Treatment Hypertension Nifedipine, A Calcium circ. nifedipine asanantihypertensive agentwill beneededbeforeconclusionscanbedrawnontheseparticular aspects. HIGH VASCULAR RESISTANCE is the prox-

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  • 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

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  • 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; nohistory or evidence of stroke, cardiac decompensa-tion, heart block or major arrhythmias, asthma orrenal 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 weretaken hourly by the same observer, from 8 a.m. to 9p.m., throughout hospitalization. Blood pressure wasmeasured 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 37C andthat present in an unincubated plasma sample at 4C.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, wit