Peptides of human immunodeficiency virus (HIV) evoke rat colonic electrolyte secretion inhibitable by the somatostatin analog octreotide.

An integral transmembrane glycoprotein of the Human Immunodeficiency Virus (HIV) is gp 41. Five peptides (P1, P2, P3, P4, and P5) containing a conserved region of the gp 41 molecule have been synthesized. We tested P3, P4 and P5 for their effects on short-circuit current (Isc) across rat colonic mucosa. All three peptides increased the Isc; P5 was the most potent agonist. Serosal pretreatment of tissues with the chloride transport inhibitor, bumetanide (0.1 mM) or chloride replacement with gluconate, inhibited the response, suggesting that the increase in Isc was due to stimulation of active chloride secretion. The synthetic somatostatin analog octreotide (0.1 mM) also inhibited (P less than .05) the response to P5 (1 microM). The data provide a possible rationale for one aspect of the efficacy of octreotide in treating secretory diarrhea in patients with Acquired Immunodeficiency Syndrome (AIDS).

Treatment of endocrine and nonendocrine secretory diarrheal states with Sandostatin.

Endocrine tumors of the gastroenteropancreatic (GEP) axis elaborate excessive amounts of peptides that are potent intestinal secretagogues. The actions of these peptides on intestinal transport of water and electrolytes lead to the accumulation of fluid in the intestinal lumen and diarrhea. One of the most clinically relevant secretagogues is vasoactive intestinal polypeptide (VIP). Other relevant secretagogues elaborated from tumors are serotonin, prostaglandins, and kinins. Sandostatin (octreotide, Sandoz, Basle, Switzerland), a long-acting octapeptide analog of somatostatin, inhibits experimentally induced intestinal secretion and has been used successfully to treat patients with secretory diarrhea refractory to other pharmacotherapy. The effective dose is in the range of 50 to 200 micrograms, given subcutaneously two or three times daily. The mechanism for the inhibitory effect on secretion is not clearly understood but it appears to involve inhibition of the adenylate cyclase-cyclic adenosine monophosphate system as well as interference with calcium as an intercellular mediator of enterocyte secretion. A particularly interesting use of this drug has been to treat the watery diarrhea seen in patients with acquired immunodeficiency syndrome. It is also effective in other types of secretory diarrhea not associated with endocrine tumors. These include diabetic diarrhea, idiopathic secretory diarrhea of infancy, and high output ileostomy diarrhea.

Octreotide inhibits increases in short-circuit current induced in rat colon by VIP, substance P, serotonin and aminophylline.

We investigated the effect of octreotide (OCT), a stable somatostatin analog, (OCT) on changes in short-circuit current (Isc) induced by vasoactive intestinal peptide (VIP), aminophylline, serotonin (5-HT) and substance P. OCT significantly decreased basal Isc at a concentration of 10(-9) M; the maximum decrease in Isc was observed at 10(-6) M. OCT (10(-7) M) significantly inhibited the intestinal secretory response to all the secretagogues studied. The maximum Isc response was reduced when tissues were stimulated with VIP (184.9 +/- 18.0 vs. 119.7 +/- 14.1, P less than 0.05), 5-HT (135.1 +/- 14.4 vs. 79.5 +/- 13.4, P less than 0.05) and substance P (156.0 +/- 19.2 vs. 30.7 +/- 5.4, P less than 0.01). In the case of aminophylline, the concentration-response curve was shifted to the right but the maximum response was not reduced. Because VIP and aminophylline increase cAMP while 5-HT and substance P stimulate intestinal secretion principally by a calcium linked mechanism, we conclude that OCT inhibits Isc in rat colon by more than one mechanism.