Differing effects of antihypertensive agents on urinary albumin excretion

Skeletal muscles in an animal model of genetic hypertension (the spontaneously hypertensive rat. SHR) exhibit significant deficits in contractile performance. These deficits appear to be unrelated to the rise in blood pressure. Slow-twitch soleus muscles show a decrease in specific muscle tension and a reduced resistance to muscle fatigue during prolonged contractile activity. We tested the hypothesis that the reduced fatigue resistance occurs as a consequence of an impaired ability to maintain or restore Na+ and K+ balance across the sarcolemma during repeated contractions. This may result from a genetically based increase in the Na+ permeability of SHR muscles, coupled with a reduction Na+, K+ pump capacity as the animals mature. Soleus muscles in adult SHR exhibit a significant increase in intracellular Na+ content and a significant decrease in intracellular K+ content at rest. B6RB+ uptake in Na(+)-loaded hypertensive muscles is 45% less than predicted from the number of ouabain-binding sites available. Activation of Na+, K+ pumps using adrenaline or insulin produces a significantly smaller hyperpolarization in hypertensive soleus than in control muscles. Control soleus muscles are hyperpolarized for at least 10 min after a 4 min period of high-frequency activity, but hypertensive soleus muscles remain at resting polarity. Nonetheless, the number of ouabain-binding sites in hypertensive muscle is significantly greater than in control soleus, and binding affinities are similar. This apparent deficit in pump capacity might lead to a greater and more prolonged increase in extracellular K+ during repetitive contractions,and an associated decline in tension. Recently, we have been able to prevent the abnormal decrease in hypertensive soleus fatigue resistance by long-term treatment (8 weeks) with the Ca2+ blocker amlodipine. The therapy prevented or reversed the contractile deficits, but did not restore the responsiveness of the Na+, K+ pump to hormonal stimulation. The current data suggest that both a reduction in Na+, K(+)-pump capacity and changes in Ca2+ distribution play a role in the development of contractile deficits in hypertensive muscles.     

Mitochondrial function in rat renal cortex in response to proteinuria and iron

1. Proximal tubular cell dysfunction in chronic glomerular disease (CGD) has been ascribed, in part, to reabsorption of transferrin-iron from tubular fluid and subsequent cytosolic peroxidative injury. To investigate a possible role for altered mitochondrial function in tubular cell injury in CGD, renal cortical mitochondrial respiratory function was examined in rats with adriamycin nephrosis. 2. State 4 (resting) respiration was increased in adriamycin nephrosis in comparison with control (51 +/- 2 vs 43 +/- 2 ng atoms oxygen (O)/min per mg protein, respectively; P < 0.02). 3. Mitochondrial iron concentration was increased in nephrotic rats compared with control (9.52 +/- 0.70 vs 5.97 +/- 0.26 nmol Fe/mg protein, respectively; P < 0.001) and rates of state 3, state 4 and uncoupled respiration and the severity of proteinuria correlated with mitochondrial iron concentration. 4. To further define the relationship between mitochondrial iron accumulation and altered respiratory function, rats were loaded with iron. 5. In comparison with control, acute iron loading of normal rats impaired creatinine clearance (1.48 +/- 0.02 vs 0.40 +/- 0.29 mL/min), increased kidney weight (1.33 +/- 0.07 vs 1.74 +/- 0.14 g) and impaired mitochondrial enzyme activity (e.g. cytochrome oxidase 185.0 +/- 46.6 vs 362.0 +/- 32.8 delta log [cytochrome C]/min per mg protein; P < 0.05), but had no significant effect on rates of mitochondrial respiration or on mitochondrial fragility. 6. Mitochondrial iron concentration was not increased by iron loading, despite a similar increment in cytoplasmic iron to that seen in rats with adriamycin nephrosis. 7. In summary, resting mitochondrial respiration is increased in nephrotic rats in proportion to mitochondrial iron accumulation. Changes in mitochondrial oxygen consumption do not appear to be a primary event in the tubular cell injury of iron loading.     

Influence of differing classes of antihypertensive agents on mesangial kinetics following partial renal ablation in rats

Mesangial kinetics were studied in six groups of rats. Rats were either sham operated or were subjected to 1 1/3 nephrectomy (4/6 Nx). Each group was either untreated or was treated with enalapril (EN) or the drug regimen of hydralazine, hydrochlorothiazide, and reserpine (HHR). Four weeks after surgery rats were injected with iodinated aggregated bovine serum albumin (I-aggBSA) and mesangial localization quantified 2, 4, or 8 h later. Mesangial kinetics in untreated 4/6 Nx rats were characterized by accumulation of I-aggBSA to 4 h after injection with rapid clearance over the 4-8-h period; i.e. mesangial trafficking was increased following 4/6 Nx. Mesangial trafficking in 4/6 Nx rats treated with EN was reduced by virtue of lesser uptake of I-aggBSA at 4 h and retarded clearance over 4-8 h when compared with untreated 4/6 Nx animals. Treatment of 4/6 Nx rats with HHR maintained the increased trafficking observed in untreated 4/6 Nx rats. At 30 weeks untreated 4/6 Nx rats had severe albuminuria and glomerulosclerosis. Both indices of renal damage were significantly less in 4/6 Nx rats treated with enalapril. Treatment with HHR did not prevent albuminuria and had only limited effectiveness in preventing glomerulosclerosis. The different effects of EN and HHR on mesangial trafficking and glomerulosclerosis provide further evidence for a relationship between mesangial trafficking following partial renal ablation and subsequent development of glomerulosclerosis.     

Hemolink-induced effects on intestinal motor function and attenuation of these effects by selected agents

Hemolink, an oxidized, ring-opened raffinose-crosslinked hemoglobin-based oxygen carrier produced by Hemosol Inc., stimulates esophageal peristalsis, possibly by interference with neural NO-mediated effects. The effects of Hemolink on jejunal tone and contractions, arterial pressure and heart rate were measured in anesthetized rats, and the effect of selected agents in attenuating or reversing these effects was studied. Infusion of L-NAME was used to validate the study model; it caused an immediate increase in tone and initiated phasic contractions indicating that the model was responsive to NO-mediated effects. Hemolink administration caused effects on intestinal motor function similar to those caused by L-NAME, including increases in basal tone and contraction amplitude. Rat whole blood caused none of these changes. The Hemolink-induced effects were less immediate in some animals compared to those observed after L-NAME. As well there was greater inter-animal variability on the effects. Hemolink administration also caused a mild increase in arterial blood pressure and a reciprocal decrease in heart rate in some animals. Co-administration of morphine, a common analgesic that has been reported to influence the motility of the GI tract; L-arginine, a substrate for NO synthesis; and glycopyrrolate, an anti-cholinergic agent, did not significantly modulate the Hemolink effects, whereas nitroglycerin, an NO donor; and nifedipine, a slow calcium-channel blocker, attenuated or reversed these effects.     

Long-term effects of transduodenal sphincterotomy: symptoms and hepatobiliary function

BACKGROUND/AIMS: Endoscopic sphincterotomy is widely used in treating common bile duct stones, but the long-term effects of destroying the sphincter of Oddi are not known. This study investigated the long-term (15-20 years) effects of transduodenal sphincterotomy on gastrointestinal symptoms and hepatobiliary function in a retrospective controlled study. METHODOLOGY: Between 1974 and 1977, choledocholithotomy was performed in 131 patients either transduodenally (60 patients) or via choledochotomy (71 patients). For the retrospective part of the study, all hospital records, death certificates and autopsy reports were reviewed. Twenty-seven patients who could be reached and volunteered to participate (12 and 15, respectively) were re-examined. In the re-examination part of the study, a standard questionnaire interview, laboratory tests, quantitative cholescintigraphy and ultrasonography were performed. RESULTS: The hospital mortality for the primary operations was 0.8%, 0% for the transduodenal sphinterotomies and 2% for the choledochotomies; the difference was not significant. During the follow-up period, no significant differences could be seen in the death rate or in the causes of death between the study groups. During re-examination, flatulence was found to be more common in the choledochotomy subgroup (7/15 vs 2/12, p<0.05). In the laboratory tests, conjugated bilirubin and serum aspartate amino transferase levels were higher in the transduodenal subgroup than in the choledochotomy subgroup (3.3 umol/L, SD 0.4 vs 2.2 umol/L, SD 0.2, p<0.02; and 25 U/L, SD 12.6 vs 18.6 U/L, SD 5.0, p<0.05, respectively). Furthermore, 6/12 (50%) of the transduodenal subgroup had elevated serum alanine aminotransferase, aspartate aminotransferase or amylase levels, as compared to 1/15 (7%) in the choledochotomy subgroup (p<0.02). In terms of ultrasonography, in the choledochotomy subgroup, the common bile duct diameter was larger than 8 mm in 8/15 (53%) patients, as compared to 1/12 (8%) in the transduodenal subgroup (p<0.02). In terms of quantitative cholescintigraphy, in 9/12 (75%) patients of the transduodenal subgroup, the hilum-duodenum transit time was less than 10 minutes, as compared to 4/12 (47%) of the choledochotomy subgroup. CONCLUSIONS: Transduodenal sphincterotomy results in decreased flatulence and enhanced common bile duct drainage, even in the long-term period, but slightly higher serum liver funtion tests, when compared to supraduodenal choledochotomy.     

Long-term renal function in heart transplant recipients receiving cyclosporine therapy

BACKGROUND: Immunosuppression with cyclosporine has improved allograft function and reduced both morbidity and mortality in organ transplantation. However, cyclosporine-induced nephrotoxicity still is a concern. The purpose of our study was to evaluate the effects of cyclosporine on renal function in orthotopic heart transplant recipients. METHODS: Thirty-nine patients who received transplants from 1985 to 1991 and had at least three yearly glomerular filtration rate measurements posttransplantation by 125I-iothalamate clearance method were included in the study. In addition, serum creatinine (before and after transplantation) and cyclosporine doses were analyzed. RESULTS: Maintenance immunosuppression at 1 year consisted of prednisone (0.1 mg/kg/day), azathioprine (2 mg/kg/day), and cyclosporine (12-hour trough level 100 to 150 ng/ml by fluorescence polarization immunoassay). The mean serum creatinine at 1 year was significantly higher than the mean pretransplantation serum creatinine (1.51 +/- 0.32 versus 1.28 +/- 0.38, p < 0.05) and stabilized after the first year. The mean glomerular filtration rate by 125I-iothalamate clearance method was 70.6 +/- 20.3 ml/min/1.73 m2 (range 32 to 105) at 1 year and remained relatively stable during the follow-up period of up to 7 years. Creatinine clearance calculated by the Cockcroft and Gault formula overestimated the true glomerular filtration rate after the third year. The mean cyclosporine dosage was significantly lower after the first-year dose of 3.9 +/- 1.8 mg/kg/day (p < 0.05). Three patients in 39 started hemodialysis at 5, 7, and 10 years after transplantation. CONCLUSION: Our data indicate that the adequacy of renal function is preserved with long-term cyclosporine therapy in heart transplant recipients.     

Angiotensin-converting enzyme inhibition in experimental in-situ immune complex glomerulonephritis: influence on renal function, proteinuria, and morphology

OBJECTIVE: To identify antigen(s) among purified deglycosylated aggrecan peptides spanning the chondroitin sulphate domain that may be responsible for the initiation or perpetuation of the autoimmune responses in rheumatoid arthritis (RA). METHODS: Aggrecan was purified from human articular cartilage and deglycosylated with either bacterial glycosidases or trifluoromethanesulphonic acid (TFMS). Twelve overlapping peptides (15 residues) spanning the chondroitin sulphate domain with N-terminal residues offset by three amino acids were synthesised. T cell responses to these antigens in RA patients and age matched controls were assessed in vitro by antigen specific T cell proliferation assays. RESULTS: Enzymically deglycosylated aggrecan (EDA) stimulated proliferation of T cells isolated from the peripheral blood in a greater proportion of patients with RA than controls. In a subset (12.5%) of RA patients, the magnitude of stimulation lay outside the control range. T cell proliferative responses to TFMS treated aggrecan were greater than, but well correlated with, responses to EDA. T cells from 15 patients were also stimulated with the pooled synthetic peptides. Four of seven patients who demonstrated T cell reactivity to EDA (seven of 15) also showed enhanced T cell proliferation to synthetic peptides. CONCLUSION: These data suggest that an autoantigenic T cell epitope may lie within the chondroitin sulphate domain of aggrecan.     

Effects of antihypertensive therapy on left atrial function

OBJECTIVES: To investigate left atrial (LA) function as a reservoir, as a conduit and as a booster pump in essential hypertension (EH). LA volumes were echocardiographically measured in 28 untreated hypertensive patients and in 20 control subjects. BACKGROUND: LA makes a large contribution in left ventricular filling, especially in patients with impaired diastolic function. LA function is fundamental in left ventricular filling in hypertensive patients as hypertension results in left ventricular diastolic dysfunction. METHODS: Diagnosis of EH (blood pressure > 140/90 mm Hg) was based on three repeated readings of blood pressure (BP). Patients with myocardial infarction, cardiomyopathy, valvular or congenital heart disease were excluded. Doppler diastolic early (E) and late (A) velocity of mitral inflow were measured. The following indexes were calculated: left ventricular mass index (LVMI) using the Penn convention; left ventricular stroke volume (LVSV); LA reservoir volume (LARV = LA maximal volume at mitral valve opening minus minimal volume); LA conduit volume (LACV = LVSV-LARV). Atrial systolic function was assessed by calculating the active emptying fraction (volume at onset of atrial systole minus minimal volume/volume at onset of atrial systole, the E/A ratio and the LA ejection force (0.5 rho A2 MOA, where rho = the density of blood, MOA = mitral orifice area from the parasternal short axis view). Measurements were obtained in all hypertensive patients before and after 16 weeks administration of either enalapril (10 or 20 mg) or enalapril +/- chlorthalidone (20/25 mg) once a day. RESULTS: After 16 weeks of treatment, BP was reduced significantly (from 172/110 to 137/86 mm Hg, P < 0.001). LVMI decreased significantly as well (from 141 to 123 g/m2) although it was higher compared to controls (94 g/m2, P < 0.001). LARV decreased significantly (from 35.4 to 29.3 cm3, P < 0.05) while LACV increased significantly (from 43.8 to 51.3 cm3, P < 0.05), LA active emptying fraction and E/A ratio did not change. LA ejection force decreased significantly (from 20.9 to 18.1 kdynes, P < 0.05) but it was greater than controls (16.7 kdynes, P < 0.01). There was a positive relationship of LVMI to LARV (P < 0.01) in controls (r = 0.77) which held true in hypertensive patients, before (r = 0.72) and after treatment (r = 0.69). There was a negative relationship of LVMI to LACV (P < 0.01) in controls (r = -0.65), and in hypertensive patients untreated (r = -0.74) and after treatment (r = -0.72). CONCLUSIONS: Our results showed that in hypertensive patients, LA reservoir function increases and LA conduit function decreases, while LA ejection force increases. Antihypertensive treatment with enalapril and/or thiazide, induces normalisation of the LA function in parallel to left ventricular hypertrophy regression.     

Twenty-four-hour ambulatory blood pressure evaluation of antihypertensive agents

EVALUATION OF A SMOOTH BLOOD PRESSURE RESPONSE TO TREATMENT: Smooth or uniform blood pressure control is an obvious goal of antihypertensive therapy, but it is difficult to assess by the traditional clinic blood pressure measurements. Ambulatory blood pressure monitoring is therefore increasingly being used to evaluate new antihypertensive drugs and to assess the adequacy of treatment. The use of ambulatory blood pressure monitoring is based on two assumptions: that treatment must be continuously optimal, and that more frequent blood pressure measurements during treatment, particularly at different times and during various types of activity and mental states, may lead to a more accurate assessment than infrequent measurements in the clinic. When ambulatory blood pressure monitoring is used, the effect of a given antihypertensive agent or of a given antihypertensive regimen can be tested on the average blood pressure values over 24 h, or on day- or night-time values. The actual verification of the achievement of a uniform reduction of blood pressure throughout the 24-h time span can be achieved by comparing 24-h blood pressure profiles before treatment and during treatment. The so-called trough: peak ratio is generally used in an attempt at a more quantitative assessment of smooth control. Recently, we have developed the Smoothness Index, defined as the ratio between the mean hourly change in blood pressure (calculated over the 24-h period), divided by the standard deviation of these hourly changes. We have some indication that this may be a more accurate measurement of smooth blood pressure control under therapy than trough: peak ratios. TWENTY-FOUR-HOUR BLOOD PRESSURE CONTROL BY IRBESARTAN: Ambulatory blood pressure assessments are important during the clinical testing of new antihypertensive agents. Our group recently performed a multicenter study to compare the anti-hypertensive effect of three irbesartan dose regimens (75 mg once a day, 150 mg once a day, 75 mg twice a day) and placebo as measured by 24-h ambulatory blood pressure monitoring and confirmed by office blood pressure measurements. All irbesartan regimens were significantly more effective than placebo. Irbesartan at 150 mg once a day provided clinically significant and sustained blood pressure reductions over a full 24 h and had the highest trough: peak ratio and Smoothness Index. No additional benefit was observed with twice-daily dosing using irbesartan at 75 mg compared with a single daily at 150 mg. Therefore irbesartan at a single daily dose of 150 mg offers real efficacy with the potential for greater ease of administration compared with twice-daily antihypertensive therapy.     

Sex- and age-related antihypertensive effects of amlodipine

PURPOSE: To report a case of retinopathy associated with chronic occupational exposure to ethyl-m-aminobenzoic acid methanesulfonate (MS-222), a retinotoxic fish anesthetic. METHOD: Case report with electroretinograms to document changes in visual electrophysiology. RESULTS: An ichthyologist with a long history of skin exposure to MS-222 was initially examined for decreased vision, photophobia, and photopsia. His electroretinogram abnormalities were similar to those seen in animal models of acute MS-222 toxicity. After terminating MS-222 contact for 7 months, his vision returned to normal, and his electroretinogram improved. CONCLUSION: Individuals with occupational exposure to MS-222 should exercise caution to avoid systemic absorption of this retinotoxic compound.     

Modern antihypertensive treatment and the progression of renal disease

BACKGROUND: In animal models of hypertension, the resistance state of the preglomerular (afferent) and postglomerular (efferent) capillary arterioles may determine whether a particular form of antihypertensive therapy will spare the kidney from hemodynamic-mediated glomerular injury. In experimental models of renal disease with impaired autoregulation, control of systemic blood pressure is a prerequisite for normalizing glomerular capillary hydraulic pressure. CLINICAL STUDIES: In humans, effective blood pressure control reverses renal hemodynamic abnormalities in hypertensive patients, reduces microalbuminuria in essential hypertensive, nondiabetic, and diabetic renal diseases, and attenuates but does not prevent the progression of nondiabetic and diabetic renal disease. Although some researchers have concluded that angiotensin converting enzyme inhibitors are the renal protective drugs of choice, these pronouncements are not based on clinical trials correlating specific drug-mediated changes in albumin or protein excretion with the longitudinal assessment of glomerular filtration rate (GFR), permitting derivation of a slope-defining change in GFR, and/or the longitudinal assessment of renal structure (i.e. renal biopsy). Definitive clinical trials have not been reported. It is important to recognize that an elevated serum creatinine is a powerful predictor of mortality and that, in most patients, death is caused by a cardiovascular or cerebrovascular event, rather than by renal failure. CONCLUSION: Because morbidity and mortality of essential hypertension and nondiabetic or diabetic renal disease is related primarily to cardiovascular or cerebrovascular events, the antihypertensive 'drugs of choice' should be those that reduce these risks, prevent or regress target-organ damage, and optimize treatment of concomitant diseases.     

Comparison between the effects of amlodipine and lisinopril on proteinuria in nondiabetic renal failure: a double-blind, randomized prospective study

Double-blind, randomized controlled studies of longer than 1 week in duration comparing the antiproteinuric potential of long-acting dihydropyridine calcium channel blockers with that of angiotensin converting enzyme (ACE) inhibitors are lacking. Therefore, we performed such a study in patients with nondiabetic renal disease and proteinuria. After a 4-week wash-out period in which patients did not use any medication known to affect proteinuria, 21 patients were randomized in a double-blind fashion to receive either the calcium channel blocker amlodipine (Amlo, 5 to 10 mg) or the ACE-inhibitor lisinopril (Lis, 5 to 10 mg). Throughout the 16-week study period, blood pressure, creatinine clearances, and proteinuria were measured every 2 weeks. In addition, device-measured blood pressure and renal hemodynamic studies were performed at the start and end of the study. Systolic blood pressure fell in the Lis group from 163+/-7 (SEM) to 140+/-8 mm Hg (P < .01) and from 157+/-10 to 147+/-6 mm Hg in the Amlo group; diastolic blood pressure fell from 101+/-3 to 86+/-7 mm Hg in the Lis group and from 98+/-3 to 91+/-2 mm Hg in the Amlo group. Renal hemodynamics were not affected by amlodipine treatment, whereas a fall in glomerular filtration rate (GFR) was seen in lisinopril-treated patients (from 55+/-11 to 50+/-10 mL/min; P < .01). Amlodipine did not significantly affect proteinuria. Lisinopril induced a decline in the protein-creatinine ratio with a maximal effect reached after 12 to 16 weeks of therapy (from 0.39+/-0.17 to 0.26 +/-0.11 g/mmol; P < .009). In conclusion, we could not demonstrate an antiproteinuric effect of the long-acting dihydropyridine calcium channel blocker amlodipine, whereas therapy with the ACE-inhibitor lisinopril resulted in a decrease in proteinuria. Amlodipine did not affect renal hemodynamics, whereas lisinopril induced a fall in GFR.     

The effects of large volume intravenous fluid infusion on neonatal renal function

Twenty healthy infants weighing less than 2,000 gm were studied at low (3.6 ml/kg/hr) or high (10.3 ml/kg/hr) rates of intravenous infusion. Inulin clearance determined by the constant infusion method was greater at the high rate of infusion (p = less than 0.05). Inulin clearance in two groups of infants over 2,000 gm studies at the same low or high rates of infusion did not increase at the higher rate of infusion. Since the GFR in infants less than 2,000 gm depends partially on the rate of intravenous infusion, small, healthy preterm infants may benefit from a rate of fluid administration greater than the low rate. When studies at low and high rates of infusion were compared in the 20 infants less than 2,000 gm, the fractional urinary sodium excretion increased with the increased fluid load. Delivery of fluid from the proximal tubule (CH2O =Na per dl GFR) increased (p less than 0.005). Free-water clearance and the absolute volume of urine increased at the high rate of infusion. These data indicate that the healthy preterm infant less than 2,000 gm, like the adult, compensates by increasing free-water clearance and urine volume when challenged with a large fluid load. Although fluid changes of short duration are appropriately handled, the effect of continuous rapid infusion on water and sodium balance in infants of this size remains to be determined.     

Repeated low-flow sevoflurane anesthesia: effects on hepatic and renal function in beagles

We studied the effects of repeated low-flow sevoflurane anesthesia for 6 hours. Five beagle dogs received 1.3 MAC (3%) sevoflurane anesthesia. Anesthesia of 6 hours was repeated on at the 7th day after the first anesthesia. Compound A gas samples were collected from the inspiratory limb during anesthesia. Concentrations of serum and renal fluoride, hepatic and renal function parameters were measured during and up to 7 days after the first and second anesthesia. The peak concentration of compound A was 23.7 +/- 3.6 ppm at 2 hours and the same level remained during the anesthesia. Plasma fluoride level exceeded 50 mmol.l-1 during anesthesia and rapidly decreased to the preanesthesia level thereafter. Serum GOT increased slightly only on the first postanesthesia day. No significant changes in other blood chemistry studies were observed. The excretion of renal tubular enzymes did not increase during and after anesthesia. Repeated low flow sevoflurane anesthesia in beagles did not affect hepatic and renal function significantly.