Biomedical subjects

L Rodríguez-Mañas

Publications and source records attributed to L Rodríguez-Mañas.

At least 19 recordsLinked to original sources

PubMed2006

Pro-inflammatory effects of early non-enzymatic glycated proteins in human mesothelial cells vary with cell donor's age.

BACKGROUND AND PURPOSE: Diabetes mellitus is prevalent in the elderly population. It is also a disease causing tissue damage through several different mechanisms. Some of these mechanisms are also activated by ageing and this overlap raises questions about how diabetes induces damage in the elderly. Early products of non-enzymatic glycation of proteins (Amadori adducts), and the ageing process share the capacity to induce oxidative stress and inflammation in human peritoneal mesothelial cells (HPMCs). We have evaluated the interactions between the age of the donor of the HPMCs and the pro-inflammatory effects of Amadori adducts in those cells. EXPERIMENTAL APPROACH: HPMCs were isolated from 20 individuals (age range 21-81 years) and grown in culture. Using different experimental approaches we determined NF-kappaB dependent transcriptional activity and different NF-kappaB-related pro-inflammatory gene and protein expressions in basal (or non-stimulated) conditions and after stimulation with two Amadori adducts; highly-glycated haemoglobin and glycated bovine serum albumin. KEY RESULTS: Amadori-induced effects on NF-kappaB dependent-transcription and on the activity of NOS, COX and several NF-kappaB-related pro-inflammatory genes (iNOS, COX-2, TNF-alpha, IL-1beta, and IL6) diminished as the donor's age increased, being practically absent in cells from donors more than 65 years old. Such decreased effects were inversely correlated with an increased basal expression and activity of these pro-inflammatory markers with age. CONCLUSIONS AND IMPLICATIONS: Pro-inflammatory effects of Amadori-adducts in HPMCs were strongly dependent on cell donor's age. This may have significant implications for the mechanisms underlying diabetes-induced tissue damage in patients of different ages.

Adult↗

PubMed2006

Changes in the human peritoneal mesothelial cells during aging.

The number of older patients admitted to peritoneal dialysis (PD) programmes is growing. At the same time, there is increasing data about the role of mesothelial cells in determining the functional alteration of the peritoneum during PD. However, little is known about the functional changes accompanying the ageing process in mesothelial cells. We aimed to evaluate whether the aging process is accompanied by changes in some functional characteristic of the human peritoneal mesothelial cells (HPMC), which could account for the poor prognosis observed in old patients with PD. HPMCs were isolated from patients undergoing a nonurgent, nonseptic abdominal surgical procedure, without renal, vascular or inflammatory disease. Cytokine levels (by enzyme-linked immunosorbent assay (ELISA)), nitrates+nitrites, and cyclooxygenase (COX) activity (by a chemiluminescence assay), cytokines, COX, nitric oxide synthase (NOS), and nuclear factor (NF)-kappaB1, two messenger ribonucleic acid (mRNA) gene expressions (by reverse transcriptase (RT)-Multiplex PCR), COX, and NOS promoter gene activities, and NF-kappaB-dependent transcription (by transient transfection assays) were determined. Our data show a significant increase in cytokines, COX, and NOS activities, and mRNA expression of cytokines, COX-2, inducible nitric oxide synthase (iNOS) and precursors of NF-kappaB in HPMCs from old people. This was also the case for COX-2 and iNOS promoter gene activities and NF-kappaB-dependent transcription. There was a positive correlation between the age of the donor's cell and the proinflammatory profile of the HPMCs. Such age-dependent increase (around two-three times) is partially abolished by different antioxidant or free-radical scavengers. Thus, aging is accompanied by the presence of an inflammatory state in HPMCs, which involves the participation of different reactive oxygen species.

Adult↗

PubMed2006

[Strategies for effective control of arterial hypertension in Spain. Consensus document].

Blood pressure (BP) control is inadequate among treated hypertensive patients in Spain. Control rates are lower than 40% of all treated patients and the cause of this problem is multifactorial. Despite the fact that possible solutions to this problem have been repeatedly suggested by expert groups along the last 10 years, BP control rates are still low. This fact have a negative impact on cardiovascular morbidity and mortality of patients with hypertension. The aim of the present document has been to achieve a consensus on effective specific measures in order to improve hypertension control rates in Spain. These measures involve health care professionals (physicians, nurses, pharmaceutics), health care authorities and patients. The document summarizes the consensus conference of several scientific societies involved in cardiovascular medicine in five group of measures: a) improvement of the methodology of office BP measurement; b) improvement of compliance to treatment by patients; c) clarification of pressure targets to be achieved in hypertensive patients; d) optimization of life style modifications and pharmacological treatment of hypertension; and e) continuous medical education. The document emphasize life style changes as a crucial aspect to be implemented in all patients. These changes have a beneficial impact on pressure reduction, contribute to a better control of associated cardiovascular risk factors, and increase the effectiveness of antihypertensive drugs. Health care professionals should base their clinical practice on the recommendations of guidelines in order to modify their therapeutic attitudes in patients whose targets have not been achieved.

Antihypertensive Agents↗

PubMed2003

Early and intermediate Amadori glycosylation adducts, oxidative stress, and endothelial dysfunction in the streptozotocin-induced diabetic rats vasculature.

AIMS/HYPOTHESIS: In a model of streptozotocin-induced Type 1 diabetes mellitus in rats of 9 weeks duration, we analysed time associations between the development of hyperglycaemia, early and intermediate glycosylation Amadori adducts, or AGE compared with enhancement of oxidative stress and endothelial dysfunction. METHODS: Endothelial function was tested at several stages of streptozotocin-induced diabetes and after treatment with insulin, resulting in different concentrations of blood glucose, glycosylated haemoglobin (an Amadori adduct), and AGE. Other animals were studied antagonising the formation of AGE with aminoguanidine. RESULTS: Relaxation in response to acetylcholine (1 nmol/l to 10 micro mol/l) was tested in isolated segments from aorta or mesenteric microvessels. Impairment of endothelium-dependent relaxations occurred after 2 weeks of untreated diabetes. Preincubation of vessels affected with 100 U/ml superoxide dismutase improved the relaxations to acetylcholine, along the time-course of the endothelial impairment. This indicates the participation of reactive oxygen species on diabetic endothelial dysfunction. The impairment of endothelium-dependent relaxations was recovered after 3 more weeks of insulin treatment. Aminoguanidine treatment did not modify this pattern of development. The time course of the rise and disappearance of endothelial dysfunction showed a higher correlation with glycosylated haemoglobin concentrations than with blood glucose or serum AGE. CONCLUSION/INTERPRETATION: Enhancement of early and intermediate Amadori adducts of protein glycosylation was the factor showing a better relation with the development of endothelium impairment. These results are consistent with a role for these products in the development of diabetic vasculopathy.

Acetylcholine↗

PubMed2001

High glucose induces cell death of cultured human aortic smooth muscle cells through the formation of hydrogen peroxide.

Alterations of the vessel structure, which is mainly determined by smooth muscle cells through cell growth and/or cell death mechanisms, are characteristic of diabetes complications. We analysed the influence of high glucose (22 mM) on cultured human aortic smooth muscle cell growth and death, as hyperglycaemia is considered one of the main factors involved in diabetic vasculopathy. Growth curves were performed over 96 h in medium containing 0.5% foetal calf serum. Cell number increased by 2 - 4 fold over the culture period in the presence of 5.5 mM (low) glucose, while a 20% reduction in final cell number was observed with high glucose. Under serum-free conditions, cell number remained constant in low glucose cultures, but a 40% decrease was observed in high glucose cultures, suggesting that high glucose may induce increased cell death rather than reduced proliferation. Reduced final cell number induced by high glucose was also observed after stimulation with 5 or 10% foetal calf serum. The possible participation of oxidative stress was investigated by co-incubating high glucose with different reactive oxygen species scavengers. Only catalase reversed the effect of high glucose. Intracellular H(2)O(2) content, visualized with 2',7'-dichlorofluorescein and quantified by flow cytometry, was increased after high glucose treatment. To investigate the cell death mechanism induced by high glucose, apoptosis and necrosis were quantified. No differences were observed regarding the apoptotic index between low and high glucose cultures, but lactate dehydrogenase activity was increased in high glucose cultures. In conclusion, high glucose promotes necrotic cell death through H(2)O(2) formation, which may participate in the development of diabetic vasculopathy.

Adult↗

PubMed2000

Highly glycated oxyhaemoglobin impairs nitric oxide relaxations in human mesenteric microvessels.

AIMS/HYPOTHESIS: It has been recently shown that glycated human haemoglobin induces endothelial dysfunction in rat vessels by generating superoxide anions that interfere with nitric oxide mediated responses. Our study analysed the effect of glycated human haemoglobin on the endothelium-dependent relaxations of human vessels. METHODS: Omental microvessels were obtained from patients (without diabetes, hypertension or vascular disease) during surgery and mounted in a small vessel myograph to study their vasoactive responses (vessels from 3-7 patients for each set of experiments). RESULTS: Cumulative vasodilatory responses to bradykinin (10 nmol/l to 3 mumol/l) were induced in vessels precontracted with 35-50 mmol/l potassium chloride. Addition of 100 mumol/l NG-nitro-L-arginine methyl ester reduced the relaxation evoked by bradykinin, but preincubation with both NG-nitro-L-arginine methyl ester and 10 mumol/l indomethacin was needed to abolish it. Bradykinin-induced responses were inhibited by 1 mumol/l non-glycated oxyhaemoglobin whereas no effect was obtained with 10 nmol/l oxyhaemoglobin. At these low concentrations (10 nmol/l), glycated human oxyhaemoglobin caused an impairment of bradykinin-induced relaxation when the percentage of glycation was 10% or higher. This effect was prevented by preincubating the vessels with ascorbic acid (10 mumol/l), superoxide dismutase (100 U/ml) and gliclazide (1 and 10 mumol/l), but not with indomethacin (10 mumol/l), catalase (400-600 U/ml), dimethylthiourea (1 mmol/l) or glibenclamide (10 mumol/l). In vessels preincubated with NG-nitro-L-arginine methyl ester (100 mumol/l), glycohaemoglobin did not add any additional effect. CONCLUSION/INTERPRETATION: Highly glycated human oxyhaemoglobin, at physiological plasmatic concentrations, impairs nitric oxide-mediated responses by a mechanism involving superoxide anions but not cyclooxygenase derivatives.

Animals↗

PubMed2000

Treatment with acarbose may improve endothelial dysfunction in streptozotocin-induced diabetic rats.

We sought to determine whether a single reduction of hyperglycemia and those derivatives from nonenzymatic protein glycosylation may be effective in reducing the development of diabetic endothelial dysfunction. Therefore, we investigated how acarbose, an inhibitor of intestinal alpha-glucosidase that reduce hyperglycemia by lowering glucose absorption, may prevent the impairment of acetylcholine (ACh)-induced endothelium-dependent relaxations observed in isolated vascular segments from untreated streptozotocin-induced diabetic rats. When administered after diabetes induction, 10 mg/kg acarbose decreased modestly the enhancement of blood glucose and glycosylated hemoglobin (HbA1c) levels, but not those of advanced glycosylation end products (AGEs). This effect was linked to a partial improvement of ACh-induced responses both in conductance vessels, such as aortic segments, and resistance vasculature, like mesenteric microvessels. When acarbose was introduced after 6 weeks of untreated diabetes, blood glucose, HbA1c, and AGE levels were not affected and endothelial dysfunction remained unchanged in mesenteric microvessels, whereas a small improvement was observed in aortic segments. The addition of 100 U/ml superoxide dismutase enhanced the impaired relaxations to values similar to vessels from nondiabetic rats, indicating a main role for superoxide anions in diabetes-induced endothelial dysfunction. We conclude that hyperglycemia itself or elevated HbA1c, but not plasma AGEs, are related to enhanced oxidative stress and to the impairment of endothelium function associated to diabetes. This process can be partially prevented by reducing glucose absorption with acarbose.

Acarbose↗

PubMed2000

Thapsigargin induces apoptosis in cultured human aortic smooth muscle cells.

Vascular remodeling is a key feature of many pathologic states, including atherosclerosis, or hypertension. Vascular smooth muscle cells participate in determining the vessel structure by several mechanisms such as cell migration, cell growth, or cell death (necrosis or apoptosis). Here we report that thapsigargin, an inhibitor of endoplasmic reticulum Ca2+ -adenosine triphosphatase (ATPase), is able to induce apoptosis in human vascular smooth muscle cells (HVSMCs). Apoptosis was assessed by three different methods: differential chromatin binding dye staining. cytoplasmic histone-associated DNA fragments detection by enzyme-linked immunosorbent assay (ELISA) and terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL). When HVSMCs were treated for 1 h with thapsigargin (100 nM-10 microM), there was a concentration-dependent increase in both parameters 24 h after the thapsigargin pulse. When a time-course experiment was performed, both parameters were significantly enhanced from 3 to 6 h after the exposure to thapsigargin. We conclude that thapsigargin promotes apoptosis in HVSMCs, providing a useful tool for the study of programmed cell death in human vascular smooth muscle.

Adult↗

PubMed1999

Pharmacological interference of vascular smooth muscle cell hypertrophy induced by glycosylated human oxyhaemoglobin.

Nonenzymatically glycosylated human oxyhaemoglobin induces vascular smooth muscle cell hypertrophy by releasing reactive oxygen species. We analysed the ability of drugs with antihypertrophic properties for the vascular wall and/or antioxidant activity, such as captopril, losartan, and nifedipine, or gliclazide, carvedilol, and ascorbic acid, to interfere with 10 nM glycosylated human oxyhaemoglobin-induced increase in vascular smooth muscle cell size (118+/-0.5% of basal). Vascular smooth muscle cell hypertrophy was abolished concentration-dependently, with pD(2) values over a 100-fold interval: 6.4+/-0.3, 7.7+/-0.4, 7.3+/-0.4, 7.4+/-0.6, 8. 8+/-0.2, and 9.0+/-0.2 for captopril, losartan, nifedipine, ascorbic acid, carvedilol and gliclazide, respectively. Drugs with powerful antioxidant properties, especially carvedilol and gliclazide, are particularly effective in preventing glycosylated human oxyhaemoglobin-induced vascular smooth muscle cell hypertrophy.

Animals↗

PubMed1999

Impairment of endothelial relaxations by glycosylated human oxyhemoglobin depends on the oxidative state of the heme group.

While nanomolar met- or cyanomethemoglobin, either non-glycosylated or glycosylated, did not alter endothelial function, glycosylated oxyhemoglobin induced contractile responses and caused an impairment of endothelium-dependent relaxations in rat aortic segments. The vascular effects induced by glycosylated oxyhemoglobin were prevented by superoxide dismutase. Furthermore, glycosylated oxyhemoglobin produced higher amounts of superoxide anions than other hemoglobin derivatives. These results suggest that glycosylated hemoglobin requires the existence of a functional heme group containing iron in ferrous state to interfere with the endothelial function at nanomolar concentrations. This effect is mediated by generation of superoxide anions.

Acetylcholine↗

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

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

Previous disability as a predictor of outcome in a geriatric rehabilitation unit.

BACKGROUND: Functional status at admission has been shown consistently to predict rehabilitation results, but the impact of previous disability has been seldom considered. METHODS: A prospective follow-up study of elderly patients admitted to a geriatric rehabilitation unit in Madrid, Spain, was carried out. The study population comprised 135 subjects aged 65 years or older, who were consecutively admitted during a 7-month period. Outcome variables included the Barthel Index (BI) at discharge, the improvement in BI from admission to discharge, the achieved percentage of potential gain, and the efficiency of gains. Previous BI, admission BI, diagnosis, source (hospital/others), mental status, age, and gender were examined as explanatory variables. RESULTS: In multiple regression analysis, previous BI was the only significant independent predictor for all the outcome variables. For each 5-point increase in previous BI, the increase in BI at discharge was 1.7 (p = .007). Corresponding values for the achieved percentage of potential gain and for the efficiency of gains were 0.05 (p = .01) and 0.05 (p = .04), respectively. Except for the achieved percentage of potential gain, admission BI and source of referral were also independent significant predictors of outcome. CONCLUSIONS: Previous functional situation of elderly people is important to predict rehabilitation outcome, even after taking into account information on disability at admission. As a consequence, a measure of the achieved percentage of potential gain corrected by the preadmission functional status is proposed, especially in the case of elderly patients.

Aged↗

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

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

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

Nisoldipine CC: clinical experience in hypertension.

Nisoldipine coat core (CC) is a long-acting formulation of the dihydropyridine calcium channel blocker nisoldipine, suitable for once-daily administration in the treatment of patients with hypertension. Data are reported from three randomized, controlled trials. In two of these, nisoldipine CC was shown to be equivalent in efficacy and tolerability to atenolol in patients with mild to moderate hypertension and to enalapril in elderly patients with hypertension. In a third study using ambulatory blood pressure monitoring in black patients with severe hypertension, nisoldipine CC maintained blood pressure control over the 24-hour dosing period. In addition, regression of left ventricular (LV) mass and improvement in LV function were observed at the end of the 4-month treatment period. Further data are presented from a pharmacokinetic pharmacodynamic modelling study investigating the potential effects of dose-dumping of nisoldipine from the controlled-release formulation, which may occur when the drug is taken with food. This study illustrates the superior control of plasma nisoldipine concentrations and blood pressure provided by the CC compared with an immediate-release formulation, and indicates that an interaction between nisoldipine CC and food is unlikely to cause adverse events. The results of these trials provide further support for the use of nisoldipine CC as an effective agent for the treatment of patients with hypertension, providing consistent antihypertensive efficacy and good tolerability with once-daily administration.

Blood Pressure Monitoring, Ambulatory↗