Treatment of Hypertension with Nifedipine,A Calcium Antagonistic Agent

MARIA T. OLIVARI, M.D., CESARE BARTORELLI, M.D., F.R.C.P., ALVISE POLESE, M.D.,

CESARE FIORENTINI, M.D., PAOLO MORUZZI, M.D.,AND MAURIzIo D. GUAZZI, M.D., F.I.C.A.

SUMMARY Hemodynamic monitoring after a single dose (10 mg) of nifedipine in 27 primary hypertensivesubjects (diastolic pressure > 110 mm Hg) documented that this calcium antagonistic agent exerts a potentarteriolar vasodilating action, which results in prompt (-21% of control at 30 minutes) and persistent (-16%of control at 120 minutes) fall in mean arterial pressure associated with a rise in cardiac output and pulse rate.The same patients received oral treatment for 3 weeks. Hourly pressure readings showed that 1) the anti-

hypertensive response to each dose lasts 8-12 hours; and 2) nifedipine every 6 hours significantly reduced bloodpressure throughout the 24 hours, without postural hypotension.

Side effects were short-lasting (headache in five patients, palpitation without arrhythmias in eight patients,burning sensation in the face and legs in five patients and sporadic extrasystoles in five patients) and tended todisappear with continued treatment.

Development of drug resistance, sodium retention, plasma volume expansion, renin release or angina pec-toris were not observed during the study. Although these findings seem to differentiate nifedipine from othervasodilators currently used in the treatment of hypertension, broader experience and more prolonged trialswith nifedipine as an antihypertensive agent will be needed before conclusions can be drawn on these particularaspects.

HIGH VASCULAR RESISTANCE is the prox-imate cause of elevated arterial pressure in mostpatients with chronic hypertension. Blood pressurecan be normalized either by decreasing cardiac outputor by lowering vascular resistance. The former,however, makes circulation doubly abnormal, sincevascular resistance remains excessive and cardiac out-put becomes abnormally low. This situation may beassociated- with tissue hypoperfusion, involvingkidneys, heart and brain. The desired hemodynamiceffect in antihypertensive therapy is dilatation of con-stricted arterioles by a compound that acts directly onthe smooth muscle, relaxes arterioles independently ofthe vasoconstrictor mechanism, and does not affectthe heart or decrease the venous return.

Hydralazine, diazoxide, minoxidil and guancydineact directly on vascular smooth muscle to producevasodilatation, and were introduced with variabledegrees of success in the chronic treatment of hyper-tension. These agents share several common sideeffects, including an exaggeration of cardiac actionthat may precipitate angina pectoris in patients withcoronary disease and the promotion of renin release,sodium retention and plasma volume expansion. Inmost circumstances ,B-blockers and diuretics should beadded to counteract these effects.' 3The cellular mechanism of vasodilatation is not yet

From the Istituto Ricerche Cardiovascolari "Giorgio Sisini",Centro Recerche Cardiovascolari del Consiglio Nazionale delleRicerche, Clinica Medica II, Cattedra di Cardiologia, University ofMilan, Milan, Italy.

Received May 22, 1978; revision accepted December 7, 1978.Address for reprints: Maurizio D. Guazzi, M.D., F.I.C.A.,

Istituto Ricerche Cardiovascolari, Via Francesco Sforza, 35, 20122Milano, Italy.

Circulation 59, No. 5, 1979.

understood, but the capacity to chelate certain tracemetals required for smooth-muscle contraction hasbeen suggested as the vasodilating mechanism ofdiazoxide4 and hydralazine.5 A distinct group of com-pounds, the so-called calcium antagonists, specificallyinhibit the penetration of extracellular calciumthrough the cell membrane and the inflow of Ca++ions from the binding sites of the sarcoplasmaticreticulum into the cell plasma, where the ATPase ofthe myofibrils is located. This enzyme needs Ca++ions to be activated and to split ATP for the energy-delivering process of muscle contraction. The reduc-tion of the contractile activity of the heart as well asthe coronary and systemic vasodilatation broughtabout by the calcium antagonistic compounds6-10provide the rationale for their use in the managementof angina pectoris. Since systemic vasodilatation canbe expected to lower elevated blood pressure, duringthe last few years interest has been focused on calciumantagonists in the medical treatment of hyper-tension.'"

Recently, we reported that the profoundvasodilating action of nifedipine [4-(2'nitrophenyl)-2,6-dimethyl-3, 5-dicarbomethoxy- 1, 4-dihydropy-ridine], (fig. 1), a calcium antagonistic agent, has aconsiderable antihypertensive effect.12 In view of thepromptness and the magnitude of the hypertensivereaction, we proposed its use for treating emergenciesof severe hypertension.The present study evaluates the chronic use of

nifedipine in the therapeutic management of sustainedhypertension. The well-documented antianginal ac-tion'13'7 seems to offer a desirable advantage.

Materials and MethodsTwenty-seven hospitalized men, average age 52

years, were admitted to the study after fulfilling the1056

by guest on June 3, 2018http://circ.ahajournals.org/

Dow

nloaded from

NIFEDIPINE IN HYPERTENSION/Olivari et al.

NO2

H

H3COOC COOCH3

H3C N CH3H

FIGURE 1. The chemical structure of nifedipine [4-(2'-nitrophenyl)-2, 6-dimethyl-3, 5-dicarbomethoxy-1, 4-dihy-dropyridinel.

following criteria: untreated or poorly treated essen-

tial hypertension with diastolic pressure > 110 mmHg on admission; free consent to the investigationafter detailed explanations of the procedures and ofthe possible clinical benefits; persistence of a diastolicpressure > 110 mm Hg after withdrawal of anti-hypertensive therapy and any other treatment thatcould interfere with cardiovascular function; no

history or evidence of stroke, cardiac decompensa-tion, heart block or major arrhythmias, asthma or

renal failure.After the diagnosis of essential hypertension was es-

tablished by clinical and laboratory evaluation, allpatients were given placebo in capsules identical inshape and color to the active compound, at regular, 6-hour intervals for 10 days. At the end of this period,hemodynamic measurements were performed, con-

sisting of continuous systemic and pulmonary arterialpressure recording (for 30 minutes before and 120minutes after a 10-mg oral dose of nifedipine) and car-

diac output determination (in the control state and 30,60 and 120 minutes after the drug). Then, patientswere separated randomly into two groups and treatedby the following regimens. In 14 patients (group 1)nifedipine (10 mg) and placebo were alternated atregular, 6-hour periods (nifedipine was administeredat 8 a.m. and 8 p.m., placebo at 2 a.m. and 2 p.m.) for3 weeks; 13 patients (group 2) received nifedipine onlyevery 6 hours for 3 weeks. At the end of the trial (4hours after the last dose of nifedipine), a hemo-dynamic evaluation was repeated in each subject, andplacebo was substituted for the active drug for 3 days.

Readings of blood pressure and pulse rate were

taken hourly by the same observer, from 8 a.m. to 9p.m., throughout hospitalization. Blood pressure was

measured with a standard mercury sphygmomanom-eter according to the recommendations of the

American Heart Association."' All blood pressureswere taken three times at 1-minute intervals in thesupine position and, subsequently, in the standingposition, at least 5 minutes after the change in posture.Results of the three determinations were averaged.Pulse rate was counted after the last pressure record-ing in each position. Body weight and urinary outputwere checked daily. Blood urea nitrogen, serumcreatinine and electrolyte concentration, glomerularfiltration rate, plasma volume (dilution of T- 1824) andplasma renin activity, both in the supine and, after 2hours, standing positions, were determined at the endof the run-in and trial periods. The patients were on astandard 100 mEq sodium diet. Plasma renin activitywas measured by radioimmunoassay'9 of angiotensin Iin plasma venous samples and calculated as thedifference between immunoreactive angiotensin Iformed during 3-hour plasma incubation at 37°C andthat present in an unincubated plasma sample at 4°C.It was expressed as nanograms of angiotensin Iformed per milliliter of plasma per hour.

For the hemodynamic measurements a #5 flow-directed Swan-Ganz catheter was inserted per-cutaneously, under local anesthesia, into anantecubital vein and floated, under fluoroscopy, to thepulmonary artery or advanced to the wedge position.A polyethylene radiopaque catheter, introduced per-cutaneously into a brachial artery and advanced to thethoracic aorta, was used to monitor arterial pressureand to sample blood for cardiac output. Reproducibledye dilution curves were obtained by a Gilford den-sitometer after rapid injection of indocyanine greendye (5 mg) into the main pulmonary artery justbeyond the pulmonary valve. Pressures were deter-mined with Statham P23De and P23Db strain gaugetransducers and recorded on a Gould-Brush eight-channel ink recorder, model 480. The zero referencelevel for pressure recording was 5 cm below the sternalangle. The mean pressures were obtained by electronicdamping. Systemic vascular resistance (SVR) andpulmonary arteriolar resistance (PAR), in dyn-sec-cm-5, were calculated from the following formulas:

AP - RAP X 1332 X 60CO (ml/min)

PAR = PAP -PWP X 1332 X 60CO (ml/min)

where AP is mean systemic arterial pressure, PAP ismean pulmonary arterial pressure, RAP is mean rightatrial pressure, PWP is mean pulmonary wedgepressure and CO is cardiac output.

For the analysis of the circulatory data, differenceswere assessed through the analysis of variance, with anOlivetti desk-top computer.

Results

The time course of the circulatory response to a 10-mg oral dose of nifedipine in the whole hypertensivegroup is shown in figure 2. Average changes from con-trol of mean systemic and pulmonary arterial

1057

by guest on June 3, 2018http://circ.ahajournals.org/

Dow

nloaded from

VOL 59, No 5, MAY 1979

kP A

NIFEDIPINE

.-1'" '"""'.'.. -.....

......... ......A A Nv;. .

. . .. ..**..

L

0 30 6030FIGURE 2. Mean ± SEM o mean systemic arterial pressure (MSAP), cardiac index (CI), systemic vascularresistance (SVR), mean pulmonary arterialpressure (MPAP), pulmonary arteriolar resistance (PAR), heartrate (HR) and stroke index (SI), in the control state and 30, 60 and 120 minutes after a 10-mg oral dose ofnifedipine. *Differences from control significant at p < 0.05. **Differences from control significant at p <0.01.

pressure, cardiac index, systemic and pulmonaryvascular resistance, pulse rate and stroke index arereported. At 30 minutes after administration of thedrug, the average decrease in supine mean arterialpressure was 28 mm Hg (-21% of control). This wasassociated with a 17% increase in heart rate, a 13% in-crease in stroke index, a 35% increase in cardiac index,and a 39% reduction in systemic vascular resistance.At 60 minutes after nifedipine, some tendency torecover was observed: Blood pressure and peripheralvascular resistance were reduced by 19% and 33%,respectively, and cardiac index was increased 28%from control. At 120 minutes after nifedipine, thistrend was more pronounced; in fact, peripheralresistance decreased 29% from control, cardiac indexincreased 16% and mean arterial pressure decreased16%. The rise in cardiac index was caused by a higherpulse rate and larger stroke index at 30 and 60 minutesafter administration of nifedipine, and exclusively by alarger stroke index after 120 minutes, as the pulse ratereverted to the control level at this point. In spite ofthe great changes in flow, pulmonary arterial pressuredid not vary significantly from control throughout thestudy.A significant correlation was detected between

systemic vascular resistance in the control state andsystolic and diastolic pressure reduction at 30 minutesafter the drug (fig. 3).

Figure 4 reports the averages of the dailysphygmomanometric systolic and diastolic readings ingroups 1 and 2 during placebo (days 1-10, and againafter day 29) and trial (days 11-29). Open arrows in-dicate placebo, solid arrows indicate the active com-pound. In both groups supine and standing pressureswere comparable in the control state, without signifi-cant fluctuations during the day. In group 1 the singlevalue derived from the average of all daily deter-minations was 190/117 mm Hg on day 1 and 181/114mm Hg on day 10. Administration of nifedipine (day11) was promptly effective and, within 1 hour, loweredsupine systolic and diastolic pressure by 21% and 19%,respectively. Subsequent measurements of bloodpressure showed a slow, progressive increase and ap-proached the control levels at about 12 hours after thedrug. Placebo did not interfere with this trend; on thecontrary, a second dose of nifedipine duplicated thehypotensive effect of the first. The pattern was similarthroughout the trial. The average of all daily deter-minations was 165/100 mm Hg on day 11, 160/97mm Hg on day 12, and 158/97 mm Hg on day 29. Thedifferences from day 10 were significant (p < 0.01).When nifedipine was discontinued after day 29,pressure rose promptly and stabilized by day 31 at thesame levels recorded on day 10, the last pretreatmentplacebo day. Heart rate was slightly, but significantly(p < 0.01) increased only for about an hour after each

O Cl MSAl/min/M2 mm Hc

5-

_200

4.5-

4-

150

3.5-

3

1002.5

A MPAPmm Hg

-20

15

_10

(i) HRb/min101

80-

60-

SVR Odynes.sec.cm-5

-2 400

-1700

_1000

PAR Sdynes. sec.cm-5110

80

Si .mu/M2[60

-55

SO

) min120

1058 CIRCULATION

by guest on June 3, 2018http://circ.ahajournals.org/

Dow

nloaded from

NIFEDIPINE IN HYPERTENSION/Olivari et al.

dynes.sec.cm-52000 3000

S @5

r = 0.72p< 0.01

0

* 0 FIGURE 3. Correlation between systolicand diastolic pressure reduction (ordinate)at 30-minutes after nifedipine and systemicvascular resistance in the control state(abscissa).

Diastolic

dose of the active compound; placeboon pulse rate.

was ineffective

In group 2, the single value of all daily supine deter-minations averaged 205/118 mm Hg on day 1 and198/122 mm Hg on day 10. Nifedipine (day 11) in-duced prompt systolic and diastolic pressure fall whichat the first hour averaged 22% and 21% of control,respectively. Then, although some trend to increasewas seen, pressure remained significantly lower thancontrol up to the second dose, which brought bloodpressure to the level attained after the first. Thepattern was similar throughout the trial. The singlevalue of all daily pressure readings averaged 166/102,164/98 and 165/97 mm Hg by days 11, 12 and 29,respectively; each of these was significantly (p < 0.01)lower than by the last pretreatment placebo day (day10). Heart rate increased for about an hour followingeach dose. When placebo was substituted for the ac-

tive compound, pressure rose promptly and stabilizedby day 31 at the same levels recorded on the last pre-treatment placebo day.

In both groups pressure variations at the variousperiods were qualitatively and quantitatively similar inthe supine and standing positions.Hemodynamic measurements carried out before

and at the end of trial in the whole hypertensive pop-ulation are reported in table 1. Systolic and diastolicsystemic arterial pressures and vascular resistancewere significantly reduced and cardiac indexsignificantly increased after treatment; systolic anddiastolic pulmonary pressure and plasma volumeremained almost unchanged. As shown in table 2,blood urea nitrogen, serum electrolyte and creatinineconcentrations, glomerular filtration rate and plasmarenin activity did not vary consistently. Body weightwas steady, and urinary output increased by an

average of 600 ml on day 11 and reverted to the con-trol value in the subsequent days.Headache in five patients, palpitation without

arrhythmias in eight patients, sporadic premature ven-tricular contractions in five patients, burning sensationin the face and legs in five patients were reported30-60 minutes after nifedipine. All these symptomstended to disappear with continued treatment. In nocase did side effects require interruption of the trial.Cardiac rhythm was normalized in six patients whohad ventricular extrasystoles in the control period.

Discussion

Continuous hemodynamic monitoring providedfurther evidence'2 that nifedipine exerts a rapid,profound and persistent antihypertensive action.Mean arterial pressure, in fact, was lowered by 21% ofcontrol at 30 minutes (average fall 28 mm Hg) and by16% at 120 minutes after the drug. The hemo-dynamics of the antihypertensive effect werecharacterized by a diminished peripheral resistanceassociated with simultaneous rise of cardiac output.The magnitude and the promptness of the fall in

peripheral vascular resistance suggest that the calciumantagonistic action of nifedipine produces a directdilating effect on the resistance vessels. Venouscapacitance vessels do not seem to be involved, sincecardiac output increased and pressures in the rightside of the heart remained unchanged. Increase of car-diac output could be caused by reflex sympathetic ac-

tivation or by left ventricular afterload reduction con-

sequent to decreased peripheral vascular resistance, or

to both. The beneficial effects of a lowered cardiacload probably were predominant 120 minutes afternifedipine, since at this point the pulse rate had

3000 2000 1000

r = 0.83p < 0.0 1

1000

- 10t

0 a

-20+

-30t

-40+

-50+

5 @0

*-0S*@

Systolic

-60t

-70t

-80tmm Hg

1059

.

by guest on June 3, 2018http://circ.ahajournals.org/

Dow

nloaded from

1060

Day 1 10

.-I .....Ji ..... .I

.....k4 L~~~.....J....~

0D 0c cO N CN q Mo

CIRCULATION

11 12

VOL 59, No 5, MAY 1979

29 31

IlIIIiT

or,, ,.lI

GROUP 11

I--T 1eXI UZ6.*@wL @

L ..L..I. ~.u...I...1

11

o co v e o

12 29

*

t t t t t t

.)O > > t

31

LI ii -r

co C I

Time of dayFIGURE 4. Mean ± SEM of hourly supine (solid lines) and standing (dotted lines) systolic and diastolicarterial pressure (AP) readings during placebo (days 1-10 and after day 29) and trial (days I1-29)periods ingroups 1 and 2. Open arrows indicate placebo; solid arrows indicate active compound. A indicates differencesfrom the corresponding value on day 10 significant at p 0.05; *differences from the corresponding valueon day 10 significant at p < 0.01.

reverted to control values, while the cardiac outputremained elevated.No correlation was found between cardiac output,

during either baseline or hypotensive phases, and themagnitude of the blood pressure fall. There was,however, a correlation between vascular resistance inthe control state and hypotensive response tonifedipine, suggesting that, within certain limits, thegreater the vasoconstriction the greater the hypo-tensive effect of the drug, and also that modulation of

this effect depends not so much upon the cardiac out-put reaction as upon the degree of vasodilatation.

In spite of the augmented flow, pulmonary pressuredid not increase. Whether this was a consequence of adirect vasodilating effect of the compound or of thehigh compliance of the pulmonary vascular bed, is notknown.Throughout chronic treatment nifedipine main-

tained its ability to lower blood pressure, as it did dur-ing acute hemodynamic monitoring in both groups.

200-

175-

3:

E 150

125-

100-

Day 1 10...

.[......T.i..

S a- ' ' 1- 1

200

1751-0)IEE 150oL

125-

100 -

10, . 0

co _tNc, O X°D2 N CN v 10 a

by guest on June 3, 2018http://circ.ahajournals.org/

Dow

nloaded from

NIFEDIPINE IN HYPERTENSION/Olivari et al.

TABLE 1. Hemndynamic DataAfter Treatment with Nifedipine

HR (beats/min) 7MSAP (mm Hg) 140.

CI (ml/min/m2) 357SI (ml/m2) 49.SVR (dyn-sec-cm-5) 176MPAP (mm Hg) 17.

PAR (dyn-sec-cm-5) 113.PV (ml) 314

*Measurements carried out 4tDifferences from control sigitDifferences from control sigiAbbreviations: HR = heart

arterial pressure; CI = cardifSVR = systemic vascular resisnary arterial pressure; PARsistance; PV = plasma volume

Although this would suggenot associated with developtachyphylaxis, more prolonto clarify this point. Thereadings at the various timeidea on the rate of decay owell as on blood pressureregimens. In group 1 (nipressure remained reducedafter nifedipine and approithe next 3-4 hours; at 12 hwas almost completely lo.blood pressure ranged fr147/89 mm Hg over a 12-tuation was 25 mm Hg, dimm Hg). As was expec

TABLE 2. Laboratory Data (rChronic Treatment with Nifedip

Blood urea concentration(mg/100 ml)

Serum creatinineconcentration (mg%)

Serum potassiumconcentration (mEq/l)

Serum sodiumconcentration (mEq/l)

Serum chlorideconcentration (mEq/l)

Glomerular filtration rate(ml/min)

Plasma renin activity(ng/ml/hr) supine

standingBody weight (kg)

X(mean - SEM) Before and nifedipine every 6 hours (group 2) maintained arterialpressure significantly lower than control throughout

,ontrol Nifedipine* the day; it also held the average systolic and diastolicr5 3. 1 74 - 1.9

fluctuation to 17 and 11 mm Hg, respectively..4 132 t120 21.6 Circulatory measurements repeated at the end of

the trial documented that the hypotensive effect after a7 162 T4076 - 210 3-week treatment was still mediated through reduc-.2 2.6 55 2.7 tion of the peripheral vascular resistance associated6 + 94.6 t1281 61.1 with increase in cardiac output, which indicates that.6 ~ 1.4 15.2 + 0.9 the hemodynamics of the hypotensive effect did not

.5 6.6 08.2 5.7vary during that time. However, no circulatory re-

5 6.6 t98.2 5.7 adjustment seems to have occurred during this period.L9 75.5 3094 75.4 In fact, when placebo was substituted for nifedipine,Lhours after the last dose. arterial pressure rose again and stabilized at pre-nificant at p <0.05. treatment levels within 2 days.nificant at p <0.01. Nifedipine did not reduce, and even tended to im-rate; MSAP = mean systemic prove renal function, and did not interfere withac index; SI = stroke index; sodium metabolism. The fact that no patienttance; MPAP = mean pulmo-= pulmonary arteriolar re- developed precordial symptoms consistent with

angina pectoris is probably attributable to the well-documented efficacy of the compound on ischemic dis-orders of the myocardium 1-1st that repeated doses are odr ftemoadu.31,st thatrepeated doses are A precise definition of the effects of the drug oniment of drug resistance or plasma renin activity obviously requires more detailed

ged trials wilt be necessary studies. It may be possible that variations in reninanalysis of the pressure secretion parallel the time course of changes in

-s provides an approx1mtsporimate arteriolar tone, blood pressure, cardiac output andf the hypotensive effect as sympathetic activation after each dose. It is in-fluctuation with the two teresting to note, however, that 3 hours (lying posi-ifedipine every 12 hours) tion) and 5 hours (standing position) after the last dosesignificantly for 7-8 hours of nifedpine (day 30), plasma renin activity did notached the control levels in differ significantly from control (table 2), even thoughours the hypotensive effect arterial pressure and vascular resistance were reducedst in each case. Average and cardiac output increased (table 1) at the time ofhour period4 (systolicHguc- plasma renin activity determination. This may in--hour period (systolic.fluc- dicate that activation of renin secretion, if any, is ofastolic fluctuation was 15 short duration, and also that the baseline level of reninted from these findings, is not elevated after 3 weeks of continued treatment.

Recently, it has been suggested that distal tubularnean SEM) Before and After calcium delivery is an important functional part of theDine macula densa-glomerular feedback mechanism;20' 21 it

Control Nifedipine has been documented that the calcium antagonisticagent, verapamil, is a complete inhibitor of the tubulo-

48 3.2 43.6 3.1 glomerular feedback operation.22 The hypothesis thatnifedipine interferes with calcium availability at the

1.34 0.07 1.32 f0.08 level of the distal tubule might explain why, in spite ofits vasodilating and hypotensive action, the com-

3.75 0.11 3.93 0.13 pound does not seem to activate renin secretion.For all these reasons nifedipine may be regarded as

140.5 0.78 140.2 - 0.65 a promising pharmacological agent in the therapy ofhigh blood pressure. Further clinical evaluation will be

04 0.96 103 0.87 required to determine the persistence of the anti-hypertensive effect during long-term administration ofthe drug.

80.5 5.09 81.8 4.9

0.566 - 0.141.007 = 0.24

71 = 2.3

The differences are not significant.*Three hours after the last dose.tSix hours after the last dose.

*0.736 i 0.2t 1.45 0.45

70.5 i 2.2References

1. Koch-Weser J: Vasodilator drugs in the treatment of hyper-tension. Arch Intern Med 133: 1017, 1974

2. Page LB, Yager HM, Sidd JJ: Drugs in the management ofhypertension. Part III. Am Heart J 92: 252, 1976

1061

by guest on June 3, 2018http://circ.ahajournals.org/

Dow

nloaded from

VOL 59, No 5, MAY 1979

3. Koch-Weser J: The comeback of hydralazine. Am Heart J 95:1, 1978

4. Koch-Weser J: Diazoxide. N Engl J Med 294: 1271, 19765. Koch-Weser J: Hydralazine. N Engl J Med 295: 320, 19766. Ross G, Jorgensen CR: Cardiovascular actions of iproveratril.

J Pharmacol Exp Ther 158: 504, 19677. Nayler WG: Calcium exchange in cardiac muscle, a basic

mechanism of drug action. Am Heart J 73: 379, 19678. Nayler WG, McInnes I, Swann JB, Price JM, Carson V, Race

D, Lowe TE: Some effects of iproveratril (isoptin) on the car-diovascular system. J Pharmacol Exp Ther 161: 247, 1968

9. Nayler WG, Szeto J: Effect of verapamil on contractility, oxy-gen utilization and calcium exchangeability on mammalianheart muscle. Cardiovasc Res 6: 120, 1972

10. Nayler WG: Effect of verapamil on ventricular contraction. BrHeart J 35: 864, 1973

11. Krikler D: Verapamil in cardiology. Eur J Cardiol 2: 3, 197412. Guazzi M, Olivari MT, Polese A, Fiorentini C, Magrini F,

Moruzzi P: Nifedipine, a new antihypertensive with rapid ac-tion. Clin Pharmacol Ther 22: 528, 1977

13. Mizuno Y, Yasui S: Effects of nifedipine treatment of ischemicheart disease. In New Therapy of Ischemic Heart Disease,edited by Hashimoto K, Kimura E, Kobayashi T. Tokyo,University of Tokyo Press, 1975, p 163

14. Ebner F: Survey and summary of results obtained during theworld-wide clinical investigations of Adalat (nifedipine). InNew Therapy of Ischemic Heart Disease, edited by Lochner W,

Braasch W, Kronenberg G. Berlin, Springer-Verlag, 1975, p348

15. Ebner F, Dunschede HB: Haemodynamics, therapeuticmechanism of action and clinical findings of Adalat use basedon worldwide clinical trials. In New Therapy of Ischemic HeartDisease, edited by Jatene AD, Lichtlen PR. Amsterdam, Ex-cerpta Medica, 1976, p 283

16. Muller JE, Gunther SJ: Nifedipine therapy for Prinzmetal'sangina. Circulation 57: 137, 1978

17. Hurst JW: The Heart. New York, McGraw-Hill, Inc, 1978, p1251

18. Kirkendall WM, Burton AC, Epstein FH, Freis ED:Recommendations for human blood pressure determination bysphygmomanometers. Circulation 36: 980, 1967

19. Richardson D, Stella A, Leonetti G, Bartorelli A, Zanchetti A:Mechanisms of renal release of renin by electrical stimulationof the brainstem in the cat. Circ Res 34: 425, 1974

20. Israelit AH, Rector FC Jr, Seldin DW: The influence of per-fusate composition (PC) and perfusion rate (PR) on glomerularcapillary hydrostatic pressure (PG). Proc Ann Meeting Am SocNephrol, 6th, Washington, D.C., 1973, p 53

21. Burke TJ, Navor LG, Clapp JR, Robinson RR: Response ofsingle nephron glomerular filtration rate to distal nephronmicroperfusion. Kidney Int 6: 230, 1974

22. Gutsche HU, Muller-Suur R, Schurek HJ: Ca++-antagonistprevents feedback induced SN-GFR decrease in rat kidney.Kidney Int 8: 477, 1975

1 062 CIRCULATION

by guest on June 3, 2018http://circ.ahajournals.org/

Dow

nloaded from

M T Olivari, C Bartorelli, A Polese, C Fiorentini, P Moruzzi and M D GuazziTreatment of hypertension with nifedipine, a calcium antagonistic agent.

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1979 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.59.5.1056

1979;59:1056-1062Circulation. 

http://circ.ahajournals.org/content/59/5/1056the World Wide Web at:

The online version of this article, along with updated information and services, is located on

  http://circ.ahajournals.org//subscriptions/

is online at: Circulation Information about subscribing to Subscriptions: 

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

  document. Permissions and Rights Question and Answer information about this process is available in the

located, click Request Permissions in the middle column of the Web page under Services. FurtherEditorial Office. Once the online version of the published article for which permission is being requested is

can be obtained via RightsLink, a service of the Copyright Clearance Center, not theCirculationpublished in Requests for permissions to reproduce figures, tables, or portions of articles originallyPermissions:

by guest on June 3, 2018http://circ.ahajournals.org/

Dow

nloaded from