To study the effects of supraphysiologically high sodium concentrations on insulin secretion, the rat pancreas was perfused with normal Krebs-Ringer bicarbonate buffer (KRBB) solution and with KRBB solutions containing an additional 25 and 50 mmol/l NaCl. The first phase of insulin secretion in response to 18 mmol/l glucose was enhanced in a dose-dependent manner, from 20.8+/-4.0 pmol for 4 min in normal KRBB to 36.2+/-10.3 pmol (P<0.05) and 60.3+/-14.6 pmol (P<0.01) with addition of 25 and 50 mmol/l NaCl, respectively. The second phase secretion was significantly increased by the addition of 50 mmol/l NaCl (259.4+/-38.6 vs 170.9+/-47.4 pmol for 16 min P<0.05). The addition of 50 mmol/l isethionate Na to normal KRBB solution also increased the first and second phases of insulin secretion in response to glucose. The increase in osmolarity by the addition of mannitol to normal KRBB solution did not affect the glucose-induced insulin secretion. A high sodium concentration affected neither tolbutamide-induced nor arginine-induced insulin secretion. It is suggested that sodium concentrations have an important role in insulin secretion in response to glucose, but not to other secretagogues.