[Antihypertensive action and renal effects of guanabenz].
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In 18 cirrhotics with impaired renal perfusion intravenous injection of aminophylline 3 mg/kg b.w. increased mean renal blood flow (133-Xenon washout) from 1.77 +/- 0.71 to 1.99 +/- 0.44 ml/g/min (p less than 0.01). No significant change in cardiac output was found. In a further 10 cirrhotic patients the administration of aminophylline 3 mg/kg decreased the mean tubular reabsorption of sodium in the proximal section of the nephron (distal delivery) from 10.5 +/- 6.2 to 16.3 +/- 16.5 (p less than 0.01). Free-water production increased as a consequence of the increased supply of sodium to the diluting segment. Thus, aminophylline acts favourably on the functional renal impairment that occurs in hepatic cirrhosis.
The plasma levels of factor VIII related antigen (F VIIIR:Ag; determined by rocket electrophoresis) and reticulo-endothelial function (measured by means of the removal kinetics of human albumin millimicrospheres) were studied in a group of patients with chronic renal failure. F VIIIR:Ag plasma levels were increased, median 304% (interquartile ranges 211-443%) compared to the controls, median 112% (interquartile ranges 100-144%); P less than 0.01. Reticulo-endothelial function was decreased, median 8.3 micrograms/min/kg body wt (interquartile ranges 6.2-10.1 micrograms/min/kg body wt) compared to the controls, median 15.0 micrograms/min/kg body wt (interquartile ranges 11.9-19.0 micrograms/min/kg body wt); P less than 0.02. A significant inverse relationship was found between plasma levels of F VIIIR:Ag and the reticulo-endothelial function rs = 0.075; P less than 0.01). As the main site of catabolism of F VIIIR:Ag is the reticulo-endothelial system, the impairment of its function appears to be a possible explanation for the elevated plasma levels of the F VIIIR:Ag found in patients with end stage renal disease.
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1. In 37 patients with cirrhosis of the liver of different severity (11 in class A, 18 in class B, and 8 in class C, according to Child's criteria modified by Hobbs), inulin and p-aminohippurate clearances, total fractional protein excretion and the fractional clearances of alpha 1-acid glycoprotein, albumin, transferrin, alpha 2-macroglobulin and beta 2-microglobulin (in 20 patients) were determined. 2. Insulin clearance was lower than 70 ml/min in 19 patients had p-aminohippurate clearance was lower than 300 ml/min in 20 patients. Total fractional protein excretion was above normal in 19 patients; alpha 1-acid glycoprotein fractional clearance was above normal in 11, albumin fractional clearance in 10, transferrin fractional clearance in five, alpha 2-macroglobulin fractional clearance in three, and beta 2-microglobulin fractional clearance in 10. 3. The increases in protein excretion were independent of any impairment of renal tubular function. An inverse relationship between protein excretion and the clearances of inulin and p-aminohippurate was found. No difference in protein excretion was found between the three groups of patients with different degrees of liver damage. 4. The results suggest that in cirrhosis an increase in glomerular permeability is frequent, though generally slight; it is correlated with an impairment of kidney function and is independent of the severity of the liver damage.
Renal involvement in patients with liver cirrhosis is characterized by renal vasoconstriction, the aetiology of which remains obscure. Endotoxaemia, frequently found in patients with liver cirrhosis and renal failure, has been emphasized as a pathogenic factor. In fifty-seven patients with liver cirrhosis without overt renal failure endotoxin plasma level (Limulus Lysate test), mean renal blood flow (MRBF) (133Xe washout technique), and effective renal plasma flow (ERPF) (p-aminohippurate clearance) were determined. MRBF was decreased in nineteen out of twenty-seven patients, averaging 1.88 +/- 0.51 ml g-1 min-1 (in fourteen controls 3.17 +/- 0.51 ml g-1 ml-1). ERPF was decreased in seventeen out of thirty patients, averaging 380 +/- 164 ml/min (in eighteen controls 624 +/- 127 ml/min). Systemic endotoxaemia was found in sixteen out of fifty-seven patients, levels ranging from 0.62 to 200 ng/ml. No significant difference in renal blood flow values was found between patients with and without endotoxaemia (MRBF = 1.78 +/- 0.51 and 1.93 +/- 0.52 ml g-1 min-1 respectively; ERPF = 429 +/- 119 and 365 +/- 175 ml/min respectively). No significant difference in the frequency of endotoxaemia was found between patients with impaired and unimpaired renal blood flow. Moreover no relation was found between endotoxin plasma levels and MRBF and ERPF respectively. In conclusion in patients with cirrhosis without overt renal failure renal vasoconstriction does not seem to be related to endotoxaemia.
Mean renal blood flow (MRBF), cortical blood flow (CBF), glomerular filtration rate (GFR), heart rate, arterial blood pressure, Na+ and K+ excretion were determined before and 10 min after intrarenal administration of dihydroergocristine (0.017 mg/kg b.w.) in 13 patients suffering from liver cirrhosis. Cardiac output was also determined in 6 patients. Baseline values of MRBF and CBF were significantly lower in cirrhotics than in the 14 control subjects. Following intrarenal administration of the drug, renal hemodynamic parameters increased significantly, while GFR decreased. Systemic hemodynamic parameters, diuresis, Na+ and K+ excretions were unchanged. These data show that dihydroergocristine has a renal vasodilator effect, probably mediated by alpha-adrenergic blockade. The effect probably is prevalent at the postglomerular site, where the increase in vascular resistance is greatest. The effect of the drug suggests that patients with liver cirrhosis have enhanced renal sympathetic activity which is, at least in part, responsible for the renal vasoconstriction.
The renal and intrarenal haemodynamic pattern in 17 patients with essential hypertension of different severity and duration was studied by means of the 133-Xenon washout technique and the selective renal angiography. The mean and the cortical renal blood flows were on average significantly decreased as compared to the controls. A good agreement was found between the reduction in renal perfusion and the degree of vascular abnormalities as shown by angiography; on the contrary no correlation was found between the impairment in renal blood flow and the degree and/or duration of hypertension.
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To assess the renal tubular damage in liver cirrhosis the fractional clearances of beta-2-microglobulin (B2m-fr.cl) and malate-dehydrogenase (MDH-fr.cl) were measured respectively in sixty-four and in forty-six out of seventy-nine patients with liver cirrhosis of different aetiology; furthermore the fractional excretions of gammaglutamyl-transpeptidase (fr-GGT) and of alpha-glucosidase (fr-AGL) were determined in fifty-three and in forty of them respectively. In all patients glomerular filtration rate (GFR) and renal plasma flow (RPF) were also measured. Twenty-five subjects were studied as a control group for the enzyme excretions, sixteen for B2m-fr.cl. B2m-fr.cl and MDH-fr.cl--indexes of tubular functions--on the average were normal and only slightly increased respectively in cirrhotics compared to controls. Nevertheless fr-GGT and fr-AGL--indexes of cytolysis of tubular cells--on the average were massively increased in cirrhosis compared to controls, particularly in those with reduced RPF and/or GFR. No clear relationship between the indexes of tubular damage studied and the indexes of liver function was found. Our results show that (1) A renal tubular anatomical damage was found by means of an increase in the release of enzyme from tubular cells in patients with liver cirrhosis, particularly in those with a significant reduction of RPF and/or GFR; even so renal reabsorption of low molecular weight proteins is generally maintained. (2) The tubular damage does not seem to be related to the degree of liver impairment.
The effects of Captopril on blood pressure and renal function were evaluated in ten patients with different degrees of hypertension. In seven, blood pressure was reduced after 7 weeks of therapy; in three it remained practically unchanged. No correlation was found between the standing plasma renin activity before treatment and the hypotensive response. Plasma renin activity increased significantly from the median value of 5.4 (range 1-16.7) to 9.5 (range 2.6-19.8) ng ml-1 h-1 (P less than 0.05) and urine aldosterone significantly fell from 13 (range 2.3-52.5) to 7.4 (range 1.6-14) microgram 24 h-1 (P less than 0.01) during therapy. Renal plasma flow decreased from 534 (range 300-616) to 471 (range 333-606) ml min-1, but the difference was not significant, and glomerular filtration rate fell significantly form 122 (range 64-143) to 88 (range 71-116) ml min-1 (P less than 0.05). No urinary excretion of alpha 2-macroglobulin was observed during Captopril. 24 h proteinuria, albumin and transferrin clearance, alanine-amino transferase, gammaglutamyl transferase and alpha glucosidase excretion rate and malate-dehydrogenase clearance remained unaltered throughout the treatment. This indicates that neither glomerular permeability nor renal tubular function were affected by the drug.
The pathogenesis of renal functional impairment in patients with cirrhosis is still poorly understood, although it is probably linked to intrarenal haemodynamic alterations, such as renal cortical vasoconstriction and opening of intrarenal shunts. To elucidate the intrarenal haemodynamic pattern in patients with cirrhosis, in eight patients with this disease mean renal blood flow (MRBF) and cortical blood flow (CBF) were determined by means of the xenon-133 washout technique; in the same subjects mean intrarenal circulation time for plasma (t) and fastest circulation time for plasma(t0) were determined by means of injection of human serum albumin tagged with technetium-99m into the renal artery. Moreover, cortical vascular volume (CVV) was obtained in all subjects by means of the following formula: CVV = CBF x t. Fourteen normal subjects constituted a control group for MRBF, 9 subjects for CBF, and 4 subjects for t, t0, and CVV. In patients with cirrhosis MRBF and CBF were significantly less than in controls; t did not show any significant alterations, whereas t0 was significantly shorter than in controls. CVV was also significantly impaired. It is concluded that renal cortical vasoconstriction is a characteristic of the renal haemodynamic pattern in patients with cirrhosis. It is suggested that the decrease in t0 is due to the opening of intrarenal shunts and that is likely to be the consequence of renal vasoconstriction.
The mechanism of the renal tubular acidosis (RTA) occurring in patients with hepatic cirrhosis remains uncertain although it has been suggested that renal and intrarenal hemodynamic alterations could play a role in its pathogenesis. To verify this hypothesis, renal acidification was studied with an intravenous acid load of arginine hydrochloride in 51 patients with cirrhosis due to various causes. In 22 patients renal and intrarenal blood flow was also measured using the 133-Xe washout technique. RTA was found in 17 of 51 patients (33%) with the greatest incidence in alcoholic cirrhosis. The tubular defect did not appear related either to the degree of liver functional impairment or to the renal and intrarenal hemodynamic alterations.
A detailed transcription map of HeLa cell mitochondrial DNA (mtDNA) has been constructed by using the S1 protection technique to localize precisely the sequences coding for the ribosomal RNA (rRNA) and poly(A)-containing species on the physical map of the DNA. This transcription map has been correlated with the positions of the tRNA genes derived from the mtDNA sequence. It has been shown that, with the exception of the D loop and another small segment near the origin of replication, the mtDNA sequences are completely saturated by the rRNAs, poly(A)-containing RNAs and tRNA coded for by the two strands. No evidence for intervening sequences has been found. The sequences coding for the individual poly(A)-containing RNA and rRNA species appear to be immediately contiguous on one side, and most frequently on both sides, to tRNA coding sequences. Furthermore, the H strand sequences coding for the two rRNAs, the poly(A)-containing RNAs and the tRNAs appear to be adjacent to each other, extending from coordinate 2/100 to coordinate 95/100 of the genome relative to the origin taken as 0/100. The results are consistent with a model of transcription of the H strand in the form of a single molecule which is processed into mature RNA species by precise endonucleolytic cleavages, occurring in almost all cases immediately before and after a tRNA sequence. The tRNA sequences may play an important role as recognition signals in the processing of the primary transcripts.
Portal hypertension has been considered a pathogenetic factor in the onset of renal haemodynamic alterations in patients with cirrhosis. This hypothesis is based on experimental evidence, whereas the clinical data are few and contradictory. Mean and cortical renal blood flows were studied in 16 patients with liver cirrhosis before and 20-40 days after a portal-systemic shunt performed by different techniques: nine patients had a non-selective shunt and seven a selective shunt (distal splenorenal according to Warren). Despite a decrease in portal pressure, mean and cortical renal blood flows did not change significantly after surgery, and there was no significant correlation between decrease in portal pressure and modification of renal blood flow. It is concluded that portal hypertension is not a pathogenetic factor in renal hypoperfusion in cirrhosis.
The case of a patient with progressive systemic sclerosis (PSS) who developed electro- and vectorcardiographic patterns of myocardial necrosis without clinical picture of myocardial infarction is reported. The coronarography showed no obstruction of coronary arteries and cineventriculography a hypodynamic enlarged left ventricle. The analysis of electrocardiograms from 43 other patients affected with PSS revealed myocardial necrosis in 5 of them. The clinical syndrome of myocardial infarction was absent in all these cases. Moreover, the hemodynamic investigation in 13 cases allowed to record a dip-plateau figure on the right ventricle pressure curve in 3 of them. In PSS, the electrocardiographic aspects of "necrosis" as well as hemodynamic restrictive findings or ventricular enlargement at ventriculography could indicate myocardial disease.
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