1. In pre-eclampsia, a functional change occurs in the role played by endothelium-derived nitric oxide (NO) in the regulation of smooth muscle contraction in resistance arteries. We investigated the underlying mechani...
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1. In pre-eclampsia, a functional change occurs in the role played by endothelium-derived nitric oxide (NO) in the regulation of smooth muscle contraction in resistance arteries. We investigated the underlying mechanism in human omental resistance arteries from normotensive pregnant and pre-eclamptic women in the presence of diclofenac (an inhibitor of cyclo-oxygenase). 2. In endothelium-intact strips, the sensitivity to 9,11-epithio-11,12-methano-thromboxane A(2) (STA(2)) was significantly higher in pre-eclampsia, and this was not modified by either N-G-nitro-L-arginine (L-NNA, an inhibitor of NO synthase) or removal of the endothelium. 3. Bradykinin and substance P each produced an endothelium-dependent relaxation of the STA(2)-induced contraction in both groups, although the relaxation was significantly smaller for pre-eclampsia. L-NNA markedly attenuated the endothelium-dependent relaxation in the normotensive pregnant group but not in the pre-eclamptic group. 4. In the presence of L-NNA, the relaxation induced by Sodium nitroprusside (SNP) on the STA(2) contraction was significantly smaller for pre-eclamptic than for normotensive pregnant women. 5. In endothelium-denuded strips, the relaxation induced by 8-para-chlorophenyl thioguanosine-3',5'-cyclic monophosphate (8-pCPT-cGMP) on the STA(2) contraction was significantly less fur pre-eclampsia. 6. In beta-escin-skinned strips from both groups of women, 8-pCPT-cGMP (1-10 mu M) concentration-dependently attenuated the contraction induced by 0.5 mu M Ca2+. However, its relaxing action was significantly weaker in pre-eclampsia. 7. It is suggested that the weaker responsiveness to NO seen in strips fr om pre-eclamptic women may he partly due to a reduced smooth muscle responsiveness to cyclic GMP.
The antitumor drug irinotecan clinically causes severe diarrhea as a side effect. Thromboxane A(2) (TXA(2)), released by irinotecan, has been shown to be a novel physiological stimulant of Cl- secretion in the rat col...
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The antitumor drug irinotecan clinically causes severe diarrhea as a side effect. Thromboxane A(2) (TXA(2)), released by irinotecan, has been shown to be a novel physiological stimulant of Cl- secretion in the rat colon. Herein, we examined the effect of loperamide, an antidiarrhea drug, on Cl- secretion induced by irinotecan;9,11-epithio-11,12-methano-thromboxane A(2) (STA(2)), a stable TXA(2) analog;and prostaglandin E-2 (PGE(2))by using isolated mucosae of the rat colon. In the presence of atropine, loperamide in a concentration-dependent manner inhibited the Cl- secretion induced by irinotecan, STA(2), and PGE(2). However, the drug inhibited more effectively the irinotecan- and STA(2)-induced secretion (IC50 = 0.7 and 1.2 mu M, respectively) than the PGE(2)-induced secretion (IC50 = 23 mu M). Naloxone, an opiate antagonist, did not affect the antisecretory action of loperamide. Similar to the case for loperamide, W-7, a specific calmodulin antagonist, inhibited more effectively the STA(2-)induced Cl- secretion (IC50 = 5 mu M) than the PGE(2)-induced secretion (IC50 = 36 mu M). W-5, a low-affinity calmodulin antagonist (a dechlorinated control analog of W-7), also inhibited the STA(2)-induced secretion, but this effect was much less than that of W-7. STA(2)-induced increase in the intracellular free Ca2+ concentration of single colonic crypt cells was not affected by loperamide. We suggest that loperamide efficiently inhibits the TXA(2)-induced secretion by blocking the calmodulin system in the colonic epithelium. The present results may explain why coadministration of loperamide with irinotecan is clinically efficient for avoiding the irinotecan- induced side effect of diarrhea.
To clarify the presence of thromboxane A(2) (TXA(2)) receptor in the colonic epithelium, we examined the effect of 9,11-epithio-11,12-methano-thromboxane A(2) (STA(2)), a stable analogue of TXA(2), on intracellular fr...
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To clarify the presence of thromboxane A(2) (TXA(2)) receptor in the colonic epithelium, we examined the effect of 9,11-epithio-11,12-methano-thromboxane A(2) (STA(2)), a stable analogue of TXA(2), on intracellular free Ca2+ concentration ([Ca2+](i)) of indo-1-loaded single cells in isolated rat colonic crypts by laser confocal microscopy. STA(2) increased [Ca2+](i) in a concentration-dependent manner with a transient peak phase and a subsequent plateau phase. The EC50 values at peak and plateau phases were 1 and 32 nM, respectively. The STA(2)-induced increase in [Ca2+](i) was completely blocked by two selective TXA(2) receptor antagonists, KW-3635 and ONO-3708. These antagonists did not affect both the basal [Ca2+](i) and the carbaco-induced increase in [Ca2+](i). Prostaglandin E-2 did not increase [Ca2+](i). These results indicate that the STA(2)-elicited increase in [Ca2+](i) is mediated specifically by a TXA(2) receptor in colonic crypt cells This is the first report showing the presence of a TXA(2) receptor that is associated with Ca2+ mobilization in the colon. (C) 1999 Academic Press.
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