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Biomedical subjects

G L Bakris

Publications and source records attributed to G L Bakris.

At least 37 records · Page 2Linked to original sources
PubMed2000

ACE inhibition or angiotensin receptor blockade: impact on potassium in renal failure. VAL-K Study Group.

BACKGROUND: Inhibition of the renin-angiotensin system is known to raise serum potassium [K(+)] levels in patients with renal insufficiency or diabetes. No study has evaluated the comparative effects of an angiotensin-converting enzyme (ACE) inhibitor versus an angiotensin receptor blocker (ARB) on the changes in serum [K(+)] in people with renal insufficiency. METHODS: The study was a multicenter, randomized, double crossover design, with each period lasting one month. A total of 35 people (21 males and 14 females, 19 African Americans and 16 Caucasian) participated, with the mean age being 56 +/- 2 years. Mean baseline serum [K(+)] was 4.4 +/- 0.1 mEq/L. The glomerular filtration rate (GFR) was 65 +/- 5 mL/min/1.73 m(2), and blood pressure was 150 +/- 2/88 +/- 1 mm Hg. The main outcome measure was the difference from baseline in the level of serum [K+], plasma aldosterone, and GFR following the initial and crossover periods. RESULTS: For the total group, serum [K(+)] changes were not significantly different between the lisinopril or valsartan treatments. The subgroup with GFR values of < or = 60 mL/min/1.73 m(2) who received lisinopril demonstrated significant increases in serum [K(+)] of 0.28 mEq/L above the mean baseline of 4.6 mEq/L (P = 0.04). This increase in serum [K(+)] was also accompanied by a decrease in plasma aldosterone (P = 0.003). Relative to the total group, the change in serum [K(+)] from baseline to post-treatment in the lisinopril group was higher among those with GFR values of < or = 60 mL/min/1.73 m(2). The lower GFR group taking valsartan, however, demonstrated a smaller rise in serum [K(+)], 0.12 mEq/L above baseline (P = 0.1), a 43% lower value when compared with the change in those who received lisinopril. This blunted rise in [K(+)] in people taking valsartan was not associated with a significant decrease in plasma aldosterone (P = 0.14). CONCLUSIONS: In the presence of renal insufficiency, the ARB valsartan did not raise serum [K(+)] to the same degree as the ACE inhibitor lisinopril. This differential effect on serum [K(+)] is related to a relatively smaller reduction in plasma aldosterone by the ARB and is not related to changes in GFR. This study provides evidence that increases in serum [K(+)] are less likely with ARB therapy compared with ACE inhibitor therapy in people with renal insufficiency.

Aldosterone↗
PubMed2000

The future of clinical trials in chronic renal disease: outcome of an NIH/FDA/Physician Specialist Conference. Evaluation of Clinical Trial Endpoints in Chronic Renal Disease Study Group.

For people with chronic renal insufficiency, the therapeutic goal is to prevent progression to end-stage renal disease, a serious condition that can only be treated with dialysis and kidney transplantation. Although restriction of dietary protein slows the progression of renal disease somewhat, the principal treatment to slow chronic renal disease is appropriate reduction of blood pressure. Antihypertensive agents, particularly those that produce sustained, long-term reductions in proteinuria, such as angiotensin-converting enzyme inhibitors, not only decrease blood pressure but also preserve renal function. Clinical trials to evaluate these and other drug therapies in renal disease progression have used both "hard end points" (e.g., dialysis, transplantation, death) and intermediate end points of renal disease progression (e.g., doubling of serum creatinine concentration, reductions in proteinuria). Trials that have used hard end points typically recruited patients with advanced renal disease to demonstrate a difference in therapies within a period of 2 to 5 years. However, proteinuria reduction, along with a decrease in the time to doubling of serum creatinine in very early diabetic renal disease, could demonstrate an altered natural history of renal disease. Although hard end points are indicators of a drug's efficacy in reducing cardiovascular events or preserving renal function, they do not assess the impact of a treatment on altering the natural history of early renal disease. For clinical trials of people with all but the most advanced renal disease, use of intermediate end points of renal disease progression is the only practical option for assessment of treatment efficacy and effectiveness. Given the available data on proteinuria reduction and doubling of serum creatinine from clinical trials, these end points, taken together, appear to provide an acceptable means of assessing a treatment's impact on slowing renal disease progression.

Antihypertensive Agents↗
PubMed2000

Evolution of drugs that preserve renal function.

Over the past 50 years, many advances have been made in slowing the progression of renal disease from various causes. These advances have been primarily linked to defining new lower levels for blood pressure goals as well as understanding the importance of proteinuria reduction. To achieve these goals, it is also appreciated that agents that lower blood pressure must also lower proteinuria. This is not true for all antihypertensive drug classes--notably, direct-acting vasodilators, alpha-blockers, and dihydropyridine calcium antagonists. Interestingly, antihypertensive agents that also reduce proteinuria have been associated with cardiovascular risk reduction. Moreover, an understanding of combinations of antihypertensive medications that provide additive reductions in proteinuria may be even more efficacious for slowing renal disease progression. It is hoped that these advances and the projected advances in pharmacogenetics will reduce the current increasing incidence of people going on dialysis.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Benefits of combination angiotensin-converting enzyme inhibitor and calcium antagonist therapy for diabetic patients.

Effective control of blood pressure is important in slowing renal disease progression in diabetic nephropathy. However, blood pressure is often difficult to control with monotherapy, especially in this patient population in whom three medications are sometimes required to attain goal blood pressures of less than 130/85 mm. Further, physicians are often reluctant to increase the dose or add another agent to an existing regimen. The advent of low-dose, fixed-dose combination therapy allows physicians the ability to prescribe two drugs in one pill and, hence, to improve compliance. In fact, the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) recommends adding a second antihypertensive agent as an option if goal blood pressure is not achieved with a single agent. The combination of an angiotensin-converting enzyme (ACE) inhibitor and calcium antagonist may confer additive antihypertensive benefit, and may even improve the side-effect profile. This paper reviews the importance of aggressive blood pressure control in diabetic patients and the clinical trials supporting the use of combination ACE inhibitor/calcium antagonist therapy in the diabetic patient population.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Class differences in the effects of calcium channel blockers in the rat remnant kidney model.

BACKGROUND: Controversy persists as to the existence of class differences between calcium channel blockers (CCBs) in their ability to provide renoprotection and as to potential mechanisms involved. METHODS: Rats with 5/6 renal ablation were left untreated or received diltiazem, verapamil, or felodipine after the first week, and the relationship between continuous radiotelemetrically measured blood pressure (BP) and glomerulosclerosis (GS) was assessed at seven weeks. Additionally, the effects of these CCBs on renal autoregulation and hypertrophy were examined at three weeks after renal ablation. RESULTS: Although an excellent linear correlation was observed between the average BP levels and GS in all groups (r = 0.75 to 0.84, P < 0.01), significant protection was not achieved with any of the CCBs, but for different reasons. The antihypertensive effects of diltiazem were not sustained beyond the second week. Verapamil significantly reduced the average BP (144 +/- 4 mm Hg vs. 181 +/- 8 in untreated rats) but shifted the slope of the relationship between BP and GS (increase in percentage GS/mm Hg increase in average systolic BP) to the left (x intercept 121 vs. 144 mm Hg for untreated rats, P < 0.01) so that GS was not reduced. Felodipine also significantly reduced the average BP (144 +/- 3 mm Hg) and shifted the slope to the left (x intercept 123 mm Hg), but additionally made the slope steeper (2.3 +/- 0.5 vs. 0.82 +/- 0.2 in untreated rats). Because of these differing effects on the relationship between BP and GS, the rank order of GS for any given BP elevation was as follows: felodipine > verapamil > diltiazem = untreated. Felodipine, but not verapamil or diltiazem, caused additional impairment of the already impaired renal autoregulation in untreated rats, thereby explaining its adverse effects on GS. By contrast, the adverse effects of verapamil on GS were attributable to the greater amplitude of BP fluctuations that was observed in the verapamil-treated rats such that for any given average BP, these rats were exposed to greater peak pressures as compared with the other groups. None of the CCBs had a significant effect on glomerular hypertrophy. CONCLUSIONS: These class differences between CCBs in their relative impact on systemic BP profiles, renal autoregulation, and glomerular pressure transmission may have clinically significant implications and may account for the variable glomeruloprotection that has been observed with these agents in both experimental models and in humans.

Animals↗
PubMed1999

Renal hemodynamics in radiocontrast medium-induced renal dysfunction: A role for dopamine-1 receptors.

BACKGROUND: Radiocontrast medium (RCM) administration induces a transient increase in renal blood flow (RBF), followed by a prolonged vasoconstriction. This vasoconstrictor phase in RBF is accompanied by a decrement in glomerular filtration rate (GFR). Nonselective dopamine (DA) receptor stimulation is known to increase RBF and GFR. Clinical studies, however, fail to demonstrate a renoprotective effect of DA following RCM administration. This lack of renoprotection may relate to nonspecific adrenergic stimulation by DA. The effect of select DA-1 receptor stimulation on renal hemodynamics following RCM administration has not been evaluated. METHODS: This study tests the hypothesis that selective DA-1 receptor stimulation blunts the declines in RBF and GFR that follow RCM injections, independent of changes in baseline RBF and GFR. Experiments were performed in six anesthetized, volume-depleted dogs. RBF was measured by an electromagnetic flow probe around the renal artery and GFR by inulin clearance. After a 60-minute equilibration period, baseline values of RBF, GFR, and arterial pressure were determined. Two separate intrarenal bolus injections of the ionic RCM Renograffin were then given in the presence of saline infusion. After a 60-minute recovery period, intra-arterial infusions of either the selective DA-1 receptor agonist fenoldopam or the selective DA-1 receptor antagonist Schering 23390 were started in random order, and experiments were repeated. RESULTS: Neither agent significantly altered baseline values of arterial pressure, RBF, or GFR rate. Fenoldopam prevented reductions in GFR (-17 +/- 2 Deltaml/min, control vs. 2 +/- 1 Deltaml/min, fenoldopam, P < 0.001). Conversely, GFR was further reduced in the presence of Schering 23390 (-15 +/- 2 Deltaml/min, control vs. -23 +/- 1 Deltaml/min, Schering 23390, P < 0.05). Similarly, the maximal reduction in RBF was blunted with fenoldopam (-71 +/- 12 Deltaml/min, control vs. -3 +/- 2 Deltaml/min, fenoldopam, P < 0. 01), whereas Schering 23390 potentiated maximal RBF reductions following the RCM injection (-85 +/- 11 Deltaml/min, control vs. -119 +/- 14 Deltaml/min, Schering 23390, P < 0.05). The duration of recovery from vasoconstriction was also prolonged in the presence of Schering 23390 (342 +/- 35 seconds, control vs. 762 +/- 56 seconds, Schering 23390, P < 0.0001). CONCLUSION: We conclude that selective DA-1 receptor stimulation protects against RCM-mediated decrements in renal hemodynamics, independent of changes in baseline GFR and RBF. Clinical trials are required to examine whether selective DA-1 receptor stimulation may have a role in prophylaxis against nephropathy development in high-risk patients undergoing procedures that require RCM.

Animals↗
PubMed1998

Progression of diabetic nephropathy. A focus on arterial pressure level and methods of reduction.

It is well accepted that a reduction of arterial pressure to levels of less than 140/90 mmHg will slow the decline in renal function among patients with diabetic nephropathy. More recently it is appreciated that the reduction of arterial pressure to levels much below 130/85 mmHg provides even greater levels of protection against the progression of renal disease. Given that the achievement of blood pressure reduction to such a level requires more than one medication and that the patient's compliance is best with a once-daily medication, it makes sense to combine antihypertensive medications so as to maximize the benefit. In this way, fixed dose combination medications yield synergistic effects on blood pressure reduction while providing, in some cases, maximal benefit to preservation of renal function. Such a combination is the verapamil/trandolapril combination. This paper discusses in great detail the advantages of blood pressure reduction and the types of medications that may achieve both protection against diabetic nephropathy progression as well as blood pressure reduction.

Antihypertensive Agents↗
PubMed1998

The role of combination antihypertensive therapy and the progression of renal disease hypertension: looking toward the next millennium.

The importance of the level to which blood pressure is reduced becomes increasingly important when one considers preservation of renal function. It is clear that three major subsets of patients emerge as requiring levels of blood pressure control of < 130/85 mm Hg to preserve renal function. Such individuals include black Americans, those with diabetic nephropathy, and those with renal insufficiency or > or = 1 g of proteinuria. It is clearly important to achieve such levels of blood pressure control in these high-risk individuals. It is also clear that single-agent therapy will never achieve these levels of blood pressure control. Therefore, multiple antihypertensive agents will be required to achieve such a goal. With increasing numbers of medications, however, there is also, unfortunately, a decrease in compliance. Therefore, fixed-dose combinations emerge as playing a major part both in achieving a level of blood pressure control as well as maintaining levels of compliance. Certain types of angiotensin-converting enzyme inhibitors, as well as calcium channel antagonist combinations, however, appear to have better overall effects than others do. These and related data are reviewed in this paper.

Antihypertensive Agents↗
PubMed1998

Differential effects of calcium channel blockers on size selectivity of proteinuria in diabetic glomerulopathy.

BACKGROUND: Calcium channel blockers (CCBs) are known to have differential effects on both changes in proteinuria as well as progression of diabetic nephropathy. No clinical study, however, has evaluated whether the differential antiproteinuric effects of CCBs may be explained by their effect on glomerular membrane permeability. We, therefore, tested the hypothesis that certain subclasses of CCBs reduce proteinuria by changing size selectivity of the glomerular membrane, hence changing its permeability. METHODS: Twenty-one patients with type 2 diabetes and the presence of nephropathy with hypertension were randomized to receive either diltiazem CD or nifedipine GITS after baseline data for mean systolic and diastolic pressure, urinary protein excretion, glomerular filtration rate, renal plasma flow, neutral dextran and IgG clearances were obtained. Glomerular filtration rate, renal plasma flow, neutral dextran and IgG clearance were measured every three months, arterial pressure and heart rate every month. Patients were followed for 21 months. RESULTS: At 21 months, both patient groups had similar levels of blood pressure control, however, only the diltiazem group had a change in proteinuria (4+/-10%delta, nifedipine vs. -57+/-18%delta, diltiazem; P < 0.001) with improvement in glomerular size selectivity and change in IgG clearance. CONCLUSIONS: These data support the hypothesis that CCBs that provide sustained reductions in proteinuria do so, in part, by improving glomerular size permselectivity.

Adult↗
PubMed1998

Effects of an ACE inhibitor/calcium antagonist combination on proteinuria in diabetic nephropathy.

BACKGROUND: The degree of proteinuria in patients with diabetes correlates strongly with both an increase in progression of nephropathy as well as cardiovascular events. Moreover, post hoc analyses of recent clinical trials support the concept that reductions of blood pressure and proteinuria correlate with a slowed progression of nephropathy. Both angiotensin converting enzyme (ACE) inhibitors and the nondihydropyridine calcium antagonists, (non-DHPCAs) reduce both arterial pressure and proteinuria in those with diabetic nephropathy. METHODS: The present randomized, open label, parallel group designed study tests the hypothesis that, at similar levels of blood pressure, the combination of an ACE inhibitor, trandolapril (T) with the non-DHPCA, verapamil (V) produces a greater reduction in proteinuria over either agent alone at one year. Thirty-seven participants, mean age 59.6 +/- 5.8 years, with nephropathy (baseline creatinine 1.4 +/- 0.3 mg/dl and proteinuria of 1342 +/- 284 mg/dl) secondary to type 2 diabetes completed the study. Doses of drug were titrated in each group over eight weeks to achieve a goal blood pressure of < 140/90 mm Hg. All participants were counseled to ingest a sodium diet of < 120 mEq/day. RESULTS: Proteinuria reduction from baseline was significantly greater in the T+V group compared to either T alone (-33 +/- 8%, T vs. -62 +/- 10%, T+V; P < 0.001) or V alone (-27 +/- 8%, V vs. -62 +/- 10%, T+V; P < 0.001). No significant differences in either glomerular filtration rate, arterial pressure, fasting blood glucose or urinary sodium excretion were noted at one year. The mean daily dose of the individual components of T+V (2.9 +/- 0.8 mg, T/219 +/- 21.1 mg V) was significantly lower than the dose of either T alone 5.5 +/- 1.1 mg/day (P < 0.01) or V alone 314.8 +/- 46.3 mg, given in two divided doses (P < 0.01). CONCLUSION: These data support the concept that the combination of an ACE inhibitor with a non-DHPCA reduce proteinuria to a greater extent than either agent alone. This added antiproteinuric effect occurs at lower doses of each drug and is independent of further reductions in arterial pressure. These findings could have ramifications for slowing renal disease progression in patients with nephropathy from type 2 diabetes.

Aged↗
PubMed1998

The renin-angiotensin system in diabetic nephropathy: the endothelial connection.

In recent years endothelial function has been forwarded a modulator in the pathogenesis of diabetic nephropathy. This review summarizes how an imbalance between endothelium-derived reactive nitrogen species and reactive oxygen species as well as increased expression of the endothelium-derived peptide endothelin-1 may contribute to loss of renal function in diabetes. In addition, the potentially beneficial effects of blockade of the renin-angiotensin system on this endothelial dysbalance is discussed.

Animals↗
PubMed1997

Calcium antagonism abolishes the antipressor action of vasopressin (V1) receptor antagonism.

Previous studies demonstrate that vasopressin (V1) receptor antagonism lowers arterial pressure in blacks. This action of V1 receptor blockade may be mediated through various mechanisms including changes in intracellular calcium fluxes. This study was undertaken to test the hypothesis that inhibition of calcium entry may attenuate the reduction in arterial pressure observed with V1 receptor blockade. Sixteen hypertensive patients, 8 whites and 8 blacks, were examined. Each had their antihypertensive therapy stopped for 1 week. Following three baseline blood pressure measurements, all patients were given an intravenous bolus injection of a V1 receptor antagonist. Blood pressure was monitored every 10 min for a period of 3 h. Subjects were then randomized to either 0.2 mg clonidine twice daily or 300 mg diltiazem CD daily for a period of 3 days and the previous experiments repeated. Patients were then crossed over to the other drug for an additional 3 days and the experiments repeated. There was a significant reduction from baseline in the mean arterial pressure among blacks but not whites (-11 +/- 3 delta mm Hg blacks versus -1 +/- 2 delta mm Hg whites, P < .01). In the presence of clonidine, there were similar reductions in arterial pressure in both groups (P = .026) with a further reduction following V1 receptor blockade only in the blacks (-7 +/- 3 delta mm Hg blacks versus 6 +/- 2 delta mm Hg whites; P < .001). Conversely, in the presence of diltiazem CD, there were no further reductions in arterial pressure in either group following the V1 receptor antagonist. We conclude that calcium channel blockade abolishes the blood pressure lowering response of V1 receptor blockade in blacks.

Aged↗