Antidiarrheal activity of alpha-2 adrenoceptor agonist SK&F 35886.
Alpha-2 adrenoceptor agonists exhibit antidiarrheal activity in animal models and in humans. However, hypotensive and sedative side effects seriously limit the use of these agents to treat diarrhea. SK&F 35886 (2,6-dimethyl phenylamino imidazoline) is an alpha-2 adrenoceptor agonist with little central nervous system activity. In Ussing chamber preparations of rabbit ileum, SK&F 35886 produces a concentration-dependent decrease in basal short-circuit current (Isc) (EC50 0.2 microM) that is dependent on the presence of mucosal HCO3. This concentration-response curve is shifted to the right of rauwolscine, increasing the EC50 to 30 microM. Prazosin had no effect on this response. Flux studies indicate that SK&F 35886 increases net Cl absorption and enhances HCO3 absorption without altering net Na flux. After PGE2 stimulation of Isc, SK&F 35886, applied either serosally or mucosally, immediately returns the Isc to base line. This effect is due to a reversal of the PGE2-induced inhibition of Na and Cl absorption. In vivo SK&F 35886 dose-dependently inhibits PGE2-induced enteropooling when given orally (ED50 approximately 31 micrograms/kg). This effect is attenuated significantly by rauwolscine (1.0 micrograms/kg s.c.). In cecectomized rats, SK&F 35886 abolishes PGE2-induced diarrhea within 1 hr after oral administration of the drug. SK&F 35886 (500 micrograms/kg p.o.) did not alter hexobarbital sleep time or elicit piloerection or lethargy, whereas clonidine (37.3 micrograms/kg p.o.) significantly enhanced hexobarbital sleep time. These results illustrate the ability of a peripheral acting alpha-2 agonist to promote absorption and inhibit secretion and diarrhea in the mammalian intestine.
Fondacaro
J D
JD
Department of Pharmacology, Smith Kline and French Laboratories, Philadelphia, Pennsylvania.
McCafferty
G P
GP
Kolpak
D C
DC
Smith
P L
PL
D015064:16,16-Dimethylprostaglandin E2 / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000930:Antidiarrheals / Q000494:pharmacology*; D001639:Bicarbonates / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains
D000316:Adrenergic alpha-Agonists; D000930:Antidiarrheals; D001639:Bicarbonates; D006993:Hypnotics and Sedatives; D007093:Imidazoles; C035857:xylonidine; D015064:16,16-Dimethylprostaglandin E2; D003000:Clonidine