Sodium excretion in response to vasopressin and selective vasopressin receptor antagonists

Abstract

The mechanisms by which arginine vasopressin (AVP) exerts its antidiuretic and pressor effects, via activation of V2 and V1a receptors, respectively, are relatively well understood, but the possible associated effects on sodium handling are a matter of controversy. In this study, normal conscious Wistar rats were acutely administered various doses of AVP, dDAVP (V2 agonist), furosemide, or the following selective non-peptide receptor antagonists SR121463A (V2 antagonist) or SR49059 (V1a antagonist). Urine flow and sodium excretion rates in the next 6 h were compared with basal values obtained on the previous day, after vehicle treatment, using each rat as its own control. The rate of sodium excretion decreased with V2 agonism and increased with V2 antagonism in a dose-dependent manner. However,for comparable increases in urine flow rate, the V2 antagonist induced a natriuresis 7-fold smaller than did furosemide. Vasopressin reduced sodium excretion at 1 mug/kg but increased it at doses >5 umg/kg,an effect that was abolished by the V1a antagonist. Combined V2 and V1a effects of endogenous vasopressin can be predicted to vary largely according to the respective levels of vasopressin in plasma,renal medulla (acting on interstitial cells), and urine (acting on V1a luminal receptors). In the usual range of regulation, antidiuretic effects of vasopressin may be associated with variable sodium retention. Although V2 antagonists are predominantly aquaretic, their possible effects on sodium excretion should not be neglected. In view of their proposed use in several human disorders, the respective influence of selective (V2) or mixed (V1a/V2) receptor antagonists on sodium handling in humans needs reevaluation.

Figure 1.

Dose-dependent effects of the V2R agonist (dDAVP) and the V2R antagonist (SR121463A) on fluid and solute excretion rates (Experiments A and B, n = 4 to 6 rats per dose). Results are expressed as Exp/Basal. Thin lines illustrate the dose-dependent effects. Paired t test, experimental versus basal: *P < 0.05; **P < 0.01; ***P < 0.001.

Figure 2.

Dose-dependent effects of AVP on fluid and solute excretion rates (Experiment C, n = 4 to 6 rats per dose). Results are expressed as Exp/Basal. Thin lines illustrate the dose-dependent effects. Paired t test, experimental versus basal: *P < 0.05; **P < 0.01; ***P < 0.001.

Figure 3.

Effects of AVP (AVP-15,15 μg/kg BW) on urine flow rate and osmolality and on sodium excretion rate without or with the co-administration of the V1aR antagonist (Experiment D, n = 4 to 6 rats per dose). The effects of the antagonist alone and of dDAVP are also shown. Results of the experimental day are expressed as percentage of values observed during the basal day in the same rats. Paired t test, experimental versus basal: *P < 0.05; **P < 0.01; ***P < 0.001.

Figure 4.

Dose-dependent effects of the V2R antagonist on urine flow rate and osmolality and on sodium excretion rate in the first 6 h after drug administration, in the subsequent 18 h (6 to 24 h), and in the whole 24 h during the experimental day (basal day not shown; Experiment B, n = 4 to 6 rats per dose). Paired t test, experimental versus basal: *P < 0.05; **P < 0.01; ***P < 0.001.

Figure 5.

Influence of the V2R antagonist (○ and dotted line, n = 27) or furosemide (• and solid line, n = 29) at various doses (0.1, 0.3, 1.0, 10.0, and 30.0 mg/kg BW for furosemide and 0.1, 0.3, 1.0, and 10.0 mg/kg BW for the V2R antagonist) on sodium (top) and potassium (bottom) excretion rates as a function of the simultaneous changes in fluid excretion rate (urine flow rate). Results are expressed as Exp/Basal for each rat, and regression lines are shown. For both the abscissa and the ordinate, a value of 1 means no change. The equations of the regression lines and corresponding correlation coefficients are as follows. For sodium with furosemide y = 1.360x − 0.54; r = 0.88, P < 0.001. For sodium with the V2R antagonist y = 0.189x + 0.82; r = 0.82, P < 0.001. For potassium with furosemide y = 0.099x + 0.88; r = 0.45, P < 0.05. For potassium with the V2R antagonist y = 0.058x + 0.86; r = 0.77, P < 0.001.

Figure 6.

Schematic representation of the dose-dependent effects of AVP on sodium excretion rate and dissociation of these effects into V2R- and V1aR-mediated responses. The abscissa represents increasing levels of plasma AVP from left (undetectable) to right. A corresponds to the lowest values of AVP which reduce urine flow rate but not sodium excretion rate. V2R antinatriuretic and V1aR natriuretic effects are depicted as sigmoid curves with different thresholds (B for V2R and C for V1aR effects). B′ and C′ correspond to the maximum effects depending on each receptor type, respectively. M corresponds to the value of plasma AVP for which the antinatriuretic and the natriuretic effects compensate each other. This value probably fluctuates according to a number of factors influencing the intensity of the responses mediated by each of the two receptor types.