Biomedical subjects

J M Lopez-Novoa

Publications and source records attributed to J M Lopez-Novoa.

At least 19 recordsLinked to original sources

PubMed2002

Cyclosporin effect on rat aorta alpha(1)-adrenoceptors and their transduction mechanisms.

A possible explanation for cyclosporin-induced arterial hypertension may be its action on the adrenergic system. In spite of the controversial results reported in literature, it seems that cyclosporin changes the vascular response to noradrenaline. Therefore, after observation that two cyclosporin doses increase rat blood pressure and vascular reactivity in response to noradrenaline, the aim of this work was to study the cellular mechanisms beside the cyclosporin-induced changes in response to noradrenaline. Therefore, the cyclosporin influence on alpha(1)-adrenoceptors as well as on their transduction mechanism in smooth muscle cells was studied. Through Scatchard analysis of specific [(3)H]-prazosin binding, the alpha(1)-adrenoceptor number and related affinity were studied, before and after cyclosporin exposure. The cyclosporin influence on alpha1-adrenoceptor transduction mechanisms was also evaluated by the quantification of intracellular free calcium contents [Ca2+]i and inositol phosphate (InsP) turnover. All in vitro experiments were performed in rat aortic smooth muscle cells in culture. Results showed that both cyclosporin concentrations (10(-6) and 10(-7) M) changed alpha1-adrenoceptor number but only 10(-7) M cyclosporin increased its affinity for [(3)H]-prazosin. Compared with control cells, only 10(-7) M cyclosporin increased InsP levels. Stimulation by noradrenaline increased InsP in 10(-7) M cyclosporin-treated cells but decreased InsP in the presence of 10(-6) M cyclosporin. Both cyclosporin concentrations increased [Ca2+]i in basal conditions and after noradrenaline stimulation. The results suggest that after noradrenaline stimulation cyclosporin increases [Ca2+]i, probably through different mechanisms, depending on the cyclosporin concentration used. However, 10(-7) M cyclosporin increases alpha1-adrenoceptor affinity and their related transduction mechanisms. The higher cyclosporin concentration (10(-6) M) seems to induce downregulation of alpha1-adrenoceptors, probably by activation of protein kinase C.

Animals↗

PubMed1997

Adenosine activates mesangial cell proliferation.

This study investigates the proliferative effect of adenosine (ADO) in cultured mesangial cells, and the possible mediation of A1 and/or A2 receptors in this proliferative effect of ADO. ADO (10(-5) M) induced a significant increase in the [3H]thymidine incorporation into DNA with respect to quiescent cells. This increase was similar to that obtained with the ADO A1 receptor agonist, R-PIA (10(-5) M), and with the ADO A2 receptor agonist, NECA (10(-5) M). Theophylline (10(-4) M), and ADO receptors inhibitor, completely inhibits the ADO-induced proliferation. The combinations NECA + A2 receptor antagonist, PD 116,948 (AT1, 10(-6) M) and PIA + A2 receptor antagonists, PD 115,199 (AT2, 10(-2) M) did not induce any significant difference with respect to cells maintained in control conditions. These findings demonstrate the proliferative effect of ADO in cultured mesangial cells, and that this effect is not specific to either of A1 or A2 receptors activation.

Adenosine↗

PubMed1993

Effect of ouabain and hypothalamic, hypophysary inhibitory factor on rat mesangial cell proliferation.

The mitogenic effect of a low-molecular-weight, Na+,K(+)-ATPase inhibitory factor isolated from bovine hypothalamus and hypophysis (hypothalamic hypophysary inhibitory factor, HHIF) and ouabain on cultured rat mesangial cells was examined. Ouabain induced a potent stimulation of the [3H]thymidine incorporation to DNA, ranging from threefold for a dose of 10(-7) M to seven times for 10(-5) M. The amount of proteins per well also increased in a dose-dependent way, which was already significant from basal values for the lower dose used. HHIF also induced a dose-dependent stimulation of [3H]thymidine incorporation into DNA, ranging from 1.7 times for a concentration of 0.02 U/ml to 4.5 times for the concentration of 2 U/ml. The amount of protein per well also increased with HHIF, but the increase was significant only for the higher dose used. These data allow us to conclude that HHIF could play a role in the vascular hypertrophy that is associated with the pathogenesis of hypertension.

Animals↗

PubMed1992

Effect of adenosine and adenosine analogues on cyclic AMP accumulation in cultured mesangial cells and isolated glomeruli of the rat.

1. Changes in intracellular levels of adenosine 3':5'-cyclic monophosphate (cyclic AMP) were studied in rat isolated glomeruli and cultured glomerular mesangial cells exposed to adenosine and to the preferential A1 receptor agonist N6-R-1-methyl-2-phenylethyl adenosine (R-PIA), or the potent A2 adenosine receptor agonist 5-(N-ethylcarboxamide)adenosine (NECA). 2. Whereas NECA and adenosine triggered a dose-dependent increase in cyclic AMP values with EC50 values of approximately 10(-6) M and 3 x 10(-5) M respectively, R-PIA lowered cyclic AMP levels at concentrations of 10(-6) M or less and increased them at higher concentrations. 3. The time-course of the increase induced by 10(-6) M NECA was slower than that induced by 10(-4) M adenosine. Adenosine produced a maximal stimulation within the first minute, whereas the effect of NECA in both glomeruli and mesangial cells was noticeable only from the second minute of incubation. 4. The effects of the agonists R-PIA and NECA on the cyclic AMP system were blocked respectively by the A1 adenosine receptor antagonist, 8-cyclopentyl-1, 3-dipropylxanthihe (DPCPX) at 10(-6) M and the A2 antagonist N-(2-dimethylaminoethyl)-N-methyl-4-(2, 3, 6, 7-tetrahydro-2,b-dioxo-1, 3-dipropyl-1H-purin-8-yl) benzene sulphonamide (PD115,199) at 10(-6) M. Theophylline, a known antagonist of adenosine receptors, inhibited the action of adenosine on cyclic AMP in mesangial cells. Dipyridamole, an inhibitor of the uptake of adenosine by the cells, enhanced the response to adenosine.5. These results suggest the existence of Al and A2 adenosine receptors with opposite actions on intracellular levels of cyclic AMP in both glomeruli and mesangial cells. Adenosine seems to increase cyclic AMP through the activation of a surface adenosine receptor with pharmacological properties distinct from those exhibited by the A2 adenosine receptor.

Adenosine↗

PubMed1991

Renal transplantation and red blood cell sodium transport: role of prednisone treatment.

This study assesses the role of prednisone and endogenous digoxin-like immunoreactivity (EDLI) in the increased Na+ pump activity in renal allograft patients. Red blood cell (RBC) Na+ transport activities and plasma concentrations of EDLI were measured in ten controls and ten renal allograft recipients (5 hypertensive) while undergoing treatment with cyclosporin, prednisone, and azathioprine, and also after prednisone withdrawal. As compared to controls, prednisone-treated patients showed an increased Na+ pump activity (0.323/h vs 0.571, P less than 0.05) and decreased RBC Na+ concentration (6.69 mM vs 4.99, P less than 0.05). They also showed a decrease in the activity of cotransport, countertransport, and passive Na+ efflux (0.02/h vs 0.005, P less than 0.05; 207 mumol/l vs 35, P less than 0.05; 0.02/h vs 0.005 respectively, P less than 0.05). After prednisone withdrawal, normotensive and hypertensive patients showed RBC Na+ transport system activities and RBC Na+ concentration similar to those of controls. EDLI was not detected in controls or in patients. We conclude that prednisone treatment increased the Na+ pump activity, and decreased the RBC Na+ concentration. Moreover, it induced a decrease in the activity of secondary RBC Na+ transport systems. This study provides no evidence for a modulatory role of EDLI in the RBC Na+ pump activity. Neither parameters can be presumed to be a marker of hypertension in these patients.

Adult↗

PubMed1991

Renal function derangements induced by portacaval anastomosis in normal rats.

The purpose of this study was to determine the renal function derangements that portacaval shunting caused in previously normal rats. Eight rats suffered a surgical portacaval shunt (PCS) and another 8 a sham operation (SHAM). Renal function was investigated by determining urinary volume, sodium, potassium, creatinine and aldosterone excretion, in basal conditions and after sodium overload. Plasma renin concentration and urinary excretion of PGE2, 6-keto-PGF1 alpha and TXB2 were also determined in basal conditions. PCS rats showed increased urinary volume, creatinine excretion and endogenous creatinine clearance, either in basal conditions or after sodium load. After the latter, PCS animals also showed sodium retention and hyperaldosteronuria. PCS caused in basal conditions a striking diminution in urinary excretion of all prostaglandins and no changes in plasma renin. In conclusion, PCS in the normal rat caused a renal dysfunction consisting of polyuria, possibly related to ADH disfunction and an inability to manage a sodium load.

Aldosterone↗

PubMed1991

Effects of physical training during the growth on the granulation of myo-epithelioid cells of the rat kidney.

The behaviour of the granulation of the myo-epithelioid cells of the juxtaglomerular apparatus of the kidney and its relationship with the plasma concentrations of renin, sodium and potassium, and plasma osmolality have been studied in male and female Wistar rats that have been subjected to a programme of moderate physical exercise throughout their period of growth. In the trained rats a significant increase in the juxtaglomerular granulation index and a significant decrease in plasma renin concentration has been observed, the changes being more prominent in the female animals. Moreover in the trained rats significant increases in plasma sodium, potassium and osmolality have been observed.

Aging↗

PubMed1990

Hepatic haemodynamic changes after portacaval anastomosis in normal, cirrhotic and chronic prehepatic portally hypertensive rats.

Radioactive microspheres were used to determine the hepatic haemodynamic response to portacaval anastomosis in normal, cirrhotic and chronic prehepatic portally hypertensive rats 20 days after operation, and in normal rats 2 months after operation. After 20 days portacaval anastomosis caused a decrease in liver mass only in normal and cirrhotic animals, whereas hepatic arterial blood flow per unit of mass increased in normal (+488 per cent), cirrhotic (+191 per cent) and prehepatic portally hypertensive rats (+133 per cent). Despite these facts, animals with portacaval anastomosis showed a reduced hepatic total perfusion (arterial plus portal inflow) per unit of mass with respect to controls in normal (-53 per cent) and cirrhotic rats (-68 per cent), but not in those with prehepatic portal hypertension. Comparing studies carried out at 2 months with those performed 20 days after portacaval anastomosis in normal rats, some recovery of liver mass and total liver blood flow was observed. In conclusion, portacaval anastomosis produced a limited increase in hepatic arterial blood flow which was unable to preserve liver mass and its total perfusion in normal and cirrhotic animals. In contrast, portacaval anastomosis did not significantly alter liver mass or its perfusion in animals with chronic prehepatic portal hypertension, as both values were previously diminished in controls. Thus, the risk of liver failure after portacaval anastomosis is higher in normal and cirrhotic rats than in those with chronic prehepatic portal hypertension.

Animals↗

PubMed1990

Role of glucagon in the splanchnic and systemic hemodynamic changes induced by portal-systemic blood shunting.

Portal-systemic blood shunting is often accompanied by hyperglucagonemia and hemodynamic changes. To determine this causal relation, splanchnic and systemic hemodynamics (radioactive microspheres) and plasma glucagon levels (radioimmunoassay) were assessed in conditions of total portal-systemic shunting in portacaval-shunted (PCS) rats and in sham-operated (SO) normal rats. To compare these results, another hemodynamic study was undertaken basally and during glucagon infusion in nonoperated normal rats. PCS rats showed a threefold greater plasma glucagon concentration than SO animals (924 +/- 134 vs. 309 +/- 18 pg/ml, p less than 0.01), and they developed a hyperdynamic splanchnic circulation with higher portal venous inflow than SO rats (8.29 +/- 1.1 vs. 5.09 +/- 0.4 ml/min/100 g, p less than 0.05). Infusion of a pharmacological dose of glucagon in normal rats increased portal venous inflow (from 4.92 +/- 0.33 to 6.24 +/- 0.48 ml/min/100 g, p less than 0.05) so as to imply this hormone in the development of the hyperdynamic splanchnic circulation in conditions of portal-systemic shunting. However, the discrepancies in systemic hemodynamics between PCS and glucagon-infused rats may be a result of the different plasma glucagon levels reached in the two groups.

Animals↗

PubMed1989

Prostanoid production in post-gastrectomy gastritis. Influence of sucralfate.

Prostaglandins seem to play an important role in the protection of the gastric mucosa, but the effect of cytoprotective drugs such as sucralfate on prostaglandin synthesis and in the prevention of gastritis induced by gastric surgery has not been definitely established. The purpose of this study was to determine: (1) the prostanoid production and the histologic changes occurring after various surgical techniques in rat gastric mucosa; and (2) the influence of sucralfate treatment on prostanoid levels and gastric damage induced by gastric surgery. Animals included in the study had undergone one of three surgical procedures: Billroth I, Billroth II, or truncal vagotomy plus pyleroplasty. Animals that had no surgery and "sham-operated" animals were used as controls. One third of the animals in each group received sucralfate treatment (an average of 100 mg/kg per day). Samples of gastric mucosa were taken after one year, and prostaglandin E2 (PGE2), 6-keto-PGF1 alpha, and thromboxane B2 synthesis were measured by radioimmunoassay. The sucralfate-treated group consistently showed higher PGE2 and 6-keto-PGF1 alpha values and a higher 6-keto-PGF1 alpha:thromboxane B2 ratio, as well as lower thromboxane B2 levels than untreated animals, although the differences were statistically significant only in the 6-keto-PGF1 alpha:thromboxane B2 ratio. Similarly, gastritis was more frequent and more severe in the untreated animals. In conclusion, sucralfate seems to provide protection against gastritis induced by gastric surgery and increases the 6-keto-PGF1 alpha:thromboxane B2 ratio.

6-Ketoprostaglandin F1 alpha↗

PubMed1989

Endogenous digoxin-like immunoreactivity and erythrocyte sodium transport in uraemic patients undergoing dialysis.

1. Erythrocyte Na+ transport (Na+ pump activity, co-transport, countertransport and passive Na+ efflux) and intracellular Na+ concentration were studied in 10 normal individuals and in 29 uraemic patients on chronic haemodialysis, before and after a haemodialysis session. Eight of them fulfilled the criteria of hypertension. 2. Normotensive patients before haemodialysis were classified in two groups: group 1 (pump-) with decreased erythrocyte Na+ pump activity, and group 2 (normal pump) with normal erythrocyte Na+ pump activity. Group 1 showed, compared with controls, a normal intracellular Na+ concentration and a decreased co-transport, but no difference in either countertransport or passive Na+ efflux. After haemodialysis this difference disappeared. Before haemodialysis, group 2 showed a high intracellular Na+ concentration, but activities of the Na+ transport systems studied were similar to those of controls. After haemodialysis, cell Na+ concentration decreased to a level not significantly different from that of controls. 3. Both before and after haemodialysis, hypertensive patients showed Na+ transport system activities and an intracellular Na+ concentration similar to those of controls. 4. Endogenous digoxin-like immunoreactivity (EDLI) and erythrocyte Na+ transport were studied in five normotensive and five hypertensive patients, before and after haemodialysis. EDLI in plasma was similar in both groups before and after haemodialysis. No correlation was found between EDLI and erythrocyte Na+ pump activity. 5. These results suggest the existence in some dialysed uraemic patients of alterations in erythrocyte Na+ fluxes, which may be corrected by haemodialysis. EDLI and erythrocyte Na+ fluxes do not seem to be markers of secondary hypertension in these patients.

Adult↗

PubMed1989

Effect of valproate on lactate and glutamine metabolism by rat renal cortical tubules.

The metabolic effects of sodium valproate (VPA) on rat renal cortical tubules have been examined. When 1 or 5 mM lactate was used as substrate in the incubation medium, VPA decreased markedly the lactate uptake by the tubules. When 1 or 5 mM glutamine was used, the addition of VPA accelerated glutamine uptake, ammoniagenesis, but also stimulated markedly the accumulation of lactate and pyruvate produced from glutamine. VPA had a dose-dependent inhibitory effect on gluconeogenesis from both glutamine and lactate. With 5 mM glutamine, VPA also induced a significant accumulation of glutamate in the medium. The oxygen consumption by the tubules was diminished by 40% following VPA addition. It is concluded that VPA modifies the metabolism of rat cortical tubules by interfering with the oxidation of natural substrates and stimulates in this fashion the production of ammonia by kidney tubules.

Animals↗

PubMed1988

Effect of valproate on renal metabolism in the intact dog.

Valproate is an antiepileptic drug known to induce hyperammonemia in humans. This hyperammonemia might result from a reduced detoxification of ammonium in the liver and/or from an accelerated renal ammoniagenesis. Six dogs with normal acid-base equilibrium and eight dogs with chronic metabolic acidosis were infused with valproate directly into their left renal artery in order to obtain arterial concentrations around 3 to 4 mM. The arterial ammonium concentration rose only in chronically acidotic dogs, whereas the lactate concentration and the lactate/pyruvate ratio increased in both groups. The urinary excretion of lactate and pyruvate increased markedly but the urinary excretion of other relevant metabolites remained minimal. Renal glutamine utilization and ammonium production were not changed by valproate administration in normal dogs but increased modestly in acidotic dogs. However, renal lactate utilization was drastically reduced and in fact, changed into a net production of lactate. Valproate strikingly reduced the renal cortical concentrations of glutamine, glutamate, alphaketoglutarate and citrate, and more modestly those of malate, oxaloacetate, aspartate, alanine and ATP. By contrast, the tissue lactate concentration and the lactate/pyruvate ratio were markedly increased. In experiments with brush border membrane vesicles, valproate inhibited the lactate transporter. These results suggest that high concentrations of valproate drastically inhibited the proximal reabsorption and the proximal and distal oxidation of lactate and pyruvate. Valproate probably became itself a significant energetic substrate for the kidney.

Acid-Base Equilibrium↗

PubMed1988

Absence of an endogenous regulator of Na+,K+-ATPase activity in the tissues of cirrhotic rats.

Microsomal Na+,K+-ATPase isolated from the renal cortex of rats with CCL4-induced cirrhosis (CIR) showed a higher specific activity than the enzyme obtained from control rats (COR). Kinetic studies showed a lower K0.5 for ATP (0.08 +/- 0.03 vs. 0.24 +/- 0.04 mM; p less than 0.05), a lower Na+ activation constant (9.6 +/- 1.5 vs. 19.0 +/- 1.7 mM; p less than 0.05), and a higher K+ activation constant (1.2 +/- 0.1 vs. 0.6 +/- 0.1 mM; p less than 0.05) for CIR. The optimal pH of the enzyme was 0.5 units higher in CIR than COR. The fluorescence of eosin-treated enzymes indicated a higher ratio of E1/E2 forms of Na+,K+-ATPase in CIR. The K+-activated p-nitrophenylphosphatase (pNPPase) activity of the enzyme was lower in CIR than COR rats (1.5 +/- 0.1 vs. 2.2 +/- 0.1 mU/mg; p less than 0.05). Dialysing (24 h) COR microsomes reproduced most of the changes observed in CIR enzymes (kinetics, optimal pH, and eosin fluorescence). Lyophilized dialysate of COR, but not of CIR microsomes, inhibits Na+,K+-ATPase activity. These results suggest that a dialysable inhibitor modifies the Na+,K+-ATPase activity in the kidney of COR which is almost absent in that of CIR. The absence of this factor may lead to the overall inability to excrete Na+ in the cirrhotic state.

Animals↗

PubMed1987

Effect of chronic and progressive hepatic outflow blockade on renal function in rats.

Systemic and splanchnic hemodynamics, plasma concentration, and urinary excretion of several hormones and the changes in renal function induced by saline infusion were studied in rats with a chronic and progressive model of postsinusoidal hypertension by hepatic vein ligation (HVL) and in a control group. HVL rats showed no differences in systemic hemodynamics compared with control rats, with the exception of decreased renal blood flow and increased renal vascular resistance. HVL rats showed increased portal and intrahepatic pressure, without other differences in splanchnic hemodynamics or in portal-systemic shunts. Clearance studies revealed that under basal conditions, HVL rats showed lower glomerular filtration rate, renal plasma flow, urinary flow, and sodium, chloride, and potassium excretion than control rats. After saline infusion (3% body weight, 15 ml/hr) differences in glomerular filtration rate became nonsignificant, but urinary flow and electrolyte excretion remained lower in HVL than in control rats. Under basal conditions, plasma norepinephrine and dopamine concentrations were higher and urinary prostaglandin E2 (PGE2) and prostaglandin F2 alpha levels were lower in HVL than in control animals. These results demonstrate that chronic and progressive hepatic congestion results in impaired renal function with decreased water and electrolyte excretion, and suggest the involvement of a hepatorenal sympathetic reflex in these alterations. Renal effects could also be mediated by the low levels of PGE.

Animals↗

PubMed1987

Role of the natriuretic hormone in the specific natriuresis induced by intraportal infusion of hypertonic saline in dogs.

Previous experiments from our laboratory demonstrated that the infusion of a small amount of hypertonic saline into the portal vein induced higher diuresis and natriuresis than those induced by the infusion of the same amount of saline into a cubital vein. The purpose of the present experiment was to study the role of the so-called natriuretic hormone in this phenomenon. For this purpose, two groups of 5 dogs each were infused with 855 mM NaCl (0.05 ml X min-1 for 20 min), one group through the portal vein and the other through the cubital vein. Samples of peripheral, arterial and suprahepatic blood and urine were obtained, and the fraction described to contain the natriuretic hormone was purified by gel filtration chromatography. Its natriuretic activity was assayed by measuring the natriuresis induced by its infusion in conscious, unilaterally nephrectomized rats. The urine taken from the dogs infused with hypertonic saline into the porta showed higher natriuretic activity than that obtained before infusion or from the dogs infused into the cubital vein. Also, natriuretic activity was observed in the suprahepatic and arterial plasma samples obtained after portal infusion but not in those obtained before the infusion. There were no differences in natriuretic activity between suprahepatic and arterial samples. These results suggest that the natriuretic hormone plays an important role in the natriuresis induced by portal hypertonic saline infusion, and they do not support the hepatic origin of this substance.

Animals↗

PubMed1986

Effects of the platelet-activating factor antagonist BN 52021 on the hemodynamics of rats with experimental cirrhosis of the liver.

Previous studies from this laboratory have shown that rats with experimental cirrhosis of the liver induced by the combined administration of oral phenobarbital and inhaled carbon tetrachloride show an hyperdynamic status with enhanced cardiac output (CO), and decreased mean arterial pressure (MAP) and peripheral vascular resistance (PVR). Cirrhotic rats also showed an increased vascular permeability. All these phenomena are similar to some of the known effects of the systemic infusion of low doses of synthetic platelet-activating factor into the systemic circulation of normal rats. The measurement of the levels of platelet-activating factor in samples of blood demonstrated significantly higher levels in cirrhotic (2.65 +/- 0.39; n = 10) than in control rats (1.50 +/- 0.57 ng/ml; n = 10; p less than 0.05). The hemodynamic changes induced by the intravenous injection of the platelet-activating factor receptor antagonist BN 52021 (5 mg/kg body weight) have been measured in 10 control and 10 cirrhotic male Wistar rats, using a radioactive microsphere technique. BN 52021 induced no significant hemodynamic changes in control animals. However, in cirrhotic animals it induced a significant decrease in CO with increase in PVR. MAP increased slightly but not significantly. From these data it can be deduced that platelet-activating factor plays a role in the hemodynamic derangement shown by cirrhotic rats and that these derangement can be reversed by BN 52021, a highly selective antagonist of the platelet-activating factor receptor.

Animals↗

PubMed1986

Hemodynamic effects of vanadate administration in rats with different levels of sodium intake.

The acute hemodynamic effect of an intravenous (IV) bolus of vanadate (10 mumol/kg bwt) followed by an IV infusion at 0.5 mumol/kg min was studied in Wistar rats at three different levels of Na intake: low Na+ (0.5 mEq/24 h), normal Na+ (1.5 mEq/24 h), and high Na+ (15 mEq/24 h). Hemodynamic changes were measured using the radioactive microsphere method. Vanadate decreased cardiac output by 52.0 +/- 6.4% in low Na+ rats, by 41.2 +/- 3.3% in normal Na+, and by 29.2 +/- 3.1% in high Na+ group. Total peripheral resistances increased by 47.1 +/- 26% in high Na+ rats, by 80.1 +/- 6.6% in normal Na+, and by 96.3 +/- 4.5% in low Na+ group. Renal blood flow decreased by 70 +/- 4% in low Na+, 58 +/- 3% in normal Na+, and 39 +/- 3% in high Na+. Cerebral, testicular, and splanchnic blood flow showed smaller changes. These results demonstrate that intravenous vanadate induces marked hemodynamic changes that depend on Na+ intake being more striking when the intake of sodium is reduced.

Animals↗