Effects of progesterone on motility and prostaglandin levels in the distal guinea pig colon

Abstract

Progesterone (P4) inhibits the gastrointestinal muscle contraction by downregulating Gαq/11proteins that mediate contraction, by upregulating Gαsproteins that mediate relaxation, and by altering the pattern of cyclooxygenase (COX) enzymes and prostaglandins. We aimed to examine whether P4 treatment of guinea pigs in vivo affects basal colon motility [basal motility index (MI)] by altering the levels and actions of PGF2αand PGE2. Guinea pigs were treated with intramuscular (IM) P4 for 4 days. The BASAL MI, the PGF2α-induced contraction, and PGE2-induced inhibition of contraction were examined in muscle strips and cells. The levels of PGF2αand PGE2were measured by radioimmunoassay. Treatment with P4 reduced the basal MI, the levels of PGF2α, and PGF2α-induced contraction. P4 increased PGE2levels, and PGE2induced relaxation. Pretreatment with IM RU-486 (10 mg/kg per day), a P4 receptor antagonist, 1 h before P4 blocked the actions of P4. The PGF2αantagonist Al-1180 abolished basal MI and PGF2α-induced contraction. N-ethylmaleimide, which blocks unoccupied membrane receptors, blocked Ach and VIP actions but had no effect on PGF2αand PGE2effects. A COX-1 inhibitor decreased and a COX-2 inhibitor increased PGF2αlevels; GTPγS increased and GDPβS decreased the levels of PGF2α. Gαq/11protein antibodies (Abs) reduced PGF2αlevels, and Gαi3Abs blocked its motor actions. Gαs Abs increased PGF2αbut decreased PGE2levels. We concluded that P4 decreases basal MI by reducing PGF2αlevels caused by downregulation of Gαq/11and that PGF2α-induced contraction was blocked by downregulating Gαi3. P4 also decreased the basal MI by increasing PGE2levels, and PGE2induced relaxation by upregulating Gαsproteins.