Effects of a Calcium Channel Blockeron Cardiac Output Distribution in

Conscious Hypertensive DogsDELVIN R. KNIGHT, DEBRA A. KIRBY, AND STEPHEN F. VATNER

SUMMARY The effects of nitrendipine, 8 /xg/kg/minute, were evaluated in six conscious dogsthrough measurements of arterial pressure and blood flow in the ascending aorta (cardiac output),mesenteric, renal, and iliac arteries before and after induction of chronic perinephritic hypertension.Before hypertension was induced, nitrendipine reduced mean arterial pressure 19 ± 2.3% (from 95± 3.2 mm Hg), decreased total peripheral resistance (60 ± 2.6%), and increased cardiac output (108± 10.5%). These values returned to baseline within 15 to 30 minutes. Nitrendipine caused the greatestincrease in blood flow in the iliac bed (98 ± 9.9%), an intermediate increase in the mesenteric bed (37± 3.7%), and the least increase in the renal bed (7 ± 2.2%). Two to six weeks after induction ofhypertension, administration of nitrendipine elicited significant (p < 0.01) decreases in mean arterialpressure (32 ± 2.5% from 151 ± 4.8 mm Hg) and total peripheral resistance (67 ± 1.3%) comparedwith its administration in normotensive dogs, while the increase in cardiac output was not significantlychanged (111 ± 10.9%). These changes in arterial pressure and vascular resistances also wereprolonged (i.e., hemodynamics returned to baseline after 75-90 minutes). The increase in iliac (99 ±16.8%) and renal (9 ± 6.1 %) blood flows after nitrendipine administration in hypertensive dogs wassimilar to that found in the normotensive dogs, but mesenteric blood flow doubled (84 ± 8.4%). Thus,in conscious, hypertensive dogs, nitrendipine administration appears to markedly decrease arterialpressure and total peripheral and regional resistances, which also require more time to returnto baseline, but appears to increase blood flow by a greater amount only in the mesenteric bed.(Hypertension 7: 380-385, 1985)

KEY WORDS • perinephritic hypertension • regional blood flow • total peripheralresistance * nitrendipine

BECAUSE of their potent action to relax vascu-lar smooth muscle, calcium channel blockersare useful for the treatment of systemic hyper-

tension.1"5 Previous studies have demonstrated thatcalcium channel blockers elicit enhanced relaxation ofvascular smooth muscle and reductions in arterial pres-sure in both experimental animal models46"8 and hu-mans2"4 7 9 l0 with hypertension. The extent to whichcalcium channel blockers affect peripheral blood flow

From the Departments of Medicine. Harvard Medical School andBrigham and Women's Hospital. Boston. Massachusetts, and theNew England Regional Primate Research Center. Southboro.Massachusetts.

Supported in part by USPHS Grants HL33I07 and HL33743. Dr.Knight was supported by USPHS NRSA Fellowship HL06440. Dr.Kirby was supported by a fellowship (13-436-823) from the Massa-chusetts Heart Association.

Address for reprints: Dr. Stephen F. Vatner, New England Re-gional Primate Research Center, I Pine Hill Drive. Southboro,Massachusetts 01772.

Received May 31, 1984; revision accepted December 6, 1984.

distribution in hypertension, particularly in the con-scious animal and human, has not been established. Infact, relatively little is known about the effects of cal-cium channel blockers on regional blood flow distribu-tion even in normotensive animals and humans.

The goal of our study was to determine the extent towhich nitrendipine alters the distribution of cardiacoutput to the major peripheral beds (i.e., mesenteric,renal, and iliac beds) in the conscious, hypertensiveanimal. To accomplish this goal, nitrendipine wasstudied in chronically instrumented dogs with normalarterial pressures and again in the same dogs afterinducing chronic, perinephritic hypertension. Nitren-dipine, a 1,4 dihydropyridine, was selected because itis relatively specific for vascular smooth muscle andhas been shown to bind to vascular smooth musclewith high affinity." It is recognized that while nitren-dipine may be representative of the dihydropyridinederivatives, it may not reflect the action of other cal-cium channel blockers.12

380

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ENHANCED MESENTERIC DILATION WITH NITRENDIPINE IN HYPERTENSION/K/ng/tf et al. 381

MethodsSix mongrel dogs weighing 20 to 40 kg were anes-

thetized with sodium pentobarbital, 30 mg/kg i.v.Through a left thoracotomy at the fourth intercostalspace, a heparin-filled Tygon catheter was implantedin the descending thoracic aorta and an electromagnet-ic flow transducer (Zepeda Instruments, Seattle, WA)was placed around the ascending aorta. Through amidline laporotomy, Doppler ultrasonic flow trans-ducers were implanted around the superior mesentericand renal arteries and an electromagnetic flow trans-ducer was implanted on the right iliac artery. A hy-draulic occluder was implanted distally on the iliacartery to establish zero blood flow.

Arterial pressure was measured by connecting theaortic catheter to a Statham P23ID strain gauge trans-ducer (Statham Instruments, Oxnard, CA). Ascendingaortic blood flow (i.e., cardiac output minus coronaryblood flow) and iliac blood flow were measured with asquare-wave electromagnetic flowmeter (Benton In-struments, Cupertino, CA). Mesenteric and renalblood flows were measured with the Doppler ultrason-ic flowmeter. The Doppler flowmeter had been cali-brated previously against the electromagnetic flow-meter and was found to be linear with a reliable zeroflow reference.11

The initial experiments were conducted 2 to 4 weeksafter instrumentation in normotensive, consciousdogs. These studies were performed in conscious,healthy animals to eliminate the effects of anesthesiaand recent operation.14 Measurements of arterial pres-sure, cardiac output, heart rate, and mesenteric, renal,and iliac blood flows were continuously recorded dur-ing the control period and for 2 hours after the infusionof nitrendipine, 8 /Mg/kg/minute for 5 minutes (MilesPharmaceuticals, New Haven, CT). Following thenormotensive studies, hypertension was induced in thesame six dogs with the method of Page.15 Through aflank incision, the renal capsule was stripped of fasciaand the kidney wrapped first in raw silk followed byplastic sheeting to prevent adhesions. One week later,the contralateral kidney was removed. Three to sixweeks after nephrectomy, when the pressure had stabi-lized at a hypertensive level, nitrendipine infusion wasrepeated. As the electromagnetic flow measurementon the iliac artery failed to operate properly in all dogs,two additional normotensive and two additional hyper-tensive animals were studied with measurements ofiliac blood flow and arterial pressure. Total renal bloodflow to one kidney was measured by implanting atransducer on either the right or left renal artery.

Nitrendipine was weighed and dissolved under asodium vapor lamp in a solution of 50% polyethyleneglycol and 50% sterile distilled water. The injectionsof the vehicle, administered before each experiment,elicited no detectable hemodynamic effects. All infu-sions of the calcium channel blocker were protectedfrom ultraviolet light during the experiments.

The data were recorded on a 14-channel magnetictape recorder (Honeywell Test Instruments Division,Denver, CO) and monitored on two multichannel os-

cillographs (Gould Instruments, Cleveland, OH).Mean arterial pressure and mean mesenteric, renal,and iliac blood flows were derived using R-C filterswith 2-second time constants. Mean aortic blood flowwas derived with an R-C filter with an 8-second timeconstant. Heart rate was measured continuously with acardiotachometer triggered by the signal from the pul-satile aortic blood flow. Total peripheral and regionalresistances were calculated as the quotient of meanarterial pressure and cardiac output and mean arterialpressure and regional blood flows respectively. Strokevolume was calculated as the quotient of cardiac outputand heart rave.

The means ± SEM were calculated for all variables.Paired responses to nitrendipine before and after sys-temic hypertension were analyzed in six dogs for allparameters except iliac blood flow. Thus, the t test forpaired comparisons was used for all statistical analysesexcept in the iliac bed, where responses were analyzedusing Student's t test for group comparisons.16

ResultsTypical responses to nitrendipine, 8 /u,g/kg/minute,

are shown in the same dog before (Figure 1) and afterhypertension was induced (Figure 2). Baseline valuesand absolute changes from baseline in response to ni-trendipine, 8 jiig/kg/minute, are shown in Tables 1through 3. All data represent steady state conditionsduring the infusions and are expressed as means ±SEM.

Effects of Nitrendipine Infusion on ConsciousNormotensive Dogs

Nitrendipine, 8 ^tg/kg/minute, reduced arterial pres-sure by 19 ± 2.3% and total peripheral resistance by60 ± 2.6%, and increased cardiac output by 108 ±10.5% and heart rate by 94 ± 12.3% without signifi-cantly increasing calculated stroke volume (8 ± 3.8%)(see Table 1). The largest increase in regional bloodflows occurred in the iliac bed (98 ± 9.9%), whereiliac resistance was decreased by 57 ± 3.0%. Anintermediate vasodilation occurred in the mesentericbed, where blood flow rose by 37 ± 3.7% and vascu-lar resistance decreased by 42 ± 3.2%. Nitrendipinewas least effective in the renal bed, where renal bloodflow increased by 7 ± 2.2% and vascular resistancedecreased by 26 ± 2.5% (see Tables 2 and 3). Allvalues returned to baseline within 15 to 30 minutesfollowing nitrendipine administration.

The percentage increases in iliac blood flow withnitrendipine were not significantly different from thatof cardiac output. Nitrendipine induced significantlylower (p < 0.01) percentage increases in mesentericblood flow than in either cardiac output or iliac bloodflow; however, the increases in mesenteric blood flowwith nitrendipine were significantly greater than theincreases in renal blood flow (p < 0.01). Nitrendipineinduced similar percentage decreases in iliac and totalperipheral resistances, which were significantly great-er (p < 0.01) than the percentage decreases in mesen-teric resistance. The decreases in mesenteric resistance

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FIGURE I. Typical response to an infusion ofnitrendipine, 8 fig/kg/minute, as shown for anormotensive dog. Phasic arterial pressure,ascending aortic blood flow, mean aorticblood flow (cardiac output), phasic and meanmesenteric blood flow, phasic renal blood flow,and phasic and mean iliac blood flow weremeasured. Nitrendipine increased iliac bloodflow more than mesenteric and renal bloodflows. All values returned to baseline within 15minutes.

HYPERTENSION

Arterial PressuremmHg

Aortic Blood Flow(ml/min)

Cardiac Output(ml/min)

MesentericBlood Flow(ml/min)

VOL 7, No 3, MAY-JUNE 1985

Smfei

MeaBlood Flow(ml/min)

Blood Flow(ml/mm)

Blood Flow(ml/mini

Mean IliacBlood Flow(ml/min,

30 mm 60 nun

Arterial Pressure

Aortic Blood Flowml mini

Cardiac Outputml mini

MesentericBlood Flowi ml/min)

Mean MesentericBlood Flow(ml/min)

RenalBlood Flow(ml/min)

IliacBlood Flow(ml/min)

Mean IliacBlood Flow(ml/min)

FIGURE 2. Response to nitrendipine, 8 ixglkgl minute, after the induction of chronic perinephritic hypertension,in the same dog and on the same measurements as shown in Figure I. The vasodilation induced by nitrendipinewas augmented in magnitude as well as duration.

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ENHANCED MESENTERIC DILATION WITH NITRENDIPINE IN HYPERTENSION/Km^/ et at. 383

TABLE I. Effects of Nitrendipine on Central Hemodynamics

Change withBaseline nitrendipine

Mean arterial pressure (mm Hg)

TABLE 2. Effects of Nitrendipine on Regional Blood Flows(mllmin)

Normotensive(" = 6)

Hypertensive

Heart rate (beats/min)

Normotensive

Hypertensive

Cardiac output (ml/min)

Normotensive

Hypertensive

Stroke volume (ml)

Normotensive. (« = 6)

Hypertensive

Total peripheral resistance(mm Hg/ml/min)

Normotensive

Hypertensive(n = 6)

95 ±3.2

151 ±4.8t

82 ±5.7

86 ±6.7

2595 ±179

2700 ± 198

32.1 ±2.7

33.0 + 4.6

0.037 ±0.002

0.058 ± 0.0061

-18 ±2.1*

-49±4.9*t

76 ±9.6*

80 ±8.4*

2715 ±142*

3043 ±438*

2.5 ±1.3

3.0 ±2.2

0.023 ±0.002*

0.039 ±0.004*1

*Response significantly different from baseline (p < 0.01).tHypertension significantly different from normotensive (p <

0.01).Values are means ± SEM.

with nitrendipine were significantly greater (p < 0.01)than the percentage decreases in renal resistance.

Effects of Nitrendipine Infusion on ConsciousHypertensive Dogs

With the development of hypertension in thesedogs, mean arterial pressure rose from 95 ± 3.2to 151± 4.8 mm Hg (p < 0.01) without significantly chang-ing any of the baseline values for aortic and regionalblood flows or heart rate. Total peripheral resistancerose from 0.037 ± 0.002 to 0.058 ± 0.006 mmHg/ml/minute (p < 0.01), mesenteric resistance rosefrom 0.24 ± 0.02 to 0.43 ± 0.04 mm Hg/ml/minute(p < 0.01), renal resistance rose from 0.63 ± 0.08 to1.28 ± 0.21 mm Hg/ml/minute (p < 0.01), and iliacresistance rose from 0.86 ± 0.08 to 1.27 ± 0.19 mmHg/ml/minute (p = 0.06).

Nitrendipine, 8 /xg/kg/minute, in the presence ofchronic hypertension, reduced mean arterial pressureby 32 ± 2.5% and total peripheral resistance by 67 ±1.3% and increased cardiac output by 111 ± 10.9%and heart rate by 96 ± 10.6%, again without signifi-cantly increasing calculated stroke volume (9 ± 6.0%;see Table 1). All values returned to baseline 75 to 90minutes after nitrendipine administration (Figure 3).

The largest increases in regional blood flows oc-curred in the iliac bed (99 ± 16.8%), where iliacresistance was decreased by 66 ± 2.9%, and in themesenteric bed, where blood flow rose by 84 ± 8.4%and vascular resistance decreased by 64 ± 1.2%. Ni-trendipine administration remained least effective inthe renal bed, where renal blood flow increased by 9 ±6.1% and vascular resistance decreased by 39 ± 4.6%(see Tables 2 and 3).

BaselineChange withnitrendipine

Mesenteric blood flow

Normotensive

Hypertensive

Renal blood flow

Normotensive

Hypertensive

Iliac blood flow

Normotensive

(n = 6)

(n = 6)

Hypertensive(n = 6)

408 ±40.9

369 ±28.3

157±17.6

134±19.7

114±14.2

132±19.2

150±16.7*

303±23.9*t

10±3.0*

11 ±6.3*

108 ±10.9*

134±31.1*

*Response significantly different from baseline (p < 0.01).tHypertension significantly different from normotensive (p <

0.01).Values are means ± SEM.

TABLE 3. Effects of Nitrendipine on Regional Resistances(mm Hg/ml/min)

BaselineChange withnitrendipine

Mesenteric resistance

Normotensive

Hypertensive

Renal resistance

Normotensive

Hypertensive

Iliac resistance

Normotensive (n = 6)

Hypertensive {n = 5)

(n = 6)

(n = 6)

0.24±0.02

0.43±0.04t

O.63±O.O81.28±0.21t

0.86±0.08

1.27 + 0.19

-0.10±0.01*

-O.28±O.O3*t

-0.17±0.03*

-0.50±0.11*t

-0.49 ±0.04*

-0.83 ±0.11**

*Response significantly different from baseline (p < 0.01).t,tHypertension significantly different from normotensive (tp

< 0.01, %p < 0.02).

Following the development of hypertension, nitren-dipine administration induced greater reductions in ar-terial pressure and total peripheral and regional resis-tances, which required a significantly longer time (p <0.05) to recover when compared with those responsesin the normotensive state (see Figure 3). After hyper-tension was induced, however, administration of ni-trendipine caused only slightly but not significantlygreater changes in cardiac output, while the increase inmesenteric blood flow doubled compared with re-sponses in the normotensive state (Figure 4).

The percentage increases in iliac blood flow wereagain not significantly different from that of cardiacoutput; however, the percentage increases in mesen-teric blood flow with nitrendipine were no longer lessthan the percentage increases in cardiac output andiliac blood flows and remained significantly greater (p< 0.01) than the percentage increases in renal bloodflow. The percentage decreases in total peripheral re-sistance, iliac resistance, and mesenteric resistancewith nitrendipine administration were similar to those

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384 HYPERTENSION VOL 7, No 3, MAY-JUNE 1985

Nitrendipine 15 30 45 60 75 90

Time after Nttrendipine Infusion (minutes)

FIGURE 3. The percent decreases in arterial pressure (AP)and total peripheral resistance (TPR) in response to nitrendi-pine, 8 fxglkglminute, are compared in the same dogs studiedbefore and following induction of hypertension. After inductionof hypertension, nitrendipine caused significantly greater (p <0.05) decreases in AP and TPR, which required significantlymore time to return to baseline.

MBF

FIGURE 4. Average ± SEM percent increases in cardiac out-put (CO), mesenteric (MBF), renal (RBF), and iliac (IBF)blood flows are shown in response to nitrendipine, 8 yiglkgl min-ute, before (open bars) and after (shaded bars) inducing peri-nephritic hypertension. After hypertension was induced, nitren-dipine administration caused a significantly greater percentageincrease in blood flow only to the mesenteric bed fp < 0.01).

obtained in the normotensive dogs, and all were sig-nificantly greater (p < 0.01) than the percentage de-crease in renal resistance.

DiscussionNitrendipine, a dihydropyridine calcium channel

blocker, elicited a differential pattern of vasodilationin the normotensive, conscious dog. It decreased arte-rial pressure and total peripheral resistance and in-duced the greatest dilation in the limb, the least dila-tion in the kidney, and an intermediate dilation in themesenteric bed. Other studies have examined theeffects of calcium channel blockers in normotensiveanimals.4-817"20 These studies, using different calci-um channel blockers, have observed vasodilation in

the gastrointestinal tract, renal and iliac vascularbeds12 l8~21 that varied depending on the animal modeland the classification of the calcium channel blockersused. We and other investigators'2 l8-19 2I found onlyslight vasodilation induced by calcium channel block-ers in the renal bed compared with other regional circu-lations. This finding might suggest that renal vesselsare less sensitive to these agents.

Previous studies have examined the effects of cal-cium channel blockers in hypertensive animal modelsand humans.2"10 These studies showed enhanced reduc-tions in arterial pressure and total peripheral resistanceto calcium channel blockers in hypertension.2"10 In thepresent investigation, conscious animals were studiedbefore and after chronic, perinephritic hypertensionwas induced. We also observed enhanced vasodilationand reductions in arterial pressure and total peripheralresistance. Even more prominent was the prolongedrecovery time for a single infusion of nitrendipine.Whereas arterial pressure and total peripheral resis-tance returned to baseline values within 15 to 30minutes after nitrendipine administration in the normo-tensive dogs, 75 to 90 minutes was required for thesevalues to return to baseline in the presence ofhypertension.

There are even less data on the effects of calciumchannel blockers on blood flow distribution to the pe-ripheral beds in hypertension. We utilized the model ofchronic, perinephritic hypertension so that nitrendi-pine could be studied in the same dogs before and afterestablishment of hypertension. In the presence of hy-pertension, neither baseline levels of cardiac outputnor any of the regional blood flows were different fromthe normotensive state, but baseline levels of total pe-ripheral and regional vascular resistances were signifi-cantly elevated. Under these conditions, nitrendipineenhanced vasodilation of all three peripheral beds stud-ied. This greater vasodilation was most likely due tothe altered baseline resistances induced by the hyper-tensive processes and the enhanced reduction in arteri-al pressure. The possibility that autoregulation is in-volved in the enhanced systemic and regional vascularresponses to nitrendipine cannot be ruled out, as auto-regulatory mechanisms may have been responsible forthe elevated levels of total peripheral and regional vas-cular resistances in the hypertensive state.

The major difference in response to nitrendipine inthe presence of hypertension occurred in the mesen-teric bed. Nitrendipine induced an intermediate vaso-dilation in the mesenteric bed in the normotensivestate, where it increased rrresenteric blood flow signifi-cantly less than either iliac blood flow or cardiac out-put. In the presence of hypertension, nitrendipine in-duced a twofold greater vasodilation in the mesentericbed that was no longer significantly less than in thelimb or the systemic circulation. Although this findinghas not been demonstrated previously, Aoki et al.7

have shown that nitrendipine induced enhanced relax-ation of mesenteric vascular strips from hypertensiverats. This greater effect in the mesenteric strips was notcompared with strips from other vascular beds.7

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ENHANCED MESENTERIC DILATION WITH NITRENDIPINE IN HYPERTENSION/A'/i/g/i/ et al. 385

The increased blood flow response to nitrendipine inthe mesenteric bed following hypertension in the pres-ent investigation could have been the result of eithergreater cardiac output or redistribution of blood flowfrom other beds. As we did not observe a reducedblood flow response in the renal or iliac bed, it is mostlikely that the greater response in the mesenteric bedwas due to increased cardiac output. In the hyperten-sive state, nitrendipine induced a slightly greater cardi-ac output response that was not statistically significant.Although the greater increase in cardiac output (300ml) was not sufficient to attain statistical significance,it could be sufficient to double the mesenteric bloodflow response to nitrendipine. This suggestion furtherpoints out the importance of studying regional bloodflow responses in addition to cardiac output, as selec-tive blood flow changes in only one bed would bedifficult to detect from the measurement of cardiacoutput alone; however, redistribution of blood flowfrom other beds not studied in these experiments (e.g.,coronary and cerebral beds), cannot be discounted.

Even though autoregulation of the regional vascularbeds may be responsible for the elevated vascular re-sistances in the hypertensive state, the possibility thatautoregulation is responsible for the difference in themesenteric blood flow response to nitrendipine follow-ing hypertension is unlikely. It is important to note thatautoregulatory theory indicates that blood flow ismaintained in the face of altered driving pressure.When nitrendipine was administered to the dogs fol-lowing induction of hypertension, a significantlygreater increase in blood flow to the mesenteric bedwas observed that cannot be explained entirely by au-toregulatory theory.

The enhanced vasodilation of the mesenteric bedcould be of therapeutic interest because, in the pres-ence of hypertension, increased vasodilation in thegastrointestinal tract would be preferred to greater va-sodilation of muscular beds. This finding might bepotentially important in patients with mesentericvascular insufficiency, in whom enhanced perfusionof the mesenteric bed would be salutary in the faceof hypertensive therapy, which reduces perfusionpressure.

In summary, administration of nitrendipine to hy-pertensive dogs produced a greater reduction in arterialpressure and total peripheral and regional resistances,which required a significantly longer time to recoverwhen compared with those responses in the normoten-sive state. In addition, the response of the mesentericbed to nitrendipine was unique when compared withthe responses of other peripheral beds studied, in thatthis calcium channel blocker induced a greater increasein blood flow only in the mesenteric bed.

AcknowledgmentsThe authors thank Miles Pharmaceuticals for their generous sup-

ply of nitrendipine (Bay e 5009) and Regina O'Donnell for herexcellent technical assistance.

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Calcium channel blocking agents in the treatment of cardiovas-cular disorders. Part II: Hemodynamic effects and clinical ap-plications. Ann Intern Med 1980;93:886-901

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8. Knorr A, Stoepel K. Effects of a new calcium antagonist,nitrendipine, on blood pressure and heart rate of conscious,unrestrained dogs. Arzneimittelforsch 1981;31(suppl II):2062-2064

9. Kiowski W, Bertel O, Erne P, et al. Hemodynamic and reflexresponses to acute and chronic antihypertensive therapy withthe calcium entry blocker nifedipine. Hypertension 1983:5(suppl I):I-70-I-74

10. Pedersen OL. Calcium blockade in arterial hypertension: re-view. Hypertension 1983;(suppl 11)4:11-74—11-79

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D R Knight, D A Kirby and S F Vatnerhypertensive dogs.

Effects of a calcium channel blocker on cardiac output distribution in conscious

Print ISSN: 0194-911X. Online ISSN: 1524-4563 Copyright © 1985 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Hypertension doi: 10.1161/01.HYP.7.3.380

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