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�-Blockers in Hypertension: IsCarvedilol Different?

Franz H. Messerli, MD, and Ehud Grossman, MD

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ost studies assessing the effects of �-blockers werearried out with traditional, �1-selective �-blockers,uch as metoprolol and atenolol. Pathophysiologic andharmacologic studies have documented that not all-blockers are created equal. In particular, the pharma-ologic and clinical profiles of the newer, vasodilating

-blockers, such as carvedilol, have been shown to

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iffer from those of the traditional �-blockers. Theseifferences, although relevant in the younger patientith hypertension, are particularly important in elderlyatients in whom traditional �-blockers may not be asffective or as well tolerated as the newer vasodilatinggents. �2004 by Excerpta Medica, Inc.

Am J Cardiol 2004;93(suppl):7B–12B

n 1993, the fifth Joint National Committee (JNCV)established new guidelines for the treatment of hy-

ertension.1 Unlike the previous iteration in which alldrug classes (diuretics, �-blockers, calcium antago-

ists, and angiotensin-converting enzyme [ACE] in-ibitors), were deemed equally acceptable as first-lineherapy, the 1993 version stated that diuretics and-blockers should be considered preferred initialgents because they had been shown to reduce cardio-ascular morbidity and mortality in controlled clinicalrials. Although epidemiologic studies attest to theafety and efficacy of diuretics in this regard, theutcome data for traditional �-blockers are unclearnd unconvincing. The clinical benefits of traditional-blockers are poorly documented. Moreover, thesegents may not be efficacious in the elderly, whoccount for a large segment of the hypertensive pop-lation.2

FFECTS OF TRADITIONAL-BLOCKERS ON MORBIDITY ANDORTALITYAlthough �-blockers have been used for the treat-

ent of hypertension for �3 decades,3 no study showshat monotherapy with traditional �-blockers reduces

orbidity and mortality compared with placebo. In aecent meta-analysis of 10 trials enrolling 16,164 el-erly patients, blood pressure was lowered signifi-antly, but traditional �-blockers (eg, atenolol, meto-rolol) were ineffective in preventing coronary arteryisease (CAD), cardiovascular mortality, and all-ause mortality (odds ratios: 1.01, 0.98, and 1.05,espectively).4 Not only was �-blocker monotherapyneffective, but patients who received �-blockers plusiuretics fared consistently worse than those receivingiuretics alone. In contrast, diuretic therapy was su-erior to �-blockade for all end points and was effec-ive in preventing CAD, fatal strokes, cardiovascularvents, as well as cardiovascular and all-cause mor-

rom the Ochsner Clinic Foundation, New Orleans, Louisiana, USAFHM); and Internal Medicine Department, The Chaim Sheba Medicalenter, Tel-Hashomer, Israel (EG).

Address for reprints: Franz H. Messerli, MD, Ochsner Clinic Foun-ation, 1514 Jefferson Highway, New Orleans, Louisiana 70121.

ality. About 66% of patients assigned to diureticsere well controlled on monotherapy, whereas �33%f the patients assigned to �-blockers as monotherapy.hus, despite having a beneficial effect on the surro-ate end point of blood pressure, traditional �-blockerherapy failed to favorably affect the real end point:ardiovascular events, cardiovascular death, and all-ause mortality. Another large meta-analysis by Psatyt al5 found that although �-blockers were superior tolacebo for the prevention of stroke, congestive heartailure, cardiovascular disease events, and total mor-ality, as a class they were inferior to low-dose diuret-cs for all outcomes, and significantly so for cardio-ascular disease events.

Why is it, then, that traditional �-blockers, despiteowering blood pressure, do not reduce cardiovascularorbidity and mortality? The following discussion

overs some points that may account for the failure ofraditional �-blockers in reducing morbidity and mor-ality in the elderly patient with hypertension.

FFECTS OF �-BLOCKERS ONYSTEMIC HEMODYNAMICS

Except in the early or borderline phase, the hemo-ynamic profile of established essential hypertensions generally characterized by normal cardiac outputnd high systemic vascular resistance.6 In most elderlyatients with essential hypertension, cardiac output isow, and systemic vascular resistance is elevated.7,8

he provocative work of Fries9 and Folkow10 docu-ented that systemic vascular resistance parallels hy-

ertensive vascular disease. Therefore, antihyperten-ive therapy should aim (1) to diminish vascularesistance by affecting it either functionally or struc-urally, and (2) to preserve systemic blood flow byaintaining cardiac output.

Most antihypertensive agents, including diuretics,roduce a decrease in vascular resistance while spar-ng systemic flow and cardiac output. Traditional-blockers are an exception to this rule. Numeroustudies have confirmed that traditional nonvasodilat-ng �-blockers lower arterial pressure by decreasingardiac output while systemic vascular resistance re-ains unchanged or even increases. Lund-Johansen11

as reported that even after 5 years of atenolol ther-

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py, cardiac output remained depressed and systemicascular resistance increased compared with pretreat-ent levels.

A review of 85 studies examining 10 different-blockers showed an increase in peripheral resistancend a decrease in cardiac output with short-term treat-ent. With long-term treatment, cardiac output re-ained depressed, although total peripheral resistance

ecreased somewhat but remained distinctly aboveormal levels.12 Thus, while lowering arterial pres-ure, traditional �-blockers produce exactly the oppo-ite hemodynamic effect than would be desirable inhe patient with essential hypertension. By shifting theemodynamic profile from a pattern of normal cardiacutput and high vascular resistance to a pattern of lowardiac output and high vascular resistance, traditional-blockers make the hypertensive patient hemody-amically older and may accelerate the biologicallock.7,8 In contrast to the hemodynamic effect ofraditional �-blockers, carvedilol lowers arterial pres-ure by maintaining cardiac output and decreasingotal �-blocking peripheral resistance.13–15 Carvedilol,s a vasodilating �-blocker, exerts a hemodynamicrofile that is similar to those of ACE inhibitors andalcium antagonists, and it sharply contrasts with theemodynamic profile of traditional �-blockers.16 Tra-itional �-blockers, such as atenolol and metoprolol,re �1-selective �-blockers, whereas carvedilol is a1-, �2-, and �-adrenergic blocker, which accounts for

ts vasodilatory effects in contrast to the �1-selectivegents.

FFECT OF �-BLOCKERS ON BLOODRESSURE

By definition, all antihypertensive drugs lowerlood pressure, and �-blockers are no exception.owever, their antihypertensive efficacy is less well

stablished than that of other drug classes, such asiuretics. In the Swedish Trial on Old Patients,STOP-1), 33% to 49% of patients assigned to-blocker therapy with metoprolol had well-con-

rolled blood pressure while on monotherapy, whereas0% of patients assigned to diuretics reached targetlood pressures.17 �-Blockers are less efficacious inatients with predominantly systolic hypertension be-ause of their negative chronotropic effect. Any de-rease in heart rate may be compensated by an in-rease in stroke volume, which will have a tendency tolevate (or to diminish the decrease in) systolic pres-ure and exacerbate the decrease of diastolic pressure.hus, bradycardia produces an increase in pulse pres-ure, and this may be a reason why traditional-blockers are less efficacious antihypertensive drugs,articularly in the elderly.

Traditional �-blockers are the only class of drugssed to treat patients with hypertension and cardio-ascular disease for which a paradoxical increase inlood pressure has been documented.18–20 Vasodilat-ng �-blockers, such as carvedilol, can be expected toave a more consistent blood pressure–lowering effecthan do the traditional �-blockers, such as metoprolol

nd atenolol. fi

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FFECTS OF �-BLOCKERS ON LEFTENTRICULAR HYPERTROPHY�-Blockers may be less effective in reducing left

entricular hypertrophy than other drug classes.21–23

n a double-blind study, Schulman et al23 reported thattenolol failed to reduce left ventricular hypertrophyn the elderly, whereas verapamil produced a decreasen left ventricular mass in parallel with a reduction inrterial pressure. Conceivably, the additional �-block-ng effect that occurs with carvedilol may exert aomewhat favorable effect on left ventricular hyper-rophy compared with conventional �-blockers. How-ver, this hypothesis should be confirmed in a head-to-ead comparison. By improving left ventricular fillingnd reducing heart rate, �-blockers may have a ben-ficial effect on hypertensive heart disease. However,eart rate decreases spontaneously with age, and, inost elderly patients, the negative chronotropic and

notropic effects of �-blockers are undesirable. Itomes, therefore, as little surprise that most studiesith newer antihypertensive drugs choose as a com-arator atenolol to demonstrate superior efficacy withegard to left ventricular hypertrophy reduction. Aypical example is the recent Losartan Intervention fornd Point Reduction in Hypertension (LIFE) study, inhich losartan was compared with atenolol.24 As pre-icted, the outcome was favorable for losartan, andeft ventricular hypertrophy was better reduced withhe angiotensin receptor blocker–based therapy thanith atenolol-based therapy. No head-to-head com-arisons of carvedilol and traditional �-blockers arevailable in patients with left ventricular hypertrophy.

FFECTS OF �-BLOCKERS ONASCULAR DISEASEHypertensive vascular disease, the common de-

ominator of hypertensive target organ involvement,s characterized by functional and structural changesn the arterial wall.10 Unlike ACE inhibitors and cal-ium antagonists, traditional �-blockers do not reduceulse pressure, arterial compliance, pulse-wave reflec-ions, or shear stress.

In double-blind randomized trials of untreated pa-ients with essential hypertension, Schiffrin et al25–28

howed that media-lumen ratios of subcutaneous re-istance arteries were reduced with ACE inhibitors,alcium antagonists, and angiotensin receptor block-rs, whereas no significant change of either atrialtructure or endothelial function was observed after 1ear of �-blocker therapy (atenolol). In all treatmentroups, blood pressure decreased to the same extent.

FFECTS OF �-BLOCKERS ONYPERTENSIVE RENAL DISEASEEarly-stage hypertensive renal disease is character-

zed by a decrease in renal blood flow, relativelyell-preserved glomerular filtration rate, and an in-

rease in filtration fraction.29–32 With the few notablexceptions of the vasodilating compounds, traditional-blockers further diminish renal blood flow and in-rease filtration fraction.32 Decreases in glomerular

ltration rate have also been reported with �-block-

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de.33 Microproteinuria has been shown, to some ex-ent, to parallel renal disease, particularly in hyperten-ive patients with diabetes mellitus.34–37 Datassessing the effects of �-blockade on microprotein-ria are inconsistent. Microproteinuria diminishesuring short-term �-blocker therapy, but prolongedherapy fails to reduce microproteinuria comparedith ACE inhibitors or nondihydropyridine calcium

ntagonists, despite equal antihypertensive efficacy.38

Of note, in a recent randomized controlled trial inatients with hypertension and chronic renal failure,nalapril significantly slowed progression to end-stageenal failure compared with �-blockers.38 Blood pres-ure control was similar in both treatment groups,ndicating that the effect on renal function was notediated through blood pressure. These data suggest

hat either enalapril has a beneficial effect independentf blood pressure or that �-blockers have a detrimen-al effect on renal function independent of bloodressure.

In contrast to conventional �-blockers, several tri-ls have documented a favorable effect of carvediloln renal hemodynamics. Plasma flow has been showno increase significantly with carvedilol, and mi-roalbuminuria has been found to decrease.39–43 Theemodynamic effects of carvedilol are prone to trans-ate into a more favorable renal effect than those seenith conventional �-blockade.

ETABOLIC EFFECTS OF �-BLOCKERSThere are conflicting reports of the effects of

IGURE 1. Metabolic effects of carvedilol compared with those ofiabetes who were treated with either drug for 24 weeks. HbA1cot significant. (Adapted from Ann Intern Med.56)

-blockers on serum lipoprotein and carbohydrate me- i

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abolism. Reviews suggest that �-blockers increaseriglyceride levels and decrease high-density lipopro-ein (HDL) cholesterol levels.44–48 �-Blockers withntrinsic sympathomimetic activity have a lesser effectn triglycerides and HDL than �-blockers withoutntrinsic sympathetic activity. In a recent review of74 studies, Kasiske et al48 showed that cardioselec-ivity diminished the increase in triglyceride levelsnd that the effects of �-blockers on HDL cholesterolppeared to diminish with duration of treatment.

Patients with hypertension but without diabetesay be at a higher risk for developing diabetes when

reated with �-blockers.49–54 However, the effects of-blockers on both lipid and carbohydrate metabolism

n the elderly may be of less concern than in youngeratients who will be exposed to these agents for aonger time.

Nowhere is the heterogeneity among various-blockers more evident than in their metabolic effect.

n contrast to conventional �-blockers,55 carvedilolas been shown to have a neutral or beneficial effectn insulin resistance, lipoprotein lipase activity, tri-lycerides, and cholesterol. The metabolic effects ofarvedilol were compared with those of atenolol in arospective study of 45 patients with hypertension andiabetes who were treated with either drug for 24eeks.56 Compared with atenolol, significant im-rovements in fasting blood sugar, glycosylated he-oglobin, and insulin levels were observed with

arvedilol. Insulin levels increased 10% with atenolol;

olol in a prospective study of 45 patients with hypertension andlycosylated hemoglobin; HDL � high-density lipoprotein; NS �

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n contrast, carvedilol elicited a 10% decrease (Figure

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). Conceivably, carvedilol’s vasodilatory effect, byncreasing glucose utilization, could lead to a decreasen the levels of circulating insulin, thus improvingnsulin sensitivity. Traditional �-blockers, because oferipheral vasoconstriction, may impair glucose utili-ation and reduce insulin sensitivity.57–59 It comes asittle surprise that in the Carvedilol or Metoprololuropean Trial (COMET) study, the risk for new-nset diabetes was significantly lower in patients ran-omized to carvedilol than in those treated with meto-rolol (relative risk, 0.78; 95% confidence interval,.61 to 0.99) (Figure 2).60

�-Adrenergic responsiveness and age: Several ex-erimental and human studies have documented thatormative aging is accompanied by a progressive de-rease in cardiovascular responsiveness to �-adrener-ic stimulation.47,61–64 The age-associated changes inardiovascular findings are accompanied by increasesn plasma catecholamine levels,7,65 similar to the ef-ects observed with �-blocker therapy. In a studyssessing the effects of acute �-adrenergic receptorlockade on age-associated changes in cardiovascularerformance with exercise, Fleg et al66 showed thathe age-associated decreases in maximal heart rate andeft ventricular contractility with exercise are probablyanifestations of a reduced �-adrenergic responsive-

ess. This would indicate that a “physiologic �-block-de” accounts for attenuated cardiac acceleration andyocardial contractility in the elderly. Not surpris-

ngly, the superimposition of a pharmacologic-blockade on the intrinsic physiologic blockade may

esult in poor tolerability in elderly patients. Carve-ilol, because of its afterload-reducing effect, mayounterbalance some of the negative inotropic effectsssociated with traditional �-blockade and may have aore favorable effect on cardiovascular function in

IGURE 2. Risk for new-onset diabetes in patients with congestivearvedilol or Metoprolol European Trial (COMET). CI � confidence

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0B THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 93 (9

HE EFFECTS OF �-BLOCKERS ONXERCISE CAPACITY

Elderly subjects respond to exercise with a bluntedncrease in heart rate and ejection fraction and areater use of the Frank-Starling mechanism, whenompared with younger subjects. Exercise capacityrogressively decreases with age, particularly in hy-ertensive populations. By exerting a negative chro-otropic and negative inotropic effect, �-blockers fur-her diminish exercise capacity in the elderly and arearticularly ill tolerated in patients who remain phys-cally active. The �-blocking effect of carvedilol mayounterbalance the negative chronotropic and inotro-ic effect to some extent, and therefore carvedilolhould be better tolerated in the physically activelderly patient than conventional �-blockers.

HE EFFECTS OF �-BLOCKERS ONOMORBIDITY IN THE ELDERLY

Hypertension is rarely an isolated disorder in thelderly patient. Chronic obstructive pulmonary dis-ase, peripheral vascular disease, diabetes, depressiveisorders, and sexual dysfunction are comorbid con-itions frequently encountered in the geriatric popu-ation. Although none of these comorbid conditions is

direct contraindication to using �-blockers, theirresence not only makes traditional �-blockers lessesirable as first-line antihypertensive drugs but theyre also prone to decrease the patient’s tolerability for-blockers.

Whereas negative effects of carvedilol on chronicbstructive pulmonary disease and depression are un-ikely to be different from conventional �-blockers,he vasodilating effects of carvedilol, as discussedbove, have been shown to be beneficial in patients

57–59 67

rt failure treated with either carvedilol or metoprolol in theerval. (Adapted from Lancet.60)

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ONCLUSIONMost studies assessing the effects of �-blockers on

orbidity and mortality as well as on systemic hemo-ynamics and target organ disease were conductedith traditional �-blockers, such as metoprolol and

tenolol. Several pathophysiologic/pharmacologictudies have documented that not all �-blockers arereated equal. In particular, the new vasodilating com-ounds, such as carvedilol, have been shown to differn their cardiovascular effects from traditional-blockers (Table 1).

Carvedilol, in contrast to the classic �-blockers,aintains cardiac output, has little effect on heart rate,

nd decreases blood pressure by decreasing systemicascular resistance. In addition, carvedilol seems toxert a more powerful effect on left ventricular hyper-rophy than does metoprolol. In the COMET study ofatients with congestive heart failure,60 all-cause mor-ality, cardiovascular mortality, and death from strokeere reduced significantly more with carvedilol thanith metoprolol. Although findings from patients with

ongestive heart failure cannot be extrapolated to pa-ients with uncomplicated hypertension, they under-core the attractiveness of carvedilol for thisndication.

Furthermore, the well-documented adverse effectsf the classic �-blockers on the metabolic syndromeinsulin resistance and dyslipoproteinemia) seem to bebsent or at least much less pronounced with carve-ilol. These unique features allow us to hypothesizehat carvedilol should exert a more beneficial effect onardiovascular morbidity and mortality than do theraditional �-blockers. Clearly, however, this hypoth-sis needs to be tested in a prospective clinical trial.

. The fifth report of the Joint National Committee on Detection, Evaluation andreatment of High Blood Pressure (JNC V). Arch Intern Med 1993;153:154–183.. Messerli FH, Beevers DG, Franklin SS, Pickering TG. �-Blockers in hyper-

ension—the emperor has no clothes: an open letter to present and prospectiverafters of new guidelines for the treatment of hypertension. Am J Hypertens003;16:870–873.. Prichard BN, Gillam PM. Use of propranolol (Inerdal) in treatment of hyper-

ension. BMJ 1964;5411:725–727.. Messerli FH, Grossman E, Goldbourt U. Are beta-blockers efficacious asrst-line therapy for hypertension in the elderly?: a systematic review. JAMA

TABLE 1 Effects of Antihypertensive Drugs in Patients with Hyper

IdealDrug

Traditional�-Blockers Carvedi

Mean arterial blood pressure 2 2 2Total peripheral resistance 2 (1) (2)Cardiac output 0 (2) 0Heart rate 0/2 2 0/2Activation of sympathetic

nervous system2 2 2

Renin-angiotensin-aldosterone system

2 2 2

Lipid metabolism 0/� � 0Glucose metabolism 0/� � 0

ACE � angiotensin-converting enzyme; ARB � angiotensin receptor blocker; Dno effect; � � positive effect; � � negative effect; ( ) � predominantly after a

998;279:1903–1907. s

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. Psaty BM, Smith NL, Siscovick DS, Koepsell TD, Weiss NS, Heckbert SR,emaitre RN, Wagner EH, Furberg CD. Health outcomes associated with anti-ypertensive therapies used as first-line agents: a systematic review and meta-nalysis. JAMA 1997;277:739–745.. Frohlich ED, Tarazi RC, Dustan HP. Re-examination of the hemodynamics ofypertension. Am J Med Sci 1969;257:9–23.. Messerli FH, Sundgaard-Riise K, Ventura HO, Dunn FG, Glade LB, FrohlichD. Essential hypertension in the elderly: haemodynamics, intravascular volume,lasma renin activity, and circulating catecholamine levels. Lancet 1983;2:983–86.. Lund-Johansen P. Hemodynamic patterns of untreated hypertensive disease.n: Laragh JH, ed. Hypertension: Pathophysiology, Diagnosis, and ManagementTwo-Volume Set). New York: Raven Press, 1995:323–342.. Fries ED. Hemodynamics of hypertension. Physiol Rev 1960;40:27–55.0. Folkow B. Physiological aspects of primary hypertension. Physiol Rev982;62:347–504.1. Lund-Johansen P. Hemodynamic consequences of long-term beta-blocker

herapy: a 5-year follow-up study of atenolol. J Cardiovasc Pharmacol 1979;1:87–495.2. Man in’t Veld AJ, Van den Meiracker AH, Schalekamp MA. Do beta-lockers really increase peripheral vascular resistance?: review of the literaturend new observations under basal conditions. Am J Hypertens 1988;1:91–96.3. Sponer G, Feuerstein G. The adrenergic pharmacology of carvedilol. Heartail Rev 1999;4:21–27.4. Frishman WH. Carvedilol. N Engl J Med 1998;339:1759–1765.5. Ruffolo RR, Feuerstein G, Yue TL, Ma X. Carvedilol: a novel cardiovascularrug with multiple actions. Cardiovasc Drug Rev 1992;10:127–157.6. Weber K, Bohmeke T, van der DR, Taylor SH. Comparison of the hemody-amic effects of metoprolol and carvedilol in hypertensive patients. Cardiovascrugs Ther 1996;10:113–117.7. Ekbom T, Dahlof B, Hansson L, Lindholm LH, Schersten B, Wester PO.ntihypertensive efficacy and side effects of three beta-blockers and a diuretic in

lderly hypertensives: a report from the STOP-Hypertension study. J Hypertens992;10:1525–1530.8. Drayer JI, Keim HJ, Weber MA, Case DB, Laragh JH. Unexpected pressoresponses to propranolol in essential hypertension: an interaction between renin,ldosterone and sympathetic activity. Am J Med 1976;60:897–903.9. Blum I, Atsmon A, Steiner M, Wysenbeek H. Paradoxical rise in bloodressure during propranolol treatment. BMJ 1975;4:623.0. Kario K, Shimada K, Pickering TG. Pressor effects of beta-blockers ontanding blood pressure may be harmful for older patients with orthostaticypertension. Circulation 2002;106:e196–e197.1. Cruickshank JM, Lewis J, Moore V, Dodd C. Reversibility of left ventricularypertrophy by differing types of antihypertensive therapy. J Hum Hypertens992;6:85–90.2. Dahlof B, Pennert K, Hansson L. Reversal of left ventricular hypertrophy inypertensive patients: a metaanalysis of 109 treatment studies. Am J Hypertens992;5:95–110.3. Schulman SP, Weiss JL, Becker LC, Gottlieb SO, Woodruff KM, WeisfeldtL, Gerstenblith G. The effects of antihypertensive therapy on left ventricularass in elderly patients. N Engl J Med 1990;322:1350–1356.4. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U,yhrquist F, Ibsen M, Kristiansson K, Lederballe-Pedersen O, et al, for the LIFEtudy Group. Cardiovascular morbidity and mortality in the Losartan Interven-

ion For Endpoint reduction in hypertension study (LIFE): a randomised trialgainst atenolol. Lancet 2002;359:995–1003.5. Schiffrin EL, Deng LY, Larochelle P. Effects of a beta-blocker or a convert-

ng enzyme inhibitor on resistance arteries in essential hypertension. Hyperten-

sion

�1-AdrenoceptorBlocker

ACEInhibitoror ARB

DHP–CalciumAntagonist

ThiazideDiuretic

2 2 2 22 2 2 20 0 0 0

(1) 0 (1) 0(1) 2 1 1

0 2 1 1

0/� 0 0 �0 0/� 0 �

� dihydropyridine;1 � increase (activation);2 � decrease (inhibition); 0 �

administration.

ten

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ion 1994;23:83–91.

MPOSIUM: CARVEDILOL IN CARDIOVASCULAR MEDICINE 11B

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6. Schiffrin EL, Deng LY, Larochelle P. Progressive improvement in thetructure of resistance arteries of hypertensive patients after 2 years of treatmentith an angiotensin I-converting enzyme inhibitor: comparison with effects of aeta-blocker. Am J Hypertens 1995;8:229–236.7. Schiffrin EL, Deng LY. Structure and function of resistance arteries ofypertensive patients treated with a �-blocker or a calcium channel antagonist. Jypertens 1996;14:1247–1255.8. Schiffrin EL, Park JB, Intengan HD, Touyz RM. Correction of arterialtructure and endothelial dysfunction in human essential hypertension by thengiotensin receptor antagonist losartan. Circulation 2000;101:1653–1659.9. Hollenberg NK, Epstein M, Basch RI, Merrill JP. “No man’s land” of theenal vasculature: an arteriographic and hemodynamic assessment of the interlo-ar and arcuate arteries in essential and accelerated hypertension. Am J Med969;47:845–854.0. London GM, Safar ME, Sassard JE, Levenson JA, Simon AC. Renal andystemic hemodynamics in sustained essential hypertension. Hypertension 1984;:743–754.1. Schmieder RE, Schachinger H, Messerli FH. Accelerated decline in renalerfusion with aging in essential hypertension. Hypertension 1994;23:351–357.2. de Leeuw PW, Gaillard CA, Birkenhager WH. Renal hemodynamic patterns

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mbulatory blood pressure, renal hemodynamics, and cardiac function in essen-ial hypertension. J Cardiovasc Pharmacol 1987;10(suppl 11):S130–S136.2. Marchi F, Ciriello G. Efficacy of carvedilol in mild to moderate essentialypertension and effects on microalbuminuria: a multicenter, randomized, open-abel, controlled study versus atenolol. Adv Ther 1995;12:212–221.3. Agrawal B, Wolf K, Berger A, Luft FC. Effect of antihypertensive treatmentn qualitative estimates of microalbuminuria. J Hum Hypertens 1996;10:551–55.4. Weidmann P, Ferrier C, Saxenhofer H, Uehlinger DE, Trost BN. Serum

ipoproteins during treatment with antihypertensive drugs. Drugs 1988;35(suppl):118–134.5. Grimm RH Jr. Antihypertensive therapy: taking lipids into consideration. Ameart J 1991;122:910–918.6. Roberts WC. Recent studies on the effects of beta blockers on blood lipid

evels. Am Heart J 1989;117:709–714.7. van Brummelen P, Buhler FR, Kiowski W, Amann FW. Age-related decrease

n cardiac and peripheral vascular responsiveness to isoprenaline: studies in

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