Switching to an L/N-type calcium channel blocker shows renoprotective effects in patients with chronic kidney disease: the Kyoto Cilnidipine Study.

OBJECTIVE: This open-label, randomized controlled trial investigated the effects of cilnidipine, an L/N-type calcium channel blocker (CCB), in patients with chronic kidney disease (CKD). METHODS: Sixty patients with CKD and well-controlled hypertension being treated with a renin- angiotensin system (RAS) inhibitor and an L-type CCB (L-CCB) were randomly assigned either to switch from the L-CCB to cilnidipine after a 4-week observation period or to continue with L-CCB treatment. Blood pressure, heart rate and renal function were monitored for 12 months. Data were available for analysis from 50 patients: 24 from the cilnidipine group and 26 from the L-CCB group. RESULTS: Blood pressure was well controlled in both groups. After 12 months, proteinuria and heart rate were significantly decreased in the cilnidipine group, but proteinuria increased and heart rate remained unchanged in the L-CCB group. There was a significant positive correlation between the percentage changes in proteinuria and heart rate. CONCLUSIONS: Cilnidipine has antihypertensive effects equivalent to those of L-CCBs. In patients with CKD, proteinuria can be decreased by switching from an L-CCB to cilnidipine, thereby improving renal function.

Matrix metalloproteinase-2 is elevated in the plasma of women with preeclampsia.

OBJECTIVE: We have recently demonstrated that matrix metalloproteinase-2 (MMP-2) alters vascular function through cleavage of vasoactive peptides, resulting in increased vasoconstriction and reduced vasodilation. We, therefore, hypothesized that MMP levels are increased in women with preeclampsia. In addition, because vascular endothelial growth factor (VEGF) has been implicated in the pathophysiology of preeclampsia and is involved in angiogenesis that requires the release of proteases to allow for migration of endothelial cells, we hypothesized that VEGF increases release of MMPs from endothelial cells. METHODS: We used zymographic analysis to evaluate MMP-2/MMP-9 levels in plasma of women with preeclampsia (n=12) compared to women with uncomplicated pregnancies (n=12). In addition, we evaluated the changes in the levels of MMP-2 and MMP-9 as well as tissue inhibitors of MMPs (TIMP-1 and TIMP-2) released by cultured human umbilical vein endothelial cells in response to VEGF (0.1-10 ng/mL). RESULTS: Our data showed that plasma MMP-2 levels were significantly higher in women with preeclampsia compared to women with uncomplicated pregnancies (arbitrary intensity units: 690 +/-111 and 252 +/-56, respectively, p<0.05). MMP-9 levels were below the level of detection. In addition, VEGF stimulated endothelial MMP-2 and MMP-9 release in a concentration- and time-dependent (6-24 h) manner. Moreover, VEGF stimulation of MMP release occurs without significantly affecting the release of TIMP-1 and TIMP-2. CONCLUSIONS: These data suggest that VEGF promotes secretion of MMPs from endothelial cells that, in turn, could alter vascular function in women with preeclampsia.

The association of transforming growth factor-beta 1 with myometrial invasion of endometrial carcinomas through effects on matrix metalloproteinase.

OBJECTIVE: The association of transforming growth factor-beta 1 (TGF-beta 1) with a matrix metalloproteinase (MMP) and a tissue inhibitor of metalloproteinase (TIMP), as well as myometrial invasion of endometrial cancer was studied. METHODS: The effects of TGF-beta 1 on cellular invasiveness, gelatinase activity, and expression of TIMP-1 were examined in 2 endometrial adenocarcinoma cell lines, KLE and Ishikawa. Plasma was obtained from 8 endometrial cancer patients with Stage-Ia disease, from 6 with Stage-Ib disease, and from 4 with Stage-Ic disease, and the levels of TGF-beta 1 were measured by enzyme immunoassays. The immunohistochemical expression of MMP-9, TIMP-1, TGF-beta 1, and TGF-beta receptor Type I in tumor tissue from the same patients also was detected. RESULTS: Invasiveness, gelatinase activity, and the expression of TIMP-1 were higher in KLE cells than in Ishikawa cells, and they were increased by treatment with rTGF-beta 1. The expression of TGF-beta receptor Type I was higher in KLE cells than in Ishikawa cells, which were unresponsive to exogenous TGF-beta 1. The plasma levels of TGF-beta 1 were greater in Stage-Ib and Stage-Ic patients than in Stage-Ia patients. MMP-9 and TGF-beta receptor Type I were expressed mainly in tumor cells, while TIMP-1 and TGF-beta 1 were localized in both tumor epithelial cells and stromal cells. MMP-9 and TIMP-1 were expressed only in Stage-Ib and Stage-Ic patients, although TGF-beta 1 and TGF-beta receptor Type I were ubiquitous. CONCLUSIONS: Myometrial invasion of endometrial cancers involves an increase in gelatinase activity, regulated to some extent by TGF-beta 1 in an autocrine or paracrine fashion.

[Relation between blood coagulability and prognosis in patients with ovarian cancer].

In 13 patients with ovarian cancer who had been treated with remission induction chemotherapy, we measured the levels of platelet PT, APTT, Hepa T, ATIII, alpha 2PI and FDP, and we also measured such molecular markers as fibrinopeptide A(FPA), fibrinopeptide B beta 1-42(FPB beta 1-42), and fibrinopeptide B beta 15-42 (FPB beta 15-42) before and after chemotherapy. Then the relation between the post chemotherapeutic trends of these substances and the prognosis for patient with ovarian cancer were investigated. 1) After chemotherapy, the levels of fibrinogen were increased, ATIII was decreased significantly in cases in the NC.PD group compared with the PR.CR group (p less than 0.05). The alpha 2PI concentrations were also slightly low, and the levels of FDP were within the normal range in cases in the PR.CR group, but in many cases in the NC.PD group were increased. 2) After chemotherapy, the concentrations of molecular markers (FPA, FPB beta 1-42 and FPB beta 15-42) were increased significantly in cases in the NC.PD group compared with the PR.CR group (p less than 0.05). 3) In cases in the recurrent group, the levels of ATIII and alpha 2PI were decreased significantly compared with the after therapy group, FDP, FPB beta 1-42 and FPB beta 15-42 were increased. Accordingly, the recovery of hemostatic balance with effective chemotherapy is related to the prognosis for patients with ovarian cancer, and the levels of fibrinogen, PT, alpha 2PI, ATIII, FDP, FPA, FPB beta 1-42 and FPB beta 15-42 may be able to be used in the prognosis for patients after chemotherapy.