Schistosoma mansoni infection enhances host portal vein contraction: role of potassium channels and p38 MAP kinase (original) (raw)
Related papers
Parasitology Research, 2002
We previously reported that portal veins from mice infected with male Schistosoma mansoni exhibited an increased reactivity to 5-hydroxytryptamine (5-HT). Here, we extended our observations to mice infected by both male and female worms and we further investigated another constrictor agent and the mechanism(s) responsible for the enhanced maximal contraction (E max). Bisexual infection increased the E max of 5-HT (from 0.66±0.06 mN.s to 1.56±0.38 mN.s), in a similar way to the unisexual (male) infection. Infection with male worms increased portal vein reactivity to acetylcholine, as revealed by a higher E max (1.03±0.2 mN.s) in relation to non-infected control animals (E max = 0.54±0.08 mN.s). Sarcoplasmic/endoplasmic reticulum Ca 2+-ATPase (SERCA) inhibition with 100 nM thapsigargin reduced the E max of 5-HT by 35% in both tissues, discharging a deficiency of SERCA pump in infected animals. In contrast, the number of voltage-dependent Ca 2+ channels (L-type) was higher in portal veins from infected than non-infected control mice. Inhibition of Ca 2+-activated chloride channels (Cl Ca) with 10 lM niflumic acid reduced the E max of 5-HT in portal veins more from infected than non-infected animals (remaining tension = 60.9±2.2% and 70.4±2.3%, respectively). Histopathological analysis revealed an increased content of collagen and elastin in portal veins from male S. mansoni-infected mice, compatible with an increased intraluminal pressure. In conclusion, male S. mansoni altered portal vein physiology, increasing the E max of two vasoconstrictors, possibly by increasing membrane depolarisation through a more effective opening of Cl Ca channels, with calcium entering through L-type Ca 2+ channels.
Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 1998
In chronic severe infection with Schistosoma mansoni, portal hypertension accompanied by anatomical changes of the portal vasculature can develop as a consequence of granulomatous response to eggs. Mice infected unisexually with male worms were used in the present study in order to investigate a direct effect of worms on the reactivity of their host portal vein. A higher reactivity in the presence of 5-hydroxytryptamine (5-HT), but not in the presence of KCl 100 mM solution, was observed in portal vein from infected mice compared to healthy mice. It was characterized by an increase in the maximal contraction and sensitivity to 5-HT. Blockade of NO-synthase with N v-nitro-L-arginine methyl ester (L-NAME) induced a small increase in 5-HT potency in the portal vein from non-infected mice, but did not change the amplitude of the contractions. In portal veins from infected mice, preincubation with L-NAME did not affect the reactivity to 5-HT. Histological analysis indicated endothelial damage, subendothelial fibrous plaques, and focal areas of inflammatory infiltrates in the adventitial layer. As a conclusion, these results show that unisexual infection of mice with male S. mansoni increased the reactivity of the portal vein to 5-HT which seems to be only partially related to an alteration in the endothelial production of nitric oxide.
PLOS Neglected Tropical Diseases, 2015
Schistosomiasis, caused by parasitic flatworms of the genus Schistosoma, is a neglected tropical disease affecting hundreds of millions globally. Praziquantel (PZQ), the only drug currently available for treatment and control, is largely ineffective against juvenile worms, and reports of PZQ resistance lend added urgency to the need for development of new therapeutics. Ion channels, which underlie electrical excitability in cells, are validated targets for many current anthelmintics. Transient receptor potential (TRP) channels are a large family of non-selective cation channels. TRP channels play key roles in sensory transduction and other critical functions, yet the properties of these channels have remained essentially unexplored in parasitic helminths. TRP channels fall into several (7-8) subfamilies, including TRPA and TRPV. Though schistosomes contain genes predicted to encode representatives of most of the TRP channel subfamilies, they do not appear to have genes for any TRPV channels. Nonetheless, we find that the TRPV1-selective activators capsaicin and resiniferatoxin (RTX) induce dramatic hyperactivity in adult worms; capsaicin also increases motility in schistosomula. SB 366719, a highly-selective TRPV1 antagonist, blocks the capsaicin-induced hyperactivity in adults. Mammalian TRPA1 is not activated by capsaicin, yet knockdown of the single predicted TRPA1-like gene (SmTRPA) in S. mansoni effectively abolishes capsaicin-induced responses in adult worms, suggesting that SmTRPA is required for capsaicin sensitivity in these parasites. Based on these results, we hypothesize that some schistosome TRP channels have novel pharmacological sensitivities that can be targeted to disrupt normal parasite neuromuscular function. These results also have implications for understanding the phylogeny of metazoan TRP channels and may help identify novel targets for new or repurposed therapeutics.
Molecular and Biochemical Parasitology, 2003
Kohn et al. [J. Biol. Chem. 276 (2001) 36873] demonstrated that cells expressing the structurally unusual schistosome β subunit SmCavβ1 in their voltage-operated calcium channels, exhibit an increased current amplitude in the presence of praziquantel (PZQ). This suggests that the beta subunit is involved in PZQ activity and is consistent with the known pharmacological effects of the drug. If this is so, the low susceptibility to PZQ noted in some Schistosoma mansoni strains could be due to some mutation(s) in the gene coding for this protein. We have sequenced the cDNAs coding for the SmCavβ1 and SmCavβ2 subunits of different sensitive and resistant strains and we have not been able to detect any meaningful differences. As an alternative hypothesis, the different sensitivity of schistosomes to PZQ action could be due to the expression of different β subunits in the parasite. This interpretation could also explain the low PZQ susceptibility of immature worms (28 days). We analyzed Northern blots of various strains and various developmental stages, but we were unable to demonstrate major quantitative differences in the expression of the β subunits.
Journal of Clinical Investigation, 1991
We investigated the role of early portal hypotensive pharmacotherapy in preventing the development of portal-systemic shunting in a portal hypertensive model of chronic murine schistosomiasis induced by infecting C3H mice with 60 cercariae of Schistosoma mansoni. Propranolol was administered in drinking water to 20 animals for a period of6 wk at a dose of 10 mgkg-'d-1, starting at 5 wk of schistosomal infection. 32 agematched mice with chronic schistosomal infection served as controls. All animals were studied 11 wk after the infection. Compared with controls the portal pressure (10.8±0.40 mmHg) was significantly lower (P < 0.001) in the propranololtreated animals (7.9±0.80 mmHg). Portal-systemic shunting was decreased by 79%, from 12.2±3.34% in controls to 2.5±0.99% in the propranolol group (P < 0.05). Portal venous inflow was reduced by 38% in the propranolol treated animals (2.50±0.73 ml/min; n = 6) compared with controls (4.00±0.34 ml/min; n = 8; P < 0.05). The worm burden, the granulomatous reaction, the collagen content of the liver, and the serum bile acid levels were not significantly different between the two groups of animals. These results demonstrate that in chronic liver disease induced by schistosomiasis, the development of portal-systemic shunting can be decreased or prevented by the reduction of flow and pressure in the portal system. (J. Clin.
Praziquantel has no direct effect on (Na++K+)-ATPases and (Ca2+-Mg2+)ATPases of Schistosoma mansoni
Life Sciences, 1997
Therapeutic concentrations of praziquantel produce a rapid and intense contraction of the human flatworm Schistosoma mansoni. As an action on ATPases responsible for calcium homeostasis arises as a possible explanation for the molecular mechanism of this effect, we tested here the effect of praziquantel on different preparations from male adult worms that were previously characterized for their content in (Nd+K+)-ATPase and (Ca'+-Mg'+)ATPase activities from different origins. Concentrations as high as 100 ?M praziquantel did not inhibit (Na++K+)-ATPase from tegument and carcass nor (Ca2'-Mg ')ATPase from heterogeneous (P,) and microsomal (P4) fractions. As 100 pM praziquantel was also without effect on calcium permeability of microsomal vesicles actively loaded with 45Ca2+, the present results discard three hypotheses recently raised for the mechanism of praziquantel-induced contraction of S. mansoni.