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Tamara Hew-Butler, Timothy D Noakes, Steven J Soldin and Joseph G Verbalis

Maintenance of fluid homeostasis during periods of heightened physical stress can be best evaluated in humans using exercise as a model. Although it is well established that arginine vasopressin (AVP), aldosterone and atrial natriuretic peptide (ANP) are the principle hormones regulating fluid balance at rest, the potential contributions of other related endocrine factors, such as oxytocin (OT) and brain natriuretic peptide (BNP), have not been well described during exercise. Seven endurance-trained runners completed three separate running trials: a maximal test to exhaustion (high intensity), a 60-min treadmill run (steady state), and a 56 km ultramarathon (prolonged endurance exercise). Statistically significant pre- to post-run increases were found only following the ultramarathon in [AVP]p (1.9 vs 6.7 pg/ml; P<0.05), [OT]p (1.5 vs 3.5 pg/ml; P<0.05), [NT-proBNP]p (23.6 vs 117.9 pg/ml; P<0.01), [interleukin 6]p (4.0 vs 59.6 pg/ml; P<0.05), [cortisol]p (14.6 vs 32.6 μg/ml; P<0.01), [corticosterone]p (652.8 vs 3491.4 ng/ml; P<0.05) and [11-deoxycortisol]p (0.1 vs 0.5 μg/ml; P<0.05) while a significant post-run increase in [aldosterone]p was documented after high-intensity (4.9 vs 12.5 ng/ml; P<0.05), steady-state (6.1 vs 16.9 ng/ml; P<0.05) and prolonged endurance running (2.6 vs 19.7 ng/ml; P<0.05). Similarly, changes in fluid balance parameters were significantly different between the ultramarathon versus high-intensity and steady-state running with regard to plasma volume contraction (less % contraction), body weight loss (increased % weight loss), plasma [Na+] Δ (decreased from baseline), and urine osmolality Δ (increase from baseline). Hypothetically driven relationships between [OT]p and [AVP]p (r=0.69; P<0.01) and between [NT-proBNP]p Δ and plasma [Na+] Δ (r=−0.79; P<0.001) – combined with the significant and unexpected pre- to post-race increases after prolonged endurance exercise – allows for possible speculation that OT and BNP may assist their better known companion hormones (AVP and ANP) in the regulation of fluid balance during conditions of extreme physical stress.

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Joseph G Verbalis, Suzanne Adler, Robert W Schrier, Tomas Berl, Qiong Zhao, Frank S Czerwiec and for the SALT Investigators

Objective

Tolvaptan, an oral antagonist of the vasopressin V2 receptor, has been found to improve hyponatremia in patients with mixed etiologies. This study analyzed a subgroup of patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) to evaluate the efficacy and safety of tolvaptan in this group.

Design and patients

Hyponatremic patients in the SALT-1 and SALT-2 studies with a diagnosis of SIADH were identified based on clinical diagnosis by individual study investigators. Subjects were randomized to receive oral placebo (n=52) or tolvaptan 15 mg daily, with further titration to 30 and 60 mg daily, if necessary, based on the response of serum [Na+] (n=58).

Results

In patients with SIADH, improvement in serum [Na+] was significantly greater (P<0.0001) with tolvaptan than placebo over the first 4 days of therapy as well as the entire 30-day study, with minimal side effects of increased thirst, dry mouth, and urination. Only 5.9% of tolvaptan-treated patients had overly rapid correction of hyponatremia as defined by current guidelines. After discontinuation of tolvaptan, serum [Na+] declined to values similar to placebo. A significant positive treatment effect favoring tolvaptan on the physical component, and a near-significant trend on the mental component, was found using the SF-12 Health Survey. Tolvaptan was associated with a significantly reduced incidence of fluid restriction.

Conclusions

Results for the SIADH subgroup were analogous to those of the combined SALT population regarding efficacy and safety but demonstrated a greater improvement in the physical component of the SF-12 Health Survey than in the full mixed etiology SALT patient group.