Beta blockers in the management of chronic kidney disease
2006; Elsevier BV; Volume: 70; Issue: 11 Linguagem: Inglês
10.1038/sj.ki.5001835
ISSN1523-1755
AutoresGeorge L. Bakris, Peter D. Hart, Eberhard Ritz,
Tópico(s)Heart rate and cardiovascular health
ResumoThe sympathetic nervous system modulates renal function through its receptors namely β1 (cardiac output and renin release), α1 (systemic and renovascular constriction), and β2 renovascular dilation. Sympathetic overactivity is commonly seen in chronic kidney disease (CKD) and is an important contributor to increasing the risk of cardiovascular events as well as increasing renal disease progression. Recent evaluations of drug use in people with CKD shows a remarkably low percentage of patients receiving β-blockers, especially in more advanced stage CKD when cardiovascular risk is higher. This is in large part due to tolerability of these agents. Moreover, water-soluble β-blockers such as atenolol and metoprolol are dialyzable and require supplementation to avoid exacerbation of arrhythmias following dialysis. Newer vasodilating β-blockers have better tolerability and different effects on renal hemodynamics as well as metabolic variables. These effects are related to the relative α1-blocking effect of agents such as carvedilol and labetolol, with carvedilol having relatively greater α-blocking effects. Few studies evaluate β-blockers on cardiovascular risk in CKD patients. Studies with carvedilol demonstrate attenuated increases in albuminuria as well as reduction in cardiovascular events in CKD patients with hypertension. This paper reviews the animal and clinical trial data that evaluate β-blockers in CKD highlighting the vasodilating β-blockers. It is apparent that greater use of this drug class for blood pressure control would further enhance reduction of risk of heart failure, the most common cause of death in the first year of starting dialysis. The sympathetic nervous system modulates renal function through its receptors namely β1 (cardiac output and renin release), α1 (systemic and renovascular constriction), and β2 renovascular dilation. Sympathetic overactivity is commonly seen in chronic kidney disease (CKD) and is an important contributor to increasing the risk of cardiovascular events as well as increasing renal disease progression. Recent evaluations of drug use in people with CKD shows a remarkably low percentage of patients receiving β-blockers, especially in more advanced stage CKD when cardiovascular risk is higher. This is in large part due to tolerability of these agents. Moreover, water-soluble β-blockers such as atenolol and metoprolol are dialyzable and require supplementation to avoid exacerbation of arrhythmias following dialysis. Newer vasodilating β-blockers have better tolerability and different effects on renal hemodynamics as well as metabolic variables. These effects are related to the relative α1-blocking effect of agents such as carvedilol and labetolol, with carvedilol having relatively greater α-blocking effects. Few studies evaluate β-blockers on cardiovascular risk in CKD patients. Studies with carvedilol demonstrate attenuated increases in albuminuria as well as reduction in cardiovascular events in CKD patients with hypertension. This paper reviews the animal and clinical trial data that evaluate β-blockers in CKD highlighting the vasodilating β-blockers. It is apparent that greater use of this drug class for blood pressure control would further enhance reduction of risk of heart failure, the most common cause of death in the first year of starting dialysis. Given the high prevalence of cardiovascular disease in people with chronic kidney disease (CKD) and the clear benefits of mortality reduction observed for most β-blockers in clinical trials, they are relatively underused in CKD patients. The reasons for this relative lack of β-blocker use as well as the role of newer subclasses of this antihypertensive group in people with CKD are discussed. In order to understand the rationale for use of β-blockers in patients with CKD, it is useful to review some background information on sympathetic overactivity in such patients as well as elucidate its role in the genesis of hypertension and progression of kidney disease as well as potentially of cardiovascular complications. Experimental evidence focused on the role of the sympathetic system will be initially presented followed by data from clinical studies and trials. Studies by DiBona1.DiBona G.F. Neural control of the kidney: past, present, and future.Hypertension. 2003; 41: 621-624Crossref PubMed Scopus (147) Google Scholar identified chemoreceptors and baroreceptors in the kidney. In models of experimental renal damage, Campese and Krol2.Campese V.M. Krol E. Neurogenic factors in renal hypertension.Curr Hypertens Rep. 2002; 4: 256-260Crossref PubMed Scopus (41) Google Scholar and Ye et al.3.Ye S. Ozgur B. Campese V.M. Renal afferent impulses, the posterior hypothalamus, and hypertension in rats with chronic renal failure.Kidney Int. 1997; 51: 722-727Abstract Full Text PDF PubMed Scopus (167) Google Scholar documented that the activation of afferent signals emanating from damaged kidneys, travel via the spinal cord into the hypothalamus, where local catecholamine turnover is upregulated, leading to increased efferent sympathetic nerve traffic into the periphery. The activation of the hypothalamic centers which occurs in response to afferent signals has been proven by experiments with sections of the dorsal roots (rhizotomy), which abrogated hypertension in subtotally nephrectomized rats.4.Campese V.M. Kogosov E. Renal afferent denervation prevents hypertension in rats with chronic renal failure.Hypertension. 1995; 25: 878-882Crossref PubMed Google Scholar Such afferent signals were seen with different types of kidney injury; most impressive was the observation that injection of as little as 20 μl phenol raised blood pressure; this hypertension was abrogated several weeks later by resection of the phenol-treated kidney.5.Ye S. Zhong H. Yanamadala V. et al.Renal injury caused by intrarenal injection of phenol increases afferent and efferent renal sympathetic nerve activity.Am J Hypertens. 2002; 15: 717-724Crossref PubMed Scopus (115) Google Scholar Sympathetic overactivity in kidney disease is involved in the genesis of hypertension, in the progression of kidney disease, and in the cardiac complications of kidney failure. The role of the sympathetic nervous system (SNS) in the progression of nephropathy has been documented by observations in subtotally nephrectomized rats in which nonhypotensive doses of β-blockers ameliorated the development of glomerulosclerotic and cardiac lesions.6.Salplachta J. Bartosikova L. Necas J. Effects of carvedilol and BL-443 on kidney of rats with cyclosporine nephropathy.Gen Physiol Biophys. 2002; 21: 189-195PubMed Google Scholar Similar observations concerning kidney disease progression were noted with the central sympathicoplegic agent moxonidine.7.Amann K. Nichols C. Tornig J. et al.Effect of ramipril, nifedipine, and moxonidine on glomerular morphology and podocyte structure in experimental renal failure.Nephrol Dial Transplant. 1996; 11: 1003-1011Crossref PubMed Google Scholar Additionally, moxonidine also reduced albumin excretion in patients with type I diabetes, despite causing no change in ambulatory blood pressure.8.Strojek K. Grzeszczak W. Gorska J. et al.Lowering of microalbuminuria in diabetic patients by a sympathicoplegic agent: novel approach to prevent progression of diabetic nephropathy?.J Am Soc Nephrol. 2001; 12: 602-605PubMed Google Scholar,9.Vonend O. Marsalek P. Russ H. et al.Moxonidine treatment of hypertensive patients with advanced renal failure.J Hypertens. 2003; 21: 1709-1717Crossref PubMed Scopus (96) Google Scholar In a separate model of kidney disease (spontaneously hypertensive rats with adriamycin nephropathy), α-/β-blocker carvedilol decreased systolic blood pressure, decreased renal vascular resistance (RVR), and significantly increased renal blood flow (RBF). Moreover, it significantly decreased interstitial infiltration in the early phase of the study, slowed development of interstitial fibrosis and tubular atrophy, and decreased blood vessel changes. These changes strongly correlated with slowed nephropathy progression as well as decreases in proteinuria. The addition of captopril to carvedilol improved its effects, especially on prevention of tubulointerstitial changes.10.Jovanovic D. Jovovic D. Mihailovic-Stanojevic N. et al.Influence of carvedilol on chronic renal failure progression in spontaneously hypertensive rats with adriamycin nephropathy.Clin Nephrol. 2005; 63: 446-453Crossref PubMed Scopus (15) Google Scholar In subtotally nephrectomized rats with known microangiopathy, β-blockers increased the capillary density in the heart.11.Amann K. Ritz E. Microvascular disease – the Cinderella of uraemic heart disease.Nephrol Dial Transplant. 2000; 15: 1493-1503Crossref PubMed Scopus (76) Google Scholar This is an important observation, as β-blockers clearly improve cardiac function and reduce cardiovascular events in hemodialyzed patients.12.Cice G. Ferrara L. D'Andrea A. et al.Carvedilol increases two-year survival in dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial.J Am Coll Cardiol. 2003; 41: 1438-1444Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar In models of chronic renal damage, norepinephrine (NE) content was decreased, yet increased NE release was noted upon stimulation of renal nerves.13.Amann K. Rump L.C. Simonaviciene A. et al.Effects of low dose sympathetic inhibition on glomerulosclerosis and albuminuria in subtotally nephrectomized rats.J Am Soc Nephrol. 2000; 11: 1469-1478PubMed Google Scholar This is consistent with increased NE discharge from reduced numbers of sympathetic nerves, possibly because of partial denervation from incipient polyneuropathy. Patchy denervation from autonomic polyneuropathy with denervation supersensitivity to catecholamines may also be relevant in the heart of uremic patients.14.Zuanetti G. Maggioni A.P. Keane W. et al.Nephrologists neglect administration of betablockers to dialysed diabetic patients.Nephrol Dial Transplant. 1997; 12: 2497-2500Crossref PubMed Scopus (35) Google Scholar These observations may explain, at least in part, the propensity for sudden death,15.Paoletti E. Specchia C. Di Maio G. et al.The worsening of left ventricular hypertrophy is the strongest predictor of sudden cardiac death in haemodialysis patients: a 10 year survey.Nephrol Dial Transplant. 2004; 19: 1829-1834Crossref PubMed Scopus (133) Google Scholar a frequent cause of death in dialysis patients, and the benefit derived from treatment with β-blockers.12.Cice G. Ferrara L. D'Andrea A. et al.Carvedilol increases two-year survival in dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial.J Am Coll Cardiol. 2003; 41: 1438-1444Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar,14.Zuanetti G. Maggioni A.P. Keane W. et al.Nephrologists neglect administration of betablockers to dialysed diabetic patients.Nephrol Dial Transplant. 1997; 12: 2497-2500Crossref PubMed Scopus (35) Google Scholar Further abnormalities of the sympathetic system in renal failure include reduction of β- and α-receptor responsiveness.16.Mann J.F. Jakobs K.H. Riedel J. et al.Reduced chronotropic responsiveness of the heart in experimental uremia.Am J Physiol. 1986; 250: H846-H852PubMed Google Scholar, 17.Leineweber K. Heinroth-Hoffmann I. Ponicke K. et al.Cardiac beta-adrenoceptor desensitization due to increased beta-adrenoceptor kinase activity in chronic uremia.J Am Soc Nephrol. 2002; 13: 117-124PubMed Google Scholar, 18.Rascher W. Schomig A. Kreye V.A. et al.Diminished vascular response to noradrenaline in experimental chronic uremia.Kidney Int. 1982; 21: 20-27Abstract Full Text PDF PubMed Scopus (43) Google Scholar Direct evidence of sympathetic overactivity was provided using the methodological gold standard of microneurography of the sural nerve in hemodialyzed patients,19.Converse Jr, R.L. Jacobsen T.N. Toto R.D. et al.Sympathetic overactivity in patients with chronic renal failure.N Engl J Med. 1992; 327: 1912-1918Crossref PubMed Scopus (965) Google Scholar in patients with advanced renal failure,20.Ligtenberg G. Blankestijn P.J. Oey P.L. et al.Reduction of sympathetic hyperactivity by enalapril in patients with chronic renal failure.N Engl J Med. 1999; 340: 1321-1328Crossref PubMed Scopus (375) Google Scholar and even in the earliest stage of renal disease, that is, patients with polycystic kidney disease despite no reduction in glomerular filtration rate (GFR).21.Klein I.H. Ligtenberg G. Oey P.L. et al.Sympathetic activity is increased in polycystic kidney disease and is associated with hypertension.J Am Soc Nephrol. 2001; 12: 2427-2433PubMed Google Scholar The role of the damaged kidney in causing sympathetic overactivity is illustrated by the observation that sympathetic activity is completely normal in hemodialyzed patients with bilateral nephrectomy.19.Converse Jr, R.L. Jacobsen T.N. Toto R.D. et al.Sympathetic overactivity in patients with chronic renal failure.N Engl J Med. 1992; 327: 1912-1918Crossref PubMed Scopus (965) Google Scholar Conversely, sympathetic overactivity is still present in renal allograft recipients and normalizes when their own shrunken kidneys are removed.22.Hausberg M. Kosch M. Harmelink P. et al.Sympathetic nerve activity in end-stage renal disease.Circulation. 2002; 106: 1974-1979Crossref PubMed Scopus (405) Google Scholar As there is overwhelming evidence for sympathetic overactivity in patients with kidney disease, coronary heart disease and heart failure (HF) are the most common causes of death in these patients.23.Eknoyan G. On the epidemic of cardiovascular disease in patients with chronic renal disease and progressive renal failure: a first step to improve the outcomes.Am J Kidney Dis. 1998; 32: S1-S4Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar This may be due to inadequate treatment, as demonstrated by a recent study in which β-adrenergic blockade was used in fewer than 30% of patients on hemodialysis.24.Abbott K.C. Trespalacios F.C. Agodoa L.Y. et al.Beta-blocker use in long-term dialysis patients: association with hospitalized heart failure and mortality.Arch Intern Med. 2004; 164: 2465-2471Crossref PubMed Scopus (102) Google Scholar This is surprising, as β-blockers interfere with the deleterious actions of the SNS on cardiac end points,14.Zuanetti G. Maggioni A.P. Keane W. et al.Nephrologists neglect administration of betablockers to dialysed diabetic patients.Nephrol Dial Transplant. 1997; 12: 2497-2500Crossref PubMed Scopus (35) Google Scholar and are well-established, evidence-based therapy for reducing cardiovascular risk in hypertension25.Chobanian A.V. Bakris G.L. Black H.R. et al.The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.JAMA. 2003; 289: 2560-2572Crossref PubMed Scopus (15057) Google Scholar and after myocardial infarction.12.Cice G. Ferrara L. D'Andrea A. et al.Carvedilol increases two-year survival in dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial.J Am Coll Cardiol. 2003; 41: 1438-1444Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar,26.Antman E.M. Anbe D.T. Armstrong P.W. et al.ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction – executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction).Circulation. 2004; 110: 588-636Crossref PubMed Scopus (1243) Google Scholar Observational studies suggest definite survival benefits derived from the use of β-blockers in patients with severe renal disease.27.Foley R.N. Herzog C.A. Collins A.J. Blood pressure and long-term mortality in United States hemodialysis patients: USRDS waves 3 and 4 study.Kidney Int. 2002; 62: 1784-1790Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar,28.Horl M.P. Horl W.H. Drug therapy for hypertension in hemodialysis patients.Semin Dial. 2004; 17: 288-294Crossref PubMed Scopus (34) Google Scholar Furthermore, in a prospective, randomized study in hemodialyzed patients with HF, Cice et al.12.Cice G. Ferrara L. D'Andrea A. et al.Carvedilol increases two-year survival in dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial.J Am Coll Cardiol. 2003; 41: 1438-1444Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar documented an impressive and significant decrease in death and hospitalization rates attributable to cardiovascular causes in patients on carvedilol compared to placebo (Figure 1). Nevertheless, β-blockers are inadequately used in patients with CKD, especially those with the most severe renal failure.29.Bakris G.L. Role for beta-blockers in the management of diabetic kidney disease.Am J Hypertens. 2003; 16: 7S-12SCrossref PubMed Google Scholar For example, the United States Renal Data System Dialysis Morbidity and Mortality Study found that only 20% of chronic dialysis patients were receiving β-blocker therapy.24.Abbott K.C. Trespalacios F.C. Agodoa L.Y. et al.Beta-blocker use in long-term dialysis patients: association with hospitalized heart failure and mortality.Arch Intern Med. 2004; 164: 2465-2471Crossref PubMed Scopus (102) Google Scholar In another study, only 24% of patients with established coronary heart disease were treated with β-blockers.30.Trespalacios F.C. Taylor A.J. Agodoa L.Y. et al.Incident acute coronary syndromes in chronic dialysis patients in the United States.Kidney Int. 2002; 62: 1799-1805Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar A similar trend occurs in the predialysis patients.31.Wright R.S. Reeder G.S. Herzog C.A. et al.Acute myocardial infarction and renal dysfunction: a high-risk combination.Ann Intern Med. 2002; 137: 563-570Crossref PubMed Scopus (504) Google Scholar One reason for this underutilization may be fear of adverse hemodynamic effects on renal physiology or on glycemic control in patients with diabetes. β-blockers vary significantly in their pharmacologic properties. These differences may determine how well an agent will work and how tolerable it will be in patients with CKD. Pharmacological properties including lipid solubility, cardioselectivity and routes of excretion, and the presence of adjunctive properties such as vasodilatory, antioxidant, and calcium-blocking activity will all influence the effect of the agent. Metabolic factors including lipoprotein and serum potassium levels and glycemic control may also respond differently to each β-blocker. This review will discuss the different properties and effects of several commonly used β-blockers in the management of CKD: propranolol, metoprolol, atenolol, labetalol, and carvedilol. Controlling hypertension is a mainstay in the management of CKD. Table 1 displays the pharmacologic and renal hemodynamic properties of several β-blockers that have been used to lower blood pressure in hypertensive patients with diabetic and nondiabetic renal impairment.32.Richards D.A. Prichard B.N. Clinical pharmacology of labetalol.Br J Clin Pharmacol. 1979; 8: 89S-93SCrossref PubMed Scopus (3) Google Scholar, 33.Inderal® (propranolol hydrochloride) tablets (prescribing information). Wyeth Pharmaceuticals Inc., Philadelphia, PA2005Google Scholar, 34.Tenormin® (atenolol) tablets (prescribing information). AstraZeneca Pharmaceuticals, Wilmington, DE2000Google Scholar, 35.Hjalmarson A. Cardioprotection with beta-adrenoceptor blockers. Does lipophilicity matter?.Basic Res Cardiol. 2000; 95: I41-I45Crossref PubMed Google Scholar, 36.Cruz F. O'Neill Jr, W.M. Clifton G. et al.Effects of labetalol and methyldopa on renal function.Clin Pharmacol Ther. 1981; 30: 57-63Crossref PubMed Scopus (18) Google Scholar, 37.Epstein M. Oster J.R. Hollenberg N.K. β-Blockers and the kidney: implications for renal function and renin release.The Physiologist. 1985; 28: 53-63PubMed Google Scholar, 38.Giugliano D. Acampora R. Marfella R. et al.Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertension. A randomized, controlled trial.Ann Intern Med. 1997; 126: 955-959Crossref PubMed Scopus (258) Google Scholar, 39.Jacob S. Rett K. Wicklmayr M. et al.Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity: the carvedilol-metoprolol study.J Hypertens. 1996; 14: 489-494Crossref PubMed Google Scholar, 40.Hylander B. Eliasson K. Nilsson-Ehle P. et al.Effects of long-term therapy with labetalol on lipoprotein metabolism in patients with mild hypertension.Acta Med Scand. 1985; 218: 51-54Crossref PubMed Scopus (12) Google Scholar, 41.Malini P.L. Strocchi E. Negroni S. et al.Renal haemodynamics after chronic treatment with labetalol and propranolol.Br J Clin Pharmacol. 1982; 13: 123S-126SCrossref PubMed Scopus (21) Google Scholar, 42.Drug Facts and Comparisons 2006. Facts and Comparisons (a Wolters Kluwer Company), St Louis, MO2005Google Scholar Lipophilic agents undergo extensive first-pass hepatic metabolism with relatively little being excreted unchanged in the urine. Hydrophilic agents are excreted primarily by the kidneys and require dose adjustment in patients with end-stage renal disease (ESRD). Hydrophilic agents may yield low blood levels due to poor absorption after oral administration.43.Meier J. Pharmacokinetic comparison of pindolol with other beta-adrenoceptor-blocking agents.Am Heart J. 1982; 104: 364-373Abstract Full Text PDF PubMed Scopus (63) Google Scholar,44.Borchard U. Pharmacokinetics of beta-adrenoceptor blocking agents: clinical significance of hepatic and/or renal clearance.Clin Physiol Biochem. 1990; 8: 28-34PubMed Google Scholar β1-selective blockers are cardio-specific and result in reduced cardiac output, blood pressure, and heart rate. β1-/β2-blockers antagonize the effects of catecholamine stimulation on β-adrenergic receptors in resistance vessels as well as the myocardium. β2-blockade has been shown to be particularly important in mediating the proarrhythmic effect of NE.45.Packer M. Beta-adrenergic blockade in chronic heart failure: principles, progress, and practice.Prog Cardiovasc Dis. 1998; 41: 39-52Abstract Full Text PDF PubMed Scopus (93) Google Scholar However, inhibition of β2-vasodilation leaves the reflex α1-mediated vasoconstrictor response to arterial underfilling unopposed in the face of decreased blood pressure or cardiac output. In general, the effects of β-blockade are amplified by reduction of plasma renin release through inhibition of β-adrenergic receptors located in the renal juxtaglomerular apparatus.37.Epstein M. Oster J.R. Hollenberg N.K. β-Blockers and the kidney: implications for renal function and renin release.The Physiologist. 1985; 28: 53-63PubMed Google ScholarTable 1Pharmacologic properties of β-blockersPropranololMetoprololAtenololLabetalolCarvedilolLipophilicYYNYYNonselective (β1/β2)YNNYYCardioselective (β1)NYYNNα1-blockadeNNNYYInsulin sensitivity↓↓↓↔↑Serum triglycerides↑↑↑↔↓Serum HDL cholesterol↓↓↓↔↑Hyperkalemia in ESRDYNNYNRenal effects in CKD RVR↑↓↔↔↓ RBF↓↔↔↔↑ GFR↓↔↔↔↑↑, increases with use of drug; ↓, decreases with use of drug; ↔, remains the same with use of drug; CKD, chronic kidney disease; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HDL, high-density lipoprotein; N, no; RBF, renal blood flow; RVR, renal vascular resistance; Y, yes.Sources:32.Richards D.A. Prichard B.N. Clinical pharmacology of labetalol.Br J Clin Pharmacol. 1979; 8: 89S-93SCrossref PubMed Scopus (3) Google Scholar, 33.Inderal® (propranolol hydrochloride) tablets (prescribing information). Wyeth Pharmaceuticals Inc., Philadelphia, PA2005Google Scholar, 34.Tenormin® (atenolol) tablets (prescribing information). AstraZeneca Pharmaceuticals, Wilmington, DE2000Google Scholar, 35.Hjalmarson A. Cardioprotection with beta-adrenoceptor blockers. Does lipophilicity matter?.Basic Res Cardiol. 2000; 95: I41-I45Crossref PubMed Google Scholar, 36.Cruz F. O'Neill Jr, W.M. Clifton G. et al.Effects of labetalol and methyldopa on renal function.Clin Pharmacol Ther. 1981; 30: 57-63Crossref PubMed Scopus (18) Google Scholar, 37.Epstein M. Oster J.R. Hollenberg N.K. β-Blockers and the kidney: implications for renal function and renin release.The Physiologist. 1985; 28: 53-63PubMed Google Scholar, 38.Giugliano D. Acampora R. Marfella R. et al.Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertension. A randomized, controlled trial.Ann Intern Med. 1997; 126: 955-959Crossref PubMed Scopus (258) Google Scholar, 39.Jacob S. Rett K. Wicklmayr M. et al.Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity: the carvedilol-metoprolol study.J Hypertens. 1996; 14: 489-494Crossref PubMed Google Scholar, 40.Hylander B. Eliasson K. Nilsson-Ehle P. et al.Effects of long-term therapy with labetalol on lipoprotein metabolism in patients with mild hypertension.Acta Med Scand. 1985; 218: 51-54Crossref PubMed Scopus (12) Google Scholar, 41.Malini P.L. Strocchi E. Negroni S. et al.Renal haemodynamics after chronic treatment with labetalol and propranolol.Br J Clin Pharmacol. 1982; 13: 123S-126SCrossref PubMed Scopus (21) Google Scholar, 42.Drug Facts and Comparisons 2006. Facts and Comparisons (a Wolters Kluwer Company), St Louis, MO2005Google Scholar Open table in a new tab ↑, increases with use of drug; ↓, decreases with use of drug; ↔, remains the same with use of drug; CKD, chronic kidney disease; ESRD, end-stage renal disease; GFR, glomerular filtration rate; HDL, high-density lipoprotein; N, no; RBF, renal blood flow; RVR, renal vascular resistance; Y, yes. Sources:32.Richards D.A. Prichard B.N. Clinical pharmacology of labetalol.Br J Clin Pharmacol. 1979; 8: 89S-93SCrossref PubMed Scopus (3) Google Scholar, 33.Inderal® (propranolol hydrochloride) tablets (prescribing information). Wyeth Pharmaceuticals Inc., Philadelphia, PA2005Google Scholar, 34.Tenormin® (atenolol) tablets (prescribing information). AstraZeneca Pharmaceuticals, Wilmington, DE2000Google Scholar, 35.Hjalmarson A. Cardioprotection with beta-adrenoceptor blockers. Does lipophilicity matter?.Basic Res Cardiol. 2000; 95: I41-I45Crossref PubMed Google Scholar, 36.Cruz F. O'Neill Jr, W.M. Clifton G. et al.Effects of labetalol and methyldopa on renal function.Clin Pharmacol Ther. 1981; 30: 57-63Crossref PubMed Scopus (18) Google Scholar, 37.Epstein M. Oster J.R. Hollenberg N.K. β-Blockers and the kidney: implications for renal function and renin release.The Physiologist. 1985; 28: 53-63PubMed Google Scholar, 38.Giugliano D. Acampora R. Marfella R. et al.Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertension. A randomized, controlled trial.Ann Intern Med. 1997; 126: 955-959Crossref PubMed Scopus (258) Google Scholar, 39.Jacob S. Rett K. Wicklmayr M. et al.Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity: the carvedilol-metoprolol study.J Hypertens. 1996; 14: 489-494Crossref PubMed Google Scholar, 40.Hylander B. Eliasson K. Nilsson-Ehle P. et al.Effects of long-term therapy with labetalol on lipoprotein metabolism in patients with mild hypertension.Acta Med Scand. 1985; 218: 51-54Crossref PubMed Scopus (12) Google Scholar, 41.Malini P.L. Strocchi E. Negroni S. et al.Renal haemodynamics after chronic treatment with labetalol and propranolol.Br J Clin Pharmacol. 1982; 13: 123S-126SCrossref PubMed Scopus (21) Google Scholar, 42.Drug Facts and Comparisons 2006. Facts and Comparisons (a Wolters Kluwer Company), St Louis, MO2005Google Scholar The addition of α1-inhibiting activity to β-adrenergic antagonists blocks reflex vasoconstriction, and may also increase blood flow to skeletal muscle, thereby improving glucose availability and disposal.46.Jacob S. Rett K. Henriksen E.J. Antihypertensive therapy and insulin sensitivity: do we have to redefine the role of beta-blocking agents?.Am J Hypertens. 1998; 11: 1258-1265Crossref PubMed Scopus (184) Google Scholar Whereas both nonselective and β1-selective blockers can increase insulin resistance, the addition of sufficient α1-blocking activity may improve insulin sensitivity in both diabetic and nondiabetic patients.46.Jacob S. Rett K. Henriksen E.J. Antihypertensive therapy and insulin sensitivity: do we have to redefine the role of beta-blocking agents?.Am J Hypertens. 1998; 11: 1258-1265Crossref PubMed Scopus (184) Google Scholar β1- and α1-stimulation have opposite effects on specific enzymes involved in lipid metabolism. Whereas β1-selective and -nonselective β-blockers tend to increase blood levels of triglycerides and lower levels of high-density lipoprotein cholesterol, α1-blockers can lower triglycerides and raise high-density lipoprotein cholesterol levels.46.Jacob S. Rett K. Henriksen E.J. Antihypertensive therapy and insulin sensitivity: do we have to redefine the role of beta-blocking agents?.Am J Hypertens. 1998; 11: 1258-1265Crossref PubMed Scopus (184) Google Scholar Consequently, the addition of α1-blocking activity to certain β-blockers may impact both diabetes and arteriosclerotic cardiovascular disease by promoting better glycemic control with less compensatory hyperinsulinemia and fewer proatherogenic changes in serum lipids.38.Giugliano D. Acampora R. Marfella R. et al.Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertension. A
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