmolality for 2 h, particularly between minutes 15 and 45 (e.g., 1.0-mg/kg dose: 63±2 mOsm/kg in urine collected between minutes 30 and 45). In a marked hypotonic diuresis, mean free water clearance of the 4-h urine increased dose proportionally into the positive range, reaching 1.80±0.21 ml/min at 1.0 mg/kg. Whereas furosemide induced marked Na and K diuresis, OPC-31260 increased urinary Na excretion only slightly. At 4 h, 0.75 and 1.0 mg/kg of OPC-31260 almost doubled the plasma arginine vasopressin; and the higher doses increased plasma osmolality and plasma Na slightly, but did not alter plasma K, blood pressure, or heart rate. OPC-31260 thus safely induced a potent aquaretic effect in men. (J. Clin. Invest. 1993. 92:2653-2659 Key words: vasopressin antagonist * aquaretic effect * urine osmolality -hyponatremia * arginine vasopressin

Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations

“…The first successful use of a nonpeptide V 2 R antagonist to produce aquaresis in humans was reported in 1993. 106 Mechanism of action. Molecular modeling of binding sites indicates that the nonpeptide antagonists penetrate deeper into the transmembrane region of the V 2 R than does native AVP, thereby preventing binding of native hormone without themselves interacting with the H1 helix site that is critical for V 2 R-mediated G-protein activation.…”

“…The increased urine output produced by the V 2 R antagonists is quantitatively equivalent to diuretics such as furosemide, but qualitatively it is different in that only water excretion is produced without significant increases in urine solute excretion, including sodium and potassium. 106 Thus, AVP V 2 R antagonists produce solute-sparing water excretion in contrast to classic diuretic agents that cause both water and electrolyte excretion by virtue of their effects to block distal tubular sodium transporters. For this reason, the renal effects produced by AVP V 2 R antagonists have been termed aquaretic to distinguish them from the renal effects produced by diuretic agents, which include not only increased water excretion but also natriuresis and kaliuresis.…”

Hyponatremia in cirrhosis: From pathogenesis to treatment

“…123,158 The aquaretic effect of oral and intravenous V 2 receptor antagonists has been demonstrated in conscious rats, dogs, and human volunteers. 123,158,[162][163][164][165] In Sprague-Dawley rats, the administration of OPC-31260, SR-121463A, or VPA-985 induced a dose-dependent increase in urine volume and a decrease in urine osmolality. When compared with traditional diuretic agents, such as furosemide, hydrochlorothiazide, and spironolactone, the renal effects of the V 2 receptor antagonists were strikingly different.…”

“…The effect of OPC-31260 in normally hydrated healthy subjects has been assessed after both intravenous and oral administration. 164,165 The intravenous administration of a bolus of 0.017 to 1 mg/kg of the drug caused a dosedependent increase in urine volume and a reduction in urine osmolality for the first 4 hours after administration. 164 Free-water clearance increased markedly with the highest dose, but urinary sodium excretion increased only slightly, as opposed to a marked increase caused by the administration of furosemide (0.33 mg/kg) to the same subjects.…”

When Is It Appropriate to Use Vasopressin Receptor Antagonists?

“…Subsequently, nonpeptide receptor antagonists were identified and used successfully for the first time in humans in the early 1990s. 6 In December 2005, the first such compound, conivaptan, a combined vasopressin 1a receptor (V1aR) and V2R antagonist, was approved by the Food and Drug Administration for use in euvolemic hyponatremia. An indication for hypervolemic hyponatremia was granted more recently.…”