Biomedical subjects

J Angulo

Publications and source records attributed to J Angulo.

At least 37 records · Page 2Linked to original sources

PubMed1999

Design and evaluation of nitrosylated alpha-adrenergic receptor antagonists as potential agents for the treatment of impotence.

We designed and evaluated a new class of molecules, nitrosylated alpha-adrenergic receptor antagonists, as potential agents for the treatment of impotence. In in vitro studies with human and rabbit corpus cavernosum strips in organ chambers, the alpha-adrenergic receptor antagonists (alpha-ARAs) moxisylyte and yohimbine and their corresponding nitrosylated compounds, SNO-moxisylyte (NMI-221) and SNO-yohimbine (NMI-187), concentration-dependently relaxed endothelin-induced contraction. The nitrosylated compounds were significantly more potent than the parent alpha-ARA. In human tissues, the specific phosphodiesterase type 5 inhibitor zaprinast potentiated the relaxing effects of the nitrosylated compounds. Only nitrosylated compounds induced accumulation of cyclic GMP in rabbit corpus cavernosum strips. Yohimbine and NMI-187 demonstrated a potent alpha2-blocking activity, with no significant differences in pA2 values (8.9 versus 8.2, respectively). Moxisylyte and NMI-221 showed moderate potency in antagonizing phenylephrine contraction, with comparable pA2 values for both molecules (6.5 versus 6.6, respectively). alpha-Adrenergic receptor-binding studies showed similar binding affinities for the alpha-ARA and their corresponding nitrosylated compounds. In vivo, intracavernosal injection of nitrosylated molecules caused greater increases in intracavernosal pressure (NMI-221 versus moxisylyte) that were more long lasting than those of moxisylyte or yohimbine. There were no significant differences between nitrosylated and non-nitrosylated compounds in the magnitude of systemic mean arterial pressure decrease after intracavernosal injection. alpha-ARA and the nitrosylated compounds showed no pain-inducing activity as evaluated with the paw-lick model in mice. In summary, nitrosylated alpha-ARA have the dual functionalities of nitric oxide donors and alpha-ARA. These drugs induced penile erection in animals, suggesting their possible therapeutic value as agents for the local pharmacological treatment of impotence.

Adrenergic alpha-Antagonists↗

PubMed1998

Expression of Kin, a nuclear protein binding to curved DNA, in mammal and avian brains.

Kin is a nuclear protein which presents cross-immunoreactivity with the bacterial RecA protein and which efficiently binds to curved DNA. This genomic interaction could be implied in DNA repair and illegitimate recombination in eukaryotic cells. Using immunocytochemistry with anti-RecA antibodies, we report the ubiquitous presence of the Kin protein in the CNS of mice and quails. However, some brain structures such as the hippocampal area, the locus coeruleus and Purkinje cells are preferentially immunolabelled and show some homologies between the two species. In conclusion, the expression of the Kin protein is preserved in the phylogeny of the brain of higher vertebrates.

Animals↗

PubMed1998

Impairment of nitric oxide-mediated relaxations in anaesthetized autoperfused streptozotocin-induced diabetic rats.

This work was designed to determine in vivo the influence of the metabolic control of streptozotocin-induced diabetic rats, measured by the levels of haemoglobin glycosylation in blood (HbA1c), on developing vascular endothelial dysfunction. For this, the vasoactive responses to basal and stimulated endothelial nitric oxide (NO) were studied using the technique of the anaesthetized autoperfused rat, analyzing the responses to acetylcholine (ACh) and N(G)-nitro-L-arginine methyl ester (L-NAME) in non-diabetic and diabetic rats with different degrees of metabolic control (four groups with HbA1c levels of 5.5-7.4%, 7.5-9.4%, 9.5-12%, and >12%, respectively). When administered over a noradrenaline-induced vasopressor tone, ACh (0.25, 0.75, 2.5, 7.5 and 25 microg kg(-1)) induced dose-dependent vasodilatatory responses in all rat groups, reducing both mean arterial pressure and perfusion pressure of the left hindlimb. These responses were similar in non-diabetic and in diabetic rats with good metabolic control (HbA1c 5.5-7.4%), while diabetic rats with levels of HbA1c higher than 7.5% showed significantly lower vasodilatatory responses to ACh. In untreated diabetic rats, the relaxant responses evoked by the NO donor sodium nitroprusside were also impaired. On the other hand, increasing doses of L-NAME (0.1 to 10 mg kg(-1)) enhanced both mean arterial pressure and left hindlimb perfusion pressure in diabetic and non-diabetic rats. As with ACh, the responses to L-NAME were significantly reduced in diabetic rats with HbA1c levels higher than 7.5%. To determine the mechanism underlying the NO-mediated endothelial dysfunction, the responses to ACh in untreated diabetic rats (HbA1c >12%) were studied in the presence of the NO substrate L-arginine, in the presence of the oxygen-derived free radical scavenger superoxide dismutase (SOD), or in the presence of both compounds. Both L-arginine and SOD produced a partial improvement of the ACh-induced vasodilatatory responses, but the effects of these agents were not additive. In this group of animals, SOD also induced a partial recovery of the L-NAME-evoked vasoconstrictions. In non-diabetic and untreated diabetic rats, the plasma levels of NO derivatives and arginine were measured. No significant differences were obtained in the amount of nitrites plus nitrates, while plasma levels of arginine were markedly reduced in the untreated diabetic animals. The results indicate that the endothelial dysfunction associated to diabetes is closely related to the level of metabolic control of the disease. Therefore, it is possible to establish a threshold for developing endothelium impairment from percentages of HbA1c higher than 7.5%. As the responses to the NO synthase blocker L-NAME were analogously impaired, it is reasonable to suggest that diabetic endothelial dysfunction is related to the interference with mechanisms linked both to stimulated and basal production of NO. We suggest that this interference is partially due to a deficit in the substrate availability for NO and to an increased generation of superoxide anions.

Acetylcholine↗

PubMed1998

The spectrum of skin, mucosa and other extra-articular manifestations.

The seronegative spondyloarthropathies appear to be the genetically predisposed host's clinical expression to acute, subacute or chronic reaction to the invasion by environmental microorganisms. In the ensuing days or weeks, depending on the infectious load, clinical manifestations may occur ranging from constitutional complaints such as fever, to a variety of symptoms and/or signs related to the portal of entry-intestinal, genitourinary or respiratory. Within weeks or months, the initial or other target organs, such as the mucocutaneous, ocular and cardiovascular systems, may develop an acute reaction of greater or lesser specificity regarding the triggering agent (oral ulcers, circinate balanitis, erythema nodosum, acute anterior uveitis, pericarditis, heart blocks). Lastly, many years later, a minority of patients, probably those with a large genetic component, exhibit a spectrum of clinical manifestations related to those organs, with a chronic or recurrent course. Acute clinical manifestations--reactive arthritis--are prominent in the initial phase of the clinical spectrum, while chronic manifestations--ankylosing spondylitis--are seen at the other end of the spectrum.

Arthritis, Reactive↗

PubMed1998

Endothelial dysfunction and metabolic control in streptozotocin-induced diabetic rats.

1. The aim of this work was to study the influence of the metabolic control, estimated by the levels of glycosylated haemoglobin in total blood samples (HbA1c), in developing vascular endothelial dysfunction in streptozotocin-induced diabetic rats. Four groups of animals with different levels of insulin treatment were established, by determining HbA1c values in 5.5 to 7.4%, 7.5 to 9.4%, 9.5 to 12% and > 12%, respectively. 2. The parameters analysed were: (1) the endothelium-dependent relaxations to acetylcholine (ACh) in isolated aorta and mesenteric microvessels; (2) the vasodilator responses to exogenous nitric oxide (NO) in aorta: and (3) the existence of oxidative stress by studying the influence of the free radical scavenger superoxide dismutase (SOD) on the vasodilator responses to both ACh and NO. 3. In both isolated aortic segments and mesenteric microvessels, the endothelium-mediated concentration-dependent relaxant responses elicited by ACh were significantly decreased when the vessels were obtained from diabetic animals but only with HbA1c values higher than 7.5%. There was a high correlation between HbA1c levels and the impairment of ACh-induced relaxations, measured by pD2 values. 4. The concentration-dependent vasorelaxant responses to NO in endothelium-denuded aortic segments were significantly reduced only in vessels from diabetic animals with HbA1c values higher than 7.5%. Again, a very high correlation was found between the HbA1c values and pD2 for NO-evoked responses. 5. In the presence of SOD, the responses to ACh or NO were only increased in the segments from diabetic rats with HbA1c levels higher than 7.5%, but not in those from non-diabetic or diabetic rats with a good metabolic control (HbA1c levels <7.5%). 6. These results suggest the existence of: (1) a close relation between the degree of endothelial dysfunction and the metabolic control of diabetes, estimated by the levels of HbA1c; and (2) an increased production of superoxide anions in the vascular wall of the diabetic rats, which is also related to the metabolic control of the disease.

Acetylcholine↗

PubMed1998

Vascular smooth muscle cell hypertrophy induced by glycosylated human oxyhaemoglobin.

1. Nonenzymatic protein glycosylation is a possible mechanism contributing to oxidative stress and vascular disease in diabetes. In this work, the influence of 14%-glycosylated human oxyhaemoglobin (GHHb), compared to the non-glycosylated protein (HHb), was studied on several growth parameters of rat cultured vascular smooth muscle cells (VSMC). A role for reactive oxygen species was also analysed. 2. Treatment of VSMC for 48 h with GHHb, but not with HHb, increased planar cell surface area in a concentration dependent manner. The threshold concentration was 10 nM, which increased cell size from 7965+/-176 to 9411+/-392 microm2. Similarly, only GHHb enhanced protein content per well in VSMC cultures. 3. The planar surface area increase induced by 10 nM GHHb was abolished by superoxide dismutase (SOD; 50 200 u ml(-1)), deferoxamine (100 nM-100 microM), or dimethylthiourea (1 mM), while catalase (50 200 u ml(-1)) or mannitol (1 mM) resulted in a partial inhibition of cell size enhancement. 4. When a known source of oxygen free radicals was administered to VSMC, the xanthine/xanthine oxidase system, the results were analogous to those produced by GHHb. Indeed, enhancements of cell size were observed, which were inhibited by SOD, deferoxamine, or catalase. 5. These results indicate that, at low concentrations, GHHb induces hypertrophy in VSMC, this effect being mediated by superoxide anions, hydrogen peroxide, and/or hydroxyl radicals. Therefore, glycosylated proteins can have a role in the development of the structural vascular alterations associated to diabetes by enhancing oxidative stress.

Animals↗

PubMed1998

Insights into the pathogenesis of psoriasis and psoriatic arthritis.

Psoriasis and its related arthritis are chronic inflammatory disorders affecting predominantly the skin and synovium. Although their etiology remains to be established, multiple factors seem to play important roles in their pathogenesis. These environmental (eg, infectious agents and trauma), genetic, and immunologic factors are reviewed in this article.

Arthritis, Psoriatic↗

PubMed1998

Complications of mandibular fractures.

Timely repair of mandibular fractures remains an effective means to reduce pain, restore function, and prevent complications. This study addresses the effect of the time interval between injury and treatment on the overall complication rate, the complication rate between various treatment modalities (mandibular-maxillary fixation [MMF] alone, MMF with intraosseous wire bone fixation, and MMF with rigid internal fixation), and the relationship of inpatient vs. outpatient management. Cost was also examined with respect to choice of management. We report a retrospective series of 308 consecutive patients managed at the University of Miami/Jackson Memorial Hospital. Patients who received treatment 3 to 10 days following injury were found to have a lower complication rate than earlier or later repair. We postulate that most patients with mandibular fractures may be managed on an outpatient basis, which represents a considerable savings in cost.

Adolescent↗

PubMed1998

Endogenous angiotensin II and cell hypertrophy in vascular smooth muscle cultures from hypertensive Ren-2 transgenic rats.

We investigated the possible role of a tissular renin-angiotensin system in promoting the growth of vascular smooth muscle cells (VSMCs) from hypertensive transgenic rats (TGRs) with the mouse renin gene Ren-2. Mean arterial pressure values were 99.4 +/- 2.8 and 186.7 +/- 5.0 mm Hg for control Sprague-Dawley rats (SDs) and TGRs, respectively (p < 0.05). The tunica media of femoral arteries obtained from hypertensive TGRs was found to be thickened compared to that of age-matched normotensive SDs. Angiotensin II could be detected by dot blot and immunocytochemistry and quantified by radioimmunoassay in transgenic VSMCs, but not in control SD ones. Under serum-free conditions, VSMCs derived from TGRs showed a higher protein content than those derived from SDs (337 +/- 19 vs. 269 +/- 14 pg/cell, p < 0.05, n = 3). Under the same basal conditions, the mean planar cell surface area was significantly higher in TGR VSMCs than in SD ones (4,764 +/- 204 vs. 4,074 +/- 238 micron 2, p < 0.05). In addition, TGR VSMCs showed an enhanced [14C]-leucine uptake but SD VSMCs did not (13,188 +/- 663 vs. 7,633 +/- 713 dpm/well, p < 0.05). VSMCs showed a concentration-dependent proliferative response to fetal calf serum (FCS) that was more marked in TGRs than in SDs. In the absence of FCS, c-fos and c-jun mRNAs were expressed only in transgenic cultures. From the present results, we can hypothesize that cultured TGR VSMCs are able to synthesize angiotensin II that, being almost exclusive into the cells, contributes to produce VSMC growth in the absence of FCS stimulation.

Angiotensin II↗

PubMed1998

Role of autonomic innervation in rat prostatic structure maintenance: a morphometric analysis.

PURPOSE: To analyze the effects of major pelvic ganglion (MPG) excision on the structure of rat prostate. MATERIALS AND METHODS: We studied 80 Sprague-Dawley rats (300-350 gm. weight). Forty-two were anesthetized and the right MPG excised. After 28-30 days, the same-side prostatic ventral lobe (VL) was obtained for macroscopic, light (LM), and transmission electron microscopy (TEM) evaluation. A computerized morphometric analysis was performed on epithelial and muscle cells. Results were compared with 38 right VL of non-operated, same-aged rats. RESULTS: A 36.6% reduction (0.14 gm.) of VL fresh weight was found in the denervated group (p <0.001). Mean tissue proportions observed in the LM study were 27.9% (epithelial), 48.3% (stromal), and 51.8% (glandular) in the non-operated group, versus 14.8% (p <0.001), 55.7%, and 44.4% (not significant) respectively, after MPG excision. No difference was found regarding the vascular pattern. In the denervated rats, TEM analysis found a significant reduction in total and supranuclear cell height (change in cell polarity), as well as in cytoplasm, Golgi and endoplasmic reticulum areas. Secretory granule count, total area (p <0.001), and density of apical microvilli were also reduced. On the other hand, only an increase in the area of cytoplasm ribosomal aggregates was detected in the smooth muscle cell analysis. CONCLUSIONS: Our study demonstrated a rat prostatic VL atrophy in the denervated side, due to a shrinkage in the epithelial component of the gland. Ultrastructural findings also suggest an overall decrease of epithelial cell secretory activity. Finally, the increase of ribosomal aggregates found in stromal smooth muscle could reflect an activation of these cells after denervation.

Animals↗

PubMed1997

Angiotensin II mediates cell hypertrophy in vascular smooth muscle cultures from hypertensive Ren-2 transgenic rats by an amiloride- and furosemide-sensitive mechanism.

We have reported that cultured vascular smooth muscle cells (VSMC) from hypertensive Ren-2 transgenic rats (TGR) are constitutively hypertrophic when compared to matched cells from normotensive Sprague-Dawley rats (SD), by a mechanism involving the endogenous production of angiotensin II (AII). In the present work, we analyzed the possible involvement of two Na+ transport mechanisms in TGR-VSMC hypertrophy. In both SD- and TGR-VSMC, AII increased both cell size, by a furosemide- and amiloride-sensitive mechanism, and Na+/K+/2Cl- cotransport activity, by an amiloride-sensitive mechanism. Under basal unstimulated conditions, TGR-VSMC showed higher cell size and Na+/K+/2Cl- cotransport activity than SD-VSMC. Under these same conditions, losartan, furosemide, or amiloride reduced cell size only in TGR-VSMC. Similarly, basal cotransport activity was reduced by losartan and amiloride to levels similar to those observed in SD-VSMC. We conclude that hypertrophy of TGR-VSMC is dependent on the endogenous production of AII and mediated by increased Na(+)-H+ exchange and Na+/K+/2Cl- cotransport activities.

Angiotensin II↗

PubMed1997

Preferential expression of kin, a nuclear protein binding to curved DNA, in the neurons of the adult rat.

The KIN17 gene product has been identified by cross immunoreactivity with anti-RecA antibodies and by DNA recombination techniques, and is probably part of the DNA recombination-repair machinery. Following Western blotting and immunocytochemistry using anti-RecA antibodies, and in situ hybridization with specific KIN17 cDNA probes, we here report the detection of high levels of KIN protein and KIN17 mRNA in the CNS of adult rats. The RecA cross-reacting protein has an apparent molecular weight of 41 kDa and is located in the nucleus of brain cells. Both the KIN17 transcript and the protein were found to be widespread, but they were present in different proportions, depending on the type of brain cells. High levels of KIN protein were seen in neurons of the motor nuclei of the brainstem, the locus coeruleus, hippocampal formation, entorhinal cortex, Purkinje cells, pyramidal cells of the cortex and mitral cells. In contrast, using a combination of KIN17 mRNA in situ hybridization and GFAP immunocytochemistry (a marker of glial cells) showed that the KIN17 messenger is preferentially transcribed in neurons, the post-mitotic and long lived brain cells. We postulate that KIN17 play a role in the illegitimate recombination of DNA sequences and/or the repair of alterations of the genome in neurons.

Age Factors↗

PubMed1997

Nifedipine, losartan and captopril effects on hyperplasia of vascular smooth muscle from Ren-2 transgenic rats.

Vascular smooth muscle cells from hypertensive transgenic rats for the mouse Ren-2 gene exhibited radioimmunoassayable angiotensin II and hyperplasia in comparison with cells from Sprague-Dawley rats. However, neither captopril, losartan, saralasin, nor PD123319 (all at 10 microM) modified DNA synthesis or cell number observed in 4-day growth curves with 10% fetal calf serum. Nifedipine reduced DNA synthesis in both cell types, the concentration required being significantly higher in Sprague-Dawley- (1 microM) than in transgenic-derived cultures (100 nM). The EC50 values were of 2.43 +/- 0.32 and 1.0 +/- 0.17 microM, respectively (P < 0.05). In both cell types, only 10 microM nifedipine reduced serum-induced cell proliferation, but inhibition percentage was higher in transgenic-derived cultures. In conclusion, hyperplasia of transgenic-derived vascular smooth muscle cells is not blocked by angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists, but these cells are more sensitive to the antiproliferative effects of nifedipine.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1997

Evaluation of epidermal growth factor receptor, transforming growth factor alpha, epidermal growth factor and c-erbB2 in the progression of invasive bladder cancer.

INTRODUCTION: Determination of the risk of invasive bladder tumors progressing is still imprecise due to the heterogeneous biological behavior of this neoplasm. The goals of this study were to evaluate the patterns of expression of the epidermal growth factor (EGF) system in invasive bladder cancer and to assess its prognostic value. METHODS: This immunohistochemical study was performed using fresh frozen tumor samples and a panel of monoclonal antibodies on a series of 43 invasive bladder cancers treated by cystectomy. RESULTS: EGF was detected in 45% of the tumors and did not correlate with survival from bladder cancer. Transforming growth factor alpha (TGF alpha) was expressed by 60% of the tumors and correlated strongly with death from bladder cancer. Epidermal growth factor receptor (EGF-R) expression was seen in 86% of cases and had no prognostic significance. c-erbB2 was expressed in 50% of cases and was inversely related to a poor prognosis. When EGF and TGF alpha were both expressed, there was little or no expression of c-erbB2. CONCLUSION: The accumulation of several growth factors and the relevant receptor are necessary for the progression of invasive bladder cancers. They could be used as indicators of tumor aggressiveness.

Adult↗

PubMed1997

Effects of captopril, losartan, and nifedipine on cell hypertrophy of cultured vascular smooth muscle from hypertensive Ren-2 transgenic rats.

1. We hypothesized that tissular renin-angotensin system (RAS) induces vascular hypertrophy in hypertensive Ren-2 transgenic rats (TGR; strain name TGR(mRen2)L27). This assumption was tested in cell cultures of vascular smooth muscle (VSMC) from both hypertensive TGR and control normotensive Sprague-Dawley (SD) rats. Planar cell surface area, protein synthesis, and protein content per cell were studied, the role for locally produced angiotensin II (AII) was evaluated and the possible pharmacological interference by different drugs was analysed. 2. By use of radioimmunoassay techniques, AII could be determined in TGR cultures (10.25 +/- 0.12 pg per 10(7) cells) while it could not be detected in SD ones. 3. Under serum-free conditions, VSMC from hypertensive TGR were hypertrophic when compared to SD VSMC, as they presented a higher protein content per cell (335 +/-18 and 288 +/- 7 pg per cell respectively; P<0.05) and increased mean planar cell surface area, as determined by image analysis (4,074 +/- 238 and 4,764 +/- 204 microm2, respectively; P < 0.05). 4. When exogenously added to cultured SD and TGR VSMC, AII (100 pM to 1 microM) promoted protein synthesis and protein content in a concentration-dependent manner without affecting DNA synthesis. Maximal effects were observed at 100 nM. At this concentration, AII effectively increased planar cell surface area in both SD and TGR cultures by approximately 20%. 5. Treatment of TGR cultures, in the absence of exogenous AII, with the angiotensin-converting enzyme inhibitor captopril or the angiotensin AT1 receptors antagonist losartan (100 nM to 10 microM) reduced planar cell surface area in a concentration-dependent manner. In addition, both captopril and losartan (10 microM), decreased protein synthesis by approximately 15%. 6. Treatment of SD VSMC, in the absence of exogenous AII, with both captopril and losartan had no effect either on planar cell surface area or protein synthesis. 7. Treatment with the Ca2+ antagonist nifedipine (100 nM to 10 microM) reduced cell size in both SD and TGR cultures. Maximal cell reduction reached by nifedipine averaged 906 +/- 58 and 1,292 +/- 57 microm2, in SD and TGR, respectively (P<0.05). In addition, nifedipine, nitrendipine and nisoldipine (all at 10 microM) decreased protein synthesis in both cell types by 15-25%. 8. We concluded that cultured VSMC from TGR are hypertrophic in comparison with those from SD. This cell hypertrophy can be the consequence of the expression of the transgene Ren-2 that activates a tissular RAS and locally produces AII, which acts in a paracrine, autocrine, or intracrine manner. Cell hypertrophy in TGR cultures could be selectively reduced by RAS blockade, while nifedipine decreased cell size and protein synthesis in both hypertrophic and non hypertrophic cells.

Angiotensin II↗

PubMed1997

[Upper urinary tract and urethral tumors in patients with bladder carcinoma].

OBJECTIVE: A clinicopathological study was conducted in patients with urothelial tumor of the bladder and urothelial neoplasm of the upper urinary tract or urethra to analyze the histological features, time interval between diagnoses and prognosis of these associated lesions. METHODS: 338 patients were reviewed retrospectively. A descriptive study was performed, including tables on the associated lesions and survival data. RESULTS: 21 cases (6.2%) had two urothelial tumors: carcinoma of the bladder associated with tumor of the upper urinary tract (14 cases) or urethra (7 cases). There is a longer time interval between diagnoses when the extravesical tumor is diagnosed after than when it is diagnosed before the bladder tumor (p < .05). A correlation between the grade, but not stage, of the extravescial and bladder tumors has been observed. We found no statistically significant differences for survival in patients with two tumors or with bladder cancer alone. Although not statistically significant, patients with metachronous extravescial tumor have a better prognosis than those with synchronous extravesical tumor. CONCLUSION: Patients with bladder cancer should be followed for years and screened for extravesical urothelial tumor. The foregoing associated lesion, especially the metachronous extravesical lesion, apparently does not make the prognosis worse.

Adult↗

PubMed1996

High levels of tissue inhibitor of metalloproteinase-2 (TIMP-2) expression are associated with poor outcome in invasive bladder cancer.

The matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) have been associated with tumor invasion and metastasis in many human cancers. Immunohistochemical studies were performed on frozen tumor samples from 42 patients with invasive bladder cancer treated by cystectomy with monoclonal antibodies against the Mr 72,000 gelatinase A (MMP-2), Mr 92,000 gelatinase B (MMP-9), and TIMP-2 to evaluate their significance in bladder cancer. Immunoreactivity for the gelatinases was predominantly tumor cell-associated, whereas strong TIMP-2 staining was mostly detected in the stroma. Tumor cells demonstrated moderate to strong reactivity for MMP-2 and MMP-9 in 71 and 71% of cases, respectively, which did not correlate with stage, grade, or outcome. Tumor cells were positive for TIMP-2 in 26 (62%) of 42 cases, and this correlated with a worse outcome (69 versus 25% died of disease; P < 0.05). In 31 (74%) of 42, there was moderate to strong stromal staining for TIMP-2; this also was associated with a poor outcome (65 versus 25% died of cancer; P < 0.05). Tumor basement membrane (BM) status was investigated using an antibody to type IV collagen. In 9 cases, the invasive tumor nests were surrounded by an intact BM; in 7 of these, stromal staining for TIMP-2 was absent. None of these 9 patients (0%) died of tumors compared with 7 (100%) of 7 with complete loss of BM staining (P < 0.001). These results suggest a potential role for TIMP-2 and BM staining as prognostic indicators in invasive bladder cancer.

Adult↗

PubMed1996

Effects of indomethacin and iloprost on contraction of the afferent arterioles by endothelin-1 in juxtamedullary nephron preparations from normotensive Wistar-Kyoto and spontaneously hypertensive rats.

The contractile effects of endothelin-1 on the afferent arterioles of normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) and the modulation of these responses by cyclooxygenase blockade or by the prostacyclin analog iloprost were investigated. For this, the preglomerular vasculature was visualized by using the juxtamedullary nephron preparation. Endothelin-1 (100 pM-1 microM) induced concentration-dependent reduction of afferent diameters either in WKY and SHR kidneys, which were inhibited by 1 microM nifedipine, indicating its dependence on extracellular calcium. After incubation with 20 microM indomethacin, the endothelin-1-induced contractions were potentiated in WKY but abolished in SHR vessels. These results could be explained if endothelin-1 is releasing vasodilator prostanoids in WKY, whereas in SHR preparations, vasoconstrictor prostanoids predominate. The prostacyclin analog iloprost (1 nM-1 microM) did not modify basal diameters of the WKY afferent arterioles, whereas a weak vasodilatatory effect was observed in the SHR afferent vasculature. Both in WKY and SHR preparations, iloprost (10 nM-1 microM) abolished the afferent contractility by endothelin-1, this effect being more prominent in SHR. We conclude that a defective production of vasodilator prostanoids or an enhanced release of vasoconstrictor cyclooxygenase derivatives may determine the renovascular effects of endothelins in SHR kidneys.

Animals↗