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Biomedical subjects

G L Bakris

Publications and source records attributed to G L Bakris.

At least 19 recordsLinked to original sources
PubMed1992

Risk for renal injury in diabetic hypertensive patients. The physiologic basis for blood pressure control.

In determining a therapeutic approach to coexistent adult-onset (type II) diabetes and hypertension in patients who are middle-aged, special attention must be given to the pathophysiology of the hypertensive disease and how it affects the kidneys. Diabetes and hypertension potentiate renal damage, which clearly leads to a reduced life span and increased morbidity. Nonpharmacologic measures (eg, exercise, weight control, glycemic control, protein-restricted diet) and pharmacologic approaches need to be combined so as to control systemic blood pressure yet maintain adequate renal perfusion. Clearly, preexisting accentuated vascular reactivity to vasoconstrictive growth factors in diabetic patients stimulates maladaptive compensatory responses in the kidney. This precipitates greater renal injury superimposed on the relative risk of the hypertension-diabetes combination itself.

Diabetes Mellitus, Type 2↗
PubMed1992

Risk for renal injury in diabetic hypertensive patients. Pharmacologic approaches.

In the first article of this pair (page 77), Drs Weir and Bakris discussed a physiologic approach to management of diabetic hypertensive patients. In this article, they discuss the latest findings regarding use of angiotensin-converting enzyme inhibitors and calcium channel blockers along with glycemic control and reduced protein intake.

Antihypertensive Agents↗
PubMed1992

Treatment of arterial hypertension in diabetic humans: importance of therapeutic selection.

This study was undertaken to test the hypothesis that, given equal arterial pressure reductions, the combination of an angiotensin converting enzyme (ACE) inhibitor and calcium antagonist slows declines in renal function and yields greater reductions in albuminuria over either agent alone. This hypothesis was evaluated in four groups of hypertensive, non-insulin dependent, diabetic subjects with renal insufficiency (N = 30). Renal hemodynamics, albuminuria and metabolic parameters were evaluated for a period of one year. Subjects were all placed on a 90 mEq sodium, 0.8 g/kg protein, 1500 calorie American Diabetes Association diet for the entire length of the study. Subjects were followed for two weeks off antihypertensive medications and were subsequently randomized to either lisinopril, alone (group I), sustained release verapamil, alone (group II), reduced doses of both lisinopril and sustained release verapamil (group III), and hydrochlorothiazide with guanfacine (group IV). At the end of one year group III had the greatest reduction in albuminuria (78 +/- 7%, group III vs. 59% +/- 4, group I: P less than 0.05). In addition, the decline in glomerular filtration rate (GFR) was the lowest in this group (0.28 +/- 0.07, group III vs. 0.69 +/- 0.12, group I; P less than 0.05) although there was no significant difference between groups II and IV. The highest side effect profiles were noted in group IV, the least in group III. The greatest reductions in renal hemodynamics occurred in all groups within the first month; however, striking differences between groups were noted (7.4 +/- 2%, group I vs. 1.4 +/- 2%, group III; P less than 0.05). We conclude that the combination of reduced doses of an ACE inhibitor and calcium antagonist attenuate both albuminuria and the rate of decline in glomerular filtration rate. Furthermore, the combination of these classes of agents appear to yield the lowest side effect profile over either agent alone. Lastly, high doses of ACE inhibition alone may be detrimental to renal function in late stage diabetics with renal insufficiency.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

The use of antisense oligonucleotides to establish autocrine angiotensin growth effects in human neuroblastoma and mesangial cells.

Local renin-angiotensin systems (RAS) exist in many cell types, and angiotensin II (AII) has growth regulatory effects in some tissues. We demonstrated the presence of angiotensinogen (ANG) mRNA in cultured human mesangial cells (MC) and SHSY-5Y human neuroblastoma cells using reverse transcription and the polymerase chain reaction (RT/PCR) followed by hybridization to a human ANG-specific oligonucleotide probe. We speculated, therefore, that AII might act in an autocrine or paracrine fashion to regulate the growth of mesangial cells and neuroblastoma cells. Sense and antisense oligonucleotides were next synthesized complementary to the ANG transcription start site. Antisense but not sense oligonucleotides decreased [3H]thymidine incorporation into DNA by both MC and neuroblastoma cells. Growth of antisense oligonucleotide-treated cells was restored to control levels by the addition of AII but not by the addition of basic fibroblast growth factor. Neither oligonucleotide affected [3H]thymidine incorporation in mouse L929 cells. These data indicate that locally produced AII can act in an autocrine or paracrine fashion to alter the growth of human mesangial and neuroblastoma cells. Therefore, they suggest a role for local RAS in the pathogenesis of growth abnormalities in the cardiovascular system as well as in some forms of malignancy.

Angiotensin II↗
PubMed1991

Renal effects of calcium antagonists in diabetes mellitus. An overview of studies in animal models and in humans.

A number of studies based on animal models of both diabetes and renal insufficiency have shown that adequately reducing blood pressure attenuates the progression of glomerulosclerosis and decreases urinary protein excretion. Furthermore, compared with conventional antihypertensive therapy, angiotensin converting enzyme (ACE) inhibitors show a greater benefit in reducing these parameters. Nineteen published animal studies have investigated the effects of calcium antagonists on renal hemodynamics and glomerulosclerosis, but only three of them have evaluated the use of calcium antagonists with models of diabetes. Of six micropuncture studies based on a 1 5/6 nephrectomy model of renal insufficiency, five demonstrated reduced efferent arteriolar resistance, two showed reduced glomerular capillary pressure (PGC), and two showed significantly reduced proteinuria and glomerulosclerosis. Studies using nifedipine with both the unilaterally nephrectomized DOCA salt rat model and the 1 5/6 nephrectomy model demonstrated reduced proteinuria and glomerulosclerosis that was independent of reduced PGC. Two separate micropuncture studies of the spontaneously hypertensive rat model also found reduced efferent arteriolar resistance and PGC as well as proteinuria. Finally, studies of Dahl "salt-sensitive" rats showed an early decrease in glomerulosclerosis without a significant change in either proteinuria or glomerulosclerosis after five weeks. The results of eleven clinical studies of diabetic patients have been published; they showed divergent effects of calcium antagonists on renal function and urinary protein excretion. In the various animal models, the divergent renal hemodynamic and histologic effects reported for calcium antagonists may be largely due to the equality of blood pressure reduction, the varied baseline hemodynamic profiles, and the divergent status of the renin-angiotensin system.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Arginine vasopressin stimulates human mesangial cell production of endothelin.

Endothelin (ET) is a vasoactive peptide produced by both endothelial epithelial cells with documented mitogenic action on mesangial cells. The present studies were designed to test the hypothesis that ET is also produced by human mesangial cells (HMC) and that other mitogens such as arginine vasopressin (AVP) and insulin stimulate cellular proliferation, in part, through modulation of endogenous production of this peptide. Studies were conducted on cultured normal HMC between the third and seventh passages. All mitogenesis experiments were carried out in 96-well plates and assessed by tritiated thymidine incorporation into DNA under various concentrations of AVP in the presence and absence of insulin, antiendothelin antisera (ETAS), a MAb against ET-1 (AbET), and a vasopressin-1 receptor antagonist. ET concentrations were measured daily from conditioned medium by a sensitive and specific RIA. ET was present in all concentrations of FCS as well as conditioned medium compared with medium alone. AVP (10(-6) M) in the presence of insulin increased ET production by quiescent HMC by 261% as well as cellular proliferation by 440% after 48 h incubation. In addition, cells cultured with ETAS or AbET demonstrated a blunted mitogenic response to AVP, a response not observed in cells cultured with ETAS where ET was added. Insulin significantly potentiated the mitogenic effects of AVP as well as media levels of ET, an effect significantly blunted by AbET. We conclude that ET is produced by HMC and its production is affected, in part, by both AVP and insulin. ET may thus serve to modulate the mitogenic effects of AVP on human mesangial cells.

Arginine Vasopressin↗
PubMed1991

The effects of calcium antagonists on renal hemodynamics, urinary protein excretion, and glomerular morphology in diabetic states.

Numerous animal studies have been performed in the early stages of diabetic renal disease documenting beneficial effects of angiotensin converting enzyme inhibitors. Over the past 5 yr, a number of animal and human studies show similar results with certain calcium antagonists. However, the data with calcium antagonists are not as consistent as that with angiotensin converting enzyme inhibitors. This article will review all of the pertinent clinical and laboratory studies involving these classes of agents in the course of diabetic nephropathy. Emphasis is placed on explaining divergent results between animal and human studies with regard to renal hemodynamic, histologic, and antiproteinic effects.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

A perspective on converting enzyme inhibitors and calcium channel antagonists in diabetic renal disease.

Hypertension and renal disease are major causes of morbidity and mortality in the diabetic population, with the presence of microalbuminuria established as a predictor of excess mortality. Numerous attempts, both pharmacologic and nonpharmacologic, have been made to intervene in the disease process. Experimental and clinical evidence suggests that the converting enzyme inhibitors and, more recently, certain calcium antagonists have beneficial effects on renal function above and beyond those simply due to blood pressure control. These effects are likely attributable to favorable systemic and renal hemodynamic changes as well as to direct cellular effects. However, intervention with these agents in various rat models of diabetes or hypertension is initiated very early. Hence, some of the beneficial renal effects may not be as dramatic in clinical practice because of the more commonly advanced stage seen at the time of intervention. We present an overview of the histologic, renal hemodynamic, and antiproteinuric effects of these agents in the experimental setting, as well as the clinical evidence supporting the use of angiotensin-converting enzyme inhibitors and certain classes of calcium antagonists in diabetic renal disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Effects of theophylline on erythropoietin production in normal subjects and in patients with erythrocytosis after renal transplantation.

BACKGROUND: Erythrocytosis occurs in 10 to 15 percent of renal-transplant recipients, and there is in vitro evidence that the production of erythropoietin is modulated by adenosine. METHODS: We prospectively evaluated the effects of theophylline, a nonselective adenosine antagonist, in eight patients with erythrocytosis after renal transplantation and in five normal controls. RESULTS: After an eight-week course of theophylline treatment, the mean (+/- SEM) serum erythropoietin levels were significantly reduced in both the renal-transplant recipients (from 60 +/- 14 units per liter at base line to 9 +/- 7 units after treatment; P less than 0.05) and the normal subjects (from 6.9 +/- 0.8 units per liter at base line to 4.7 +/- 0.5 units per liter after treatment; P less than 0.05). Similarly, the hematocrits were reduced in both the transplant recipients (from 0.58 +/- 0.04 at base line to 0.46 +/- 0.03 after treatment; P less than 0.05) and the normal subjects (from 0.43 +/- 0.01 at base line to 0.39 +/- 0.01; P less than 0.05). In the renal-transplant recipients, red-cell mass was also reduced after eight weeks of theophylline (from 3197 +/- 82 ml at base line to 2273 +/- 69 ml after treatment; P less than 0.05). The previous requirement of weekly phlebotomy was eliminated in all recipients. Plasma and urinary cyclic AMP levels were not increased. These effects were reproducible when the subjects were rechallenged with theophylline after a recovery period. CONCLUSIONS: Theophylline attenuates the production of erythropoietin in both normal subjects and patients with erythrocytosis after renal transplantation and may be useful in the treatment of the latter condition.

Adult↗
PubMed1990

The effects of enalapril on urinary protein excretion in patients with idiopathic membranous nephropathy.

High doses of the angiotensin converting enzyme inhibitor, captopril, is known to cause significant increases in urinary protein excretion in patients with idiopathic membranous nephropathy. To find whether other angiotensin converting enzyme inhibitors yield similar results, we prospectively examined the effect of enalapril in five consecutive patients with idiopathic membranous nephropathy, elevated arterial pressure, and proteinuria and compared them to age-matched controls receiving clonidine. Glomerular filtration rate, 24-hour urinary protein excretion, and arterial pressure were measured. All patients served as their own controls. Those who received enalapril demonstrated an initial increase in proteinuria (-0.3 +/- 0.7 delta gm/day, clonidine vs 3.9 +/- 0.9 delta gm/day, enalapril: P less than .05) despite similar decreases in arterial pressure (-18 +/- 6 delta mm Hg, clonidine vs -22 +/- 6 delta mm Hg, enalapril: NS) and glomerular filtration rate (-1.1 +/- 0.8 delta mL/min, clonidine vs -1.9 +/- 1.2 delta mL/min, enalapril: NS) when compared to the clonidine group. This increase in proteinuria, however, did not occur when these patients were rechallenged with enalapril. To our knowledge, this is the first report to document a significant increase in preexisting nephrotic range proteinuria following administration of nonsulfhydryl ACE inhibitor. This increase, however, appears to be unique to the initial treatment phase of the disease and does not affect long-term management.

Adult↗
PubMed1990

Acute interstitial nephritis with glomerulopathy due to nonsteroidal anti-inflammatory agents: a review of its clinical spectrum and effects of steroid therapy.

We reviewed case reports of patients who developed acute renal failure and/or nephrotic range proteinuria in the course of receiving treatment with nonsteroidal anti-inflammatory agents (NSAIA). Those cases that contained information sufficient to confirm the diagnosis of acute interstitial nephritis with glomerulopathy (AING), including a suggestive clinical syndrome with appropriate renal biopsy findings, were further analyzed to achieve a more complete description of this clinical entity and its responsiveness to steroid treatment. Analysis of the cases that fulfilled the inclusion criteria confirmed that the disorder is twice as common in women and occurs mainly in elderly people, usually after long-term use of NSAIAs for musculoskeletal problems. Fenoprofen was implicated in 47% of the cases. Evidence of systemic hypersensitivity was uncommon. Two thirds of the cases displayed clinical and/or histological evidence of both acute interstitial nephritis and increased glomerular permeability. These findings strongly suggest that this condition is distinct from other drug-induced "allergic" acute interstitial nephritides. In the absence of complicating factors, all patients improved following discontinuation of the offending agents. No evidence was found to suggest that steroid therapy altered the clinical course of this process.

Age Factors↗
PubMed1990

Oxygen free radical involvement in urinary Tamm-Horsfall protein excretion after intrarenal injection of contrast medium.

To discover whether the increase in urinary excretion of Tamm-Horsfall protein (THP) is mediated by oxygen free radicals generated after injection of contrast medium, the authors tested the hypothesis that inhibition of oxygen free radical production after injection of sodium methylglucamine diatrizoate or iothalamate sodium diminishes urinary THP excretion. In three groups of dogs, kidneys received continuous infusions of either superoxide dismutase (SOD) and normal saline (six dogs), heat-inactivated SOD and normal saline (six dogs), or normal saline alone (four dogs). Urinary THP excretion, glomerular filtration rate, renal blood flow, mean arterial pressure, and renal venous malondialdehyde concentrations were measured before and after administration of contrast medium to each kidney. During the postcontrast period, SOD significantly attenuated the increase in urinary THP excretion, accompanied by an attenuated increase in renal venous malondialdehyde concentration. Heat-inactivated SOD did not attenuate renal hemodynamics or urinary THP excretion. The use of another contrast medium, iothalamate sodium, similarly increased urinary THP excretion. These results show that intrarenal administration of contrast medium induces a transient increase in urinary THP mediated in part by oxygen free radical damage to the kidney. Thus, THP may be a marker of renal tubular injury after injection of contrast medium.

Animals↗
PubMed1990

Radiocontrast medium-induced declines in renal function: a role for oxygen free radicals.

Intrarenal injection of radiocontrast medium (RCM) results in transient vasoconstriction and a persistent decline in glomerular filtration rate (GFR). Adenosine modulates this vasoconstrictor response and is postulated to increase oxygen free radical (OFR) generation. We hypothesized that the persistent decline in (GFR that follows RCM administration results in an increased generation of OFR. We evaluated the effects of RCM injection on renal blood flow, inulin clearance, hypoxanthine, xanthine, and malondialdehyde concentrations in four groups of non-volume-expanded, pentobarbital sodium anesthetized dogs in the presence and absence of intravenous allopurinol, 25 mg/min (group 1), intrarenal superoxide dismutase (SOD), 400 U/min (group 2), heat-inactivated intrarenal SOD, 400 U/min (group 3), and simultaneous infusions of intrarenal SOD, 400 U/min, to one kidney and saline to the other (group 4). Both allopurinol and SOD significantly attenuated the fall in GFR after RCM administration over control. Malondialdehyde concentrations were attenuated over control in all treated groups, indicating a decrease in OFR generation. We conclude that intrarenal injection of RCM results in increased production of OFR. Inhibition of OFR production by allopurinol and increased OFR removal by SOD attenuates the effects of RCM on declines in GFR.

Allopurinol↗
PubMed1989

The evolution of antihypertensive therapy: an overview of four decades of experience.

Hypertension is a major public health problem amendable to treatment. Numerous large scale clinical trials have demonstrated that effective, sustained control of elevated arterial pressure to a level below 140/90 mm Hg results in reduced cardiovascular morbidity and mortality. Over the past 4 decades antihypertensive drug therapy has evolved from a stepwise, but physiologically rational, selection of agents to specific programs tailored to individualized therapy for specific clinical situations. This evolution has taken place because of a greater understanding of the pathophysiology of hypertensive diseases, the development of new classes of antihypertensive agents that attack specific pressor mechanisms, and the ability to wed these concepts into a rational and specific therapeutic program. Thus, with the currently available spectrum of antihypertensive therapy, we are now able to select treatment for special patient populations utilizing a single agent and, therefore, we can protect the heart, brain and kidneys and maintain organ function without exacerbating associated diseases. These benefits are clear-cut and have resulted in many millions of patients becoming the beneficiaries of this transfer of careful, painstaking and purposeful investigative experiences into clinical practice.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Renal dysfunction resulting from NSAIDs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a common cause of acute renal failure. The clinical presentation differs from that of interstitial nephritis due to antibiotic use: proteinuria is much more common in NSAID-induced nephritis, while eosinophilia, eosinophiluria, fever and rash are more common in antibiotic-related nephritis. Tubulointerstitial disease associated with NSAID use is more common in women than in men and is more frequently seen in the elderly. Because no prospective study of treatment for NSAID-induced acute tubulointerstitial nephritis has been performed, the efficacy of steroid therapy remains uncertain.

Anti-Bacterial Agents↗
PubMed1988

Comparison of the effects of dopamine and fenoldopam, a selective dopamine-1 agonist, on parathyroid hormone release in man.

Dopamine has been reported to transiently increase parathyroid hormone (PTH) secretion in man; however, the mechanism is unclear. To test the hypothesis that selective dopamine-1 receptor (DA1) stimulation increases PTH secretion, we compared the effects of fenoldopam, a novel selective DA1 receptor agonist, as well as dopamine on serum PTH secretion and total serum calcium concentration in seven normal human subjects. Dopamine was infused at 1 and 3 micrograms/kg/min, each for 10 minutes, and 5 micrograms/kg/min for 25 min. Fenoldopam was infused at 0.1 and 0.3 micrograms/kg/min, each for 10 min. and thereafter at 0.5 micrograms/kg/min for 25 min. The infusions were given at least 1 week apart. Blood samples for PTH, calcium and dopamine or fenoldopam concentrations were drawn prior to and at the 25th minute of each drug infusion. PTH concentrations increased in all subjects at the 25th minute of dopamine but not fenoldopam infusion. Serum calcium was not significantly affected. The plasma concentrations of both dopamine (83.6 +/- 7.1 ng/ml) and fenoldopam (13.0 +/- 3.4 ng/ml) were in the range known to cause equivalent DA1 receptor stimulation. Since dopamine but not fenoldopam increased PTH secretion in man, we conclude that selective DA1 receptor stimulation alone does not increase PTH release and the effects of dopamine must be mediated through some other mechanism.

Adolescent↗