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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
PubMed1995

Hypertension in diabetic patients: an update of interventional studies to preserve renal function.

Hypertension and diabetes mellitus are a malignant combination of diseases for the kidney. They markedly increase the risk for progressive renal injury and are the largest single cause of renal failure. Strategies to reduce the risk for renal injury in hypertensive diabetics are very important. Although Type I and Type II diabetes are different diseases, they may be associated with similar mechanisms of renal injury in hypertensive patients. Reduction of elevated systemic arterial pressure is of proven benefit in limiting progressive renal injury in diabetic hypertensives. However, converting enzyme inhibitors and possibly the nondihydropyridine calcium antagonists may possess antiproteinuric abilities independent of blood pressure reduction which, in addition to their antihypertensive effects, may be important in limiting the progression of human diabetic renal disease. Long-term clinical trials have evaluated the impact of these and other agents on progression of diabetic renal disease. This paper reviews these trials and focuses on renal effects of antihypertensive agents independent of blood pressure reduction.

Animals↗
PubMed1995

Renal effects of oral prostaglandin supplementation after ibuprofen in diabetic subjects: a double-blind, placebo-controlled, multicenter trial.

Prostaglandins of the E series (PGE) are known to contribute to the maintenance of renal hemodynamics in subjects with chronic renal insufficiency. Agents that block PGE synthesis, nonsteroidal anti-inflammatory agents (NSAID), are widely used by people with renal insufficiency. This study was undertaken in subjects with renal insufficiency secondary to diabetes to evaluate the acute effects of a PGE1 analog, misoprostol, on NSAID-induced changes in RBF, as calculated by para-aminohippurate clearance, and GFR, as calculated by inulin clearance. Sodium excretion was also assessed. Twenty-five fasting subjects with a mean age of 56 +/- 4 yr received 800 mg of ibuprofen orally. A concomitant dose of either a placebo (PL) or 200 micrograms of misoprostol was also given. This was followed in 1 h by either a placebo or an additional 200-micrograms dose of misoprostol. Measurements for the determination of RBF, GFR, blood pressure, and fractional excretion of sodium were performed every 30 min for the next 5 h. The greatest reduction in both GFR (-25 +/- 7 mL/min per 1.73 m2 PL versus -10 +/- 4 mL/min per 1.73 m2, misoprostol delta GFR; P < 0.05) and RBF (-48 +/- 21 mL/min per 1.73 m2 PL versus -15 +/- 8 mL/min per 1.73 m2, M delta RBF; P < 0.05) occurred approximately 2 h after the NSAID dose. No significant differences were noted in blood pressure, fractional excretion of sodium, or other measured parameters between groups during the entire study. Gastrointestinal upset was the most common side effect observed in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

ACE inhibitor-mediated attenuation of mesangial cell growth. A role for endothelin.

Endothelin modulates human mesangial cell (HMC) proliferation in response to angiotensin II (Ang II). Angiotensin converting enzyme inhibitors (ACEIs) have variable effects on HMC growth depending on culture conditions. No studies, however, have investigated the effects of ACEIs on HMC production of endothelin-1 in either actively proliferating or quiescent HMCs. The present study was designed to evaluate the effects of ACEIs on HMC-associated mitogenesis, cell counts, and endothelin-1 production in the presence and absence of insulin in both quiescent and proliferating HMCs. It tests the hypothesis that ACEIs attenuate HMC growth through a reduction in HMC-associated endothelin-1 generation. The effects of four different ACEIs, an Ang II receptor antagonist, losartan, and a monoclonal antibody to endothelin-1 were evaluated. ACEIs inhibited HMC mitogenesis and cell counts in proliferative but not quiescent cells. This was due to the absence of ACE activity in HMCs and its presence in 10% fetal calf serum. Both ACEIs and losartan reduced endothelin-1 production per cell. Compared to vehicle, losartan reduced the amount of endothelin-1 in conditioned media to a greater extent than any ACEI (2.2 +/- 0.3, captopril v 1.9 +/- 0.5, quinaprilat v 3.8 +/- 0.3 delta pg/cell x 10(-3) endothelin-1, losartan; P < .05). Moreover, insulin potentiated the antimitogenic effects of both ACEIs and losartan on HMCs. Lastly, the attenuated increase of endothelin-1 in conditioned media and associated antimitogenic effect on HMCs with losartan alone was not potentiated by the addition of any ACEI to losartan. These data provide indirect evidence that Ang II production may occur in culture media when both its precursors and a sufficient amount of converting enzyme activity are present. This is predicated on the observation that HMCs lack ACE activity and that ACEIs blunt mitogenesis of proliferating HMCs. The kinetics of this reaction, as well as the mechanism of how insulin potentiates the antimitogenic effects of ACEIs, were not studied.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Microalbuminuria and progressive renal disease.

Microalbuminuria is a predictor of excess cardiovascular morbidity and mortality in both hypertensive and diabetic subjects. The reasons for this are multifactorial and relate to metabolic and haemodynamic problems seen in this population. In diabetic patients, microalbuminuria correlates more with glycosylated haemoglobin than with the duration of diabetes. The pathogensis of microalbuminuria includes alterations in glomerular shunting of albumin, increased intraglomerular pressure and increased amounts of certain growth factors that alter cell permeability. The urine Micral test is an easy way to screen for the presence of microalbuminuria. The increase in microalbuminuria over time can be documented by annual quantitation using a radioimmunoassay technology. Aggressive control of BP is vitally important in order to preserve renal function. Antihypertensive agents that lower both intraglomerular pressure and volume are preferable, since they consistently attenuate both the increase in microalbuminuria and structural changes within the glomerulus. In addition to BP control, other measures known to reduce the rise in microalbuminuria include a reduced dietary protein intake and good long-term blood glucose control. Unfortunately, there is no definitive study, in humans, that conclusively demonstrates a preservation of renal function directly relates to an attenuated rise in microalbuminuria. Thus, while microalbuminuria is clearly a risk factor for development of diabetic nephropathy and an indicator of hypertensive renal disease, its reduction has not demonstrated functional or structural benefit in humans. This is in large part due to the inpracticality of such a trial because of the duration needed to see an effect. Interestingly, a beneficial effect on renal survival has been shown with albuminuria reduction independent of BP reduction.

Albuminuria↗
PubMed1994

Renal adaptation to the failing heart. Understanding the cascade of responses.

Progressive systolic dysfunction of the heart results in a broad array of physiologic compensatory mechanisms within the kidney. These mechanisms are primarily stimulated by diminution of the effective arterial blood volume and resultant activation of a biochemical cascade of neurohormonal responses, including activation of the renin-angiotensin-aldosterone system and enhanced release of norepinephrine, arginine vasopressin, prostaglandins, endothelin, and atrial natriuretic peptide. The interaction of these neurohormonal systems within the kidney is complex. Vasoconstriction induced by angiotensin II, arginine vasopressin, and catecholamines may decrease renal perfusion by both endocrine and neural actions. In contrast, systemic pressures may rise, which may facilitate perfusion.

Adaptation, Physiological↗
PubMed1994

Renal adaptation to the failing heart. Avoiding a 'therapeutic misadventure'.

Systolic dysfunction of the heart represents a state of "prerenal" azotemia, in which the excess of total body salt and water is redistributed to venous and interstitial fluid compartments. This results in a diminished effective circulating blood volume and thereby decreases tissue perfusion. The kidneys perceive the ineffective circulating volume and employ a complex series of interconnected hemodynamic and neurohumoral effector mechanisms to restore "adequate" perfusion. This is done by reclaiming a greater fraction of filtered sodium and water and elevating systemic vascular resistance to keep perfusion pressure to vital organs constant despite diminished cardiac output. Knowledge of the physiologic compensatory responses that occur in the kidneys of heart failure patients allows clinicians to develop a logical treatment plan. This knowledge should also help avoid a therapeutic misadventure by making it possible to exclude drugs known to adversely affect renal function in patients with a failing heart and poorly compensating kidneys.

Adaptation, Physiological↗
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↗