Interactions between receptors that increase cytosolic calcium and cyclic AMP in guinea-pig liver cells.
The action of agonists which increase the K+ permeability of liver cells was studied by using a K+-sensitive electrode to record the net movement of K+ between guinea-pig isolated hepatocytes and their suspension medium. Two types of agonist were examined. Type 1 comprised angiotensin II, ATP, noradrenaline and amidephrine, all of which are thought to raise cytosolic Ca2+ in hepatocytes. The Type 2 agonists were isoprenaline and glucagon, which activate adenylate cyclase. Each type of agonist initiated K+ loss from the hepatocytes though the response to Type 2 agonists was more variable than that to Type 1, and sometimes absent. Simultaneous application of a small concentration of an agonist from each class caused a loss of K+ which was much larger than the sum of that seen with each agonist alone, i.e. potentiation occurred. The alpha-adrenoceptor antagonist, WB 4101, abolished potentiation if applied after an alpha-agonist, and before a Type 2 agonist, showing that both receptors have to be active for potentiation to occur. Simultaneous application of a maximal concentration of each type of agonist caused a larger loss of K+ (approximately 17% of the cell total within 45 s) than did a maximal concentration of a Type 1 agonist alone (approximately 10%). Since the K+ loss caused by these agonists is thought to be a consequence of a rise in cytosolic Ca2+, the influence of both types of agonist on 45Ca and 42K efflux from guinea-pig liver slices was studied. The effect of isoprenaline on 45Ca and 42K efflux became much greater following a previous application of the alpha-adrenoceptor agonist, amidephrine. In the presence of apamin, the potentiated effect of isoprenaline on 42K efflux was greatly reduced whereas that on 45Ca efflux was little affected. The effects of Type 1 and Type 2 agonists separately and together on the cyclic AMP content of isolated hepatocytes were examined. Type 2 agonists increased cyclic AMP in the expected way. The increase became slightly smaller, if anything, when a Type 1 agonist was applied at the same time. Hence potentiation could not be ascribed to changes in cyclic AMP formation. Possible mechanisms for potentiation are discussed. Our evidence suggests, albeit indirectly, that it is a consequence of an interaction between the effects of the two types of agonist on cytosolic Ca2+.
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D005934:Glucagon / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011188:Potassium / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000187:drug effects*
D011956:Receptors, Cell Surface; D000804:Angiotensin II; D000255:Adenosine Triphosphate; D005934:Glucagon; D000242:Cyclic AMP; D007545:Isoproterenol; D011188:Potassium; D002118:Calcium