Regional variations in the ion transport properties of the colon may have significant physiological and pathophysiological implications. However, only limited studies have been performed in cecum, which comprises 50% of the macrosurface of the rabbit colon. In vitro under short-circuit conditions, cecum actively absorbed Na and Cl (JnetNa = 5.6 +/- 0.3, JnetCl = 1.5 +/- 0.3 mu eq.cm-2.h-1) with a short-circuit current (Isc) of 6.29 +/- 0.2 mu eq.cm-2.h-1.Cl substitution with sulfate decreased both JnetNa and Isc by 1.3 mu eq/cm2.h-1.HCO3 removal decreased both JnetNa and Isc 3.3 mu eq.cm-2.h-1. This effect was due primarily to removal of serosal HCO3. There was both a linear correlation between JNanet and Isc (r = 0.845) and a concentration-dependent stimulation of Isc by increasing [Na] in the bathing media. However, 10(-4) M amiloride did not significantly alter either Isc or JnetNa. In contrast, 10(-4) M phenamil, an amiloride analogue highly specific for the Na channel, significantly blocked both Isc and JnetNa. The sulfhydryl reagent PCMBS increased Isc; this response was reversed by phenamil. Electrogenic Cl secretion was stimulated by 1 mM theophylline, 10(-4) M 8BrcAMP and 10(-4) M 8BrcGMP. None of the secretagogues inhibited JnetNa. Epinephrine (5.5 microM) increased JnetNa from 5.9 +/- 1.3 to 7.8 +/- 1.1 (P = 0.02) and JnetCl from 0.1 +/- 1.2 to 2.0 +/- 0.8 (P NS) mu eq.cm-2.h-1. Studies of pH stat demonstrated an epinephrine-stimulated increase in Jm-sHCO3 without a change in Js-mHCO3. Thus, cecum exhibits a distinct type of electrogenic Na electrogenic Na absorption which is partially dependent on the presence of Cl and HCO3, not blocked by amiloride but by phenamil. Because of its large surface area and its novel mechanism of electrogenic Na transport, the cecum exerts an important regulatory role in colonic fluid and electrolyte balance.