The Circulatory Effects of Intravenous Phentolamine in Man

The Circulatory Effects of IntravenousPhentolamine in Man

By S. H. TAYLOR, B.Sc., M.B., CH.B., G. R. SUTHERLAND, M.B., CH.B.,

G. J. MACKENZIE, M.B., CH.B., H. P. STAUNTON, B.Sc., M.B., CH.B.,AND K. W. DONALD, D.Sc., M.D.

THE recognition of the importance of thesympathetic nervous system in the con-

trol of the systemic arterial blood pressure

has stimulated the search for therapeuticallyuseful sympathoadrenergic blocking agents

that may be of use in the diagnosis andtreatment of hypertensive vascular disease.Numerous agents of diverse chemical struc-

ture have been developed and explored forsuch therapeutic effectiveness but few haveproved to be of any clinical value.Among those, however, that have achieved

a place in clinical practice is phentolamine,a drug of the imidazoline group, chemicallyrelated to both tolazoline (Priscoline) andhistamine. This agent has been shown to cause

both adrenergic and sympathetic blockade inanimals' 5 and in man.2 9 These latter au-

thors all reported that a considerable reduc-tion in systemic arterial pressure resulted fromthe parenteral administration of the drug toboth hypertensive and normal subjects, andthe majority remarked particularly on its or-

thostatic effects.The initial hope that the chronic oral ad-

ministration of the drug would be of practicaluse in the treatment of hypertensive dis-ease2' 10 was not borne out in later reports dueto the production of intolerable gastrointesti-nal side effects by the preparation and therapid development of refractoriness to its an-

tihypertensive properties.9 However, due toits supposed propensity in blocking the ef-fects of circulating catecholamines, the drug

rapidly achieved eminence as a routine biolog-ical screening test for pheochromocytoma."-'7Nevertheless, the rapid waning of interest in

its use as a practical antihypertensive agentno doubt largely accounts for the absence ofany comprehensive study of its circulatoryeffects in man.

Our interest first centered on phentolamineduring the search for an effective catechol-amine-blocking drug as part of wider study ofthe role of the autonomic nervous system inthe control of blood pressure in normal man

and in patients with hypertensive vasculardisease. Although the drug has been found tohave circulatory effects that preclude itsusefulness in this particular respect, thecontinued widespread use of the drug as a

routine diagnostic screening test for pheochro-mocytoma in hypertensive disease promptedthe consideration that the findings would beof some general interest. The following re-

port, part of a detailed study of the circula-tory effects of the drug, concerns an analysisof the hemodynamic effects of the acute intra-venous injection of phentolamine in normalsubjects and patients with hypertensive dis-ease.

MethodsClinical Data

Studies were made on six normal subjectsand six hypertensive patients; details of each

individual are listed in tables 1 and 2.All the hypertensive patients were considered

to be suffering from uncomplicated essentialhypertension on the basis of the usual diagnosticclinical criteria. None had any symptoms refer-able to the cardiovascular system except patientA.A., who had mild exertional dyspnea. In five

of the six patients the resting aortic diastolicpressure, recorded in the supine position at thetime of the study exceeded 120 mm. Hg. Infour of the hypertensive patients there was no

radiologic or electrocardiographic evidence ofleft ventricular enlargement. In the remainingtwo patients (A.S. and A.A.) there was radio-

741

From the Department of Medicine, The RoyalInfirmary, Edinburgh, Scotland.

Circulation, Volume XXXI, May 1965

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TAYLOR ET AL.

logic evidence of cardiac hypertrophy withoutdilatation, and in both instances this was associat-ed with electrocardiographic changes indicativeof moderate left ventricular hvpertrophy. Theoptic fundi were without papilledema, hemor-rhages, or exudates in all six hypertensive pa-tients. Routine tests of renal function werewithin normal limits in all six patients, and renalarteriographs showed no evidence of renal vas-cular disease in any patient. The 24-hour uri-nary excretion of vanillyl-mandelic acid was with-in normal limits in all the hypertensive patients.

Plan of InvestigationThe investigation was designed to study the

general hemodynamic changes following theabrupt intravenous injection of phentolamine, asusually used in the clinical diagnostic procedure.In all individuals, systemic arterial pressure,cardiac output, and heart rate were measuredduring a control period of 10 minutes and thenfor a further 30 minutes after the rapid intra-venous injection of 5 mg. of phentolamine in avolume of 2 ml.; the injection was completedwithin 2 seconds. Systemic arterial pressure andheart rate were monitored continuously through-out the study. Cardiac output was determinedon alternate minutes during the control period,every minute for the 6 minutes after the in-jection of the drug, and then on alternate min-utes again for the remainder of the study.Oxygen uptake, derived from the product ofthe blood oxygen arteriovenous oxygen contentdifference (AV diff.) and cardiac output, wasdetermined at minute or alternate minute inter-vals, at the same frequency as the measure-

ments of cardiac output. Due to the possibilitythat the circulatory changes may in part havebeen due to possible hypoglycemia, serial esti-mations of the blood sugar were made through-out the period of observation in two of thenormal subjects (L.D. and J.A.) and two ofthe hypertensive patients (A.A. and J.N.). Theinjection of phentolamine, 2- (N-p-tolyl-N-m-hy-droxyphenyl-amino-methyl)-imidazoline, was giv-en as the methane sulfonate salt.

Laboratory TechnicsLaboratory air temperature was controlled at

23 C, in all studies; the relative humidityvaried between 50 and 70 per cent betweendifferent studies.

Following prior familiarization with the planof the procedure, the laboratory surroundings,and the personnel involved, all patients were

studied in the supine position in the fastingstate without sedation.

Previous studies have demonstrated that a

rnore basal and stable circulatory state may be

induced in patients under investigation by ashort period of nonfatiguing leg exercise.18 Inthe present study, therefore, the definitive con-trol observations were commenced 20 minutesafter completion of a 5-minute period of lightleg exercise.

Systemic arterial pressure was taken through aNylon catheter, bore 0.80 mm., length 55 cm.,introduced percutaneously into the brachial arteryby a modified Seldinger technic and advancedinto the aortic root. Pressures were transduced bya Statham P23Db strain-gage manometer. Thecatheter-manometer system was critically dampedto give a virtually flat frequency response to20 cycles per second. The square wave responseof the system was 95 per cent within 0.03second, with less than 5 per cent overshoot.The electrical output from the manometer wasarranged to allow synchronous recording of bothpulsatile and mean aortic pressures. The sys-temic arterial calibration was arranged to extendapproximately 10 mm. Hg on either side ofthe aortic pulse pressure to allow maximumrecording precision with the least electrome-chanical distortion. The saline-filled calibrationpressure heads for the system were maintainedby specially calibrated Reckla anaeroid manome-ters. Zero reference level of the manometer was10 cm. above the plane of the x-ray table,the manometer and pressure heads being fixedat this level.

Cardiac output was determined by an indicator-dilution technic employing indocyanine green.Precisely known amounts of the dye, approxi-mately 2 mg. in 1.5 ml. of volume, were in-jected into the pulmonary artery through onelumen of a triple-lumen cardiac catheter by arapid-action electrically activated compressed-airdriven syringe-pump, each injection being com-pleted within 0.3 second. The dve-dilution curveswere taken from the aortic root through a secondarterial catheter of identical dimensions to thatused for arterial pressure measurement. Bloodwas withdrawn through the cuvette at a samplingrate of 38 ml. per minute by a constant-speedsyringe-type Harvard pump. The dye curveswere transcribed by a Waters X300A cuvettedensitometer in conjunction with an ultravioletrecorder. By this technic duplicate determinationsof cardiac output, carried out under strictlycontrolled conditions of circulatory stability havebeen shown to differ by less than 2 per cent.The standardization and precision of this dye-dilution method are being reported elsewhere.'9The heart rate was determined from a contin-uously recorded electrocardiographic tracing.

All analogue tracings were recorded on a multi-channel ultraviolet recorder (New ElectronicProducts Ltd., Type 1185) using galvanometers


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EFFECTS OF INTRAVENOUS PHENTOLAMINE

of 35-cm. focal length and a distortion-free de-flection arc of 10 cm., arranged as previouslydescribed.18 The frequency response of thegalvanometers used for recording the intravas-cular pressures was 90 cycles per second at -95per cent of true fidelity.

Mixed venous blood samples were taken fromthe pulmonary artery and systemic arterial bloodsamples from the aorta. Both groups of sampleswere analyzed for percentage oxygen saturationby a standardized hemoreflector technic cali-brated against the Van Slyke method.'9 Arterialblood samples were also used to determine the

blood oxygen capacity by a standardized spectro-photometric technic.19 Blood sugar determinationswere made by the method of Huggett andNixon.20

Measurements and CalculationsIntravascular pressures and heart rate were

measured as the average of the 15-secondvalues falling equally about the definitive point.Cardiac outputs were measured by conventionalintegration technics, the final 10 per cent onlyof the downslope requiring to be replottedaccording to the Hamilton semilogarithmic extrap-olation method. The calculation of the mean

systemic vascular resistance was modified to in-corporate a correction for the body surface area,the arguments for which have been discussedelsewhere.'8 The oxygen uptake was derived as

the product of the cardiac output and arteriove-nous oxygen difference. The validity and precisionof this method have been established by com-

parison of the dye-dilution method as used inthe present study with a standardized Fick meth-

MEANSYSTEMICARTERIALPRESSURE

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eter relate to the differences between the averageof the control values and that at the stated time.

ResultsThe individual values of the primary meas-

urements and derived data are detailed intables 1 and 2 and illustrated in figures 1 to6. The percentage differences between theaverage control value and that obtaining atthe first minute after injection of the drug foreach parameter in each subject are detailedand summarized in table 3.

Clinical Effects of the Acute Injectionof Phentolamine

None of the normal subjects nor any of thehypertensive patients complained of symp-

toms due to the acute injection of the drug,despite considerable reductions in the sys-

temic blood pressure and increases in heartrate following its intravenous injection. Theelectrocardiogram showed no significantchange during the study in any individual.This is of particular importance in view of themyocardial ischemia that may follow the in-

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Hemodynamic efects of an acute injection of phentolamine in three normal subjects.

travenous injection of the drug and in viewof its myocardial effects.22

Changes in Systemic Arterial Blood Pressure

The acute intravenous injection of 5 mg. ofphentolamine was immediately followed by an

abrupt reduction in blood pressure in all sub-jects. The systemic arterial pressure started tofall within 15 seconds of completion of the in-jection and had reached its lowest value with-in 1 minute in all normal subjects and hyper-tensive patients alike. The average reductionin mean arterial pressure was 15 mm. Hg(range of reduction 13 to 20) and 34 mm. Hg(range of reduction 18 to 55) in the normalsubjects and hypertensive patients, respective-ly. These values, expressed as a percentage ofthe average preinjection levels of pressure,

represent reductions of 14 per cent(p<O.OOl) and 20 per cent (p<0.001) re-

spectively in the two groups. Thereafter thesystemic blood pressure gradually returnedtoward preinjection levels, although the pat-tern of recovery varied considerably betweendifferent subjects (figs. 1 to 4).With regard to the criteria usually em-

ployed in clinical practice to interpret thechanges in blood pressure, the intravenousinjection of phentolamine was followed by a

prompt reduction in systemic arterial pres-

sure in all subjects, and in no instance was

a preceding hypertensive response observed.In three of the six hypertensive patients (J.W.,A.S., and F.E.) the maximum reductions insystolic pressure were 53, 94, and 36 mm. Hgand in diastolic pressure 39, 41, and 27 mm.Hg, respectively. The reduction in systolicpressure exceeded 35 mm. Hg for 3 minutesand the diastolic reduction exceeded 25 mm.

Hg for 2 minutes in all three patients. Thesevalues are all appreciably in excess of thoseusually used to define a positive response tothe drug. None of these patients had any evi-dence of an excess of circulating catechola-mines, none was sedated, and none had any

clinical condition that might have predisposedto such false-positive results.

In all but one (K.J.) of the normal sub-jects, the reduction in mean systemic arterialpressure that followed the injection of phentol-amine was accompanied by a small increasein pulse pressure. However, all of the hyper-tensive patients exhibited considerable reduc-tions in arterial pulse pressure after the drug.The changes in pulse pressure in the normalsubjects demonstrated a strong positive cor-

relation with the changes in cardiac output(r= 0.971; p < 0.001) but not with changes

in stroke volume or changes in mean systemic

Circulation, Volumze XXXI, May 1965

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Hemodynamic effects of an acute injection of phentolamine in three hypertensive patients.

arterial pressure. No similar correlation be-tween changes in pulse pressure and cardiacoutput was observed in the hypertensivegroup of patients (r = 0.510, p < 0.10). Inthis group, likewise, the changes in pulse pres-

sure were not directly related to changes inmean arterial pressure or stroke volume.

Changes in Heart Rate, Cardiac Output,and Stroke Volume

The fall in systemic arterial pressure thatfollowed the rapid intravenous injection ofphentolamine was followed in all subjects bya somewhat less prompt increase in heart rateand cardiac output without large or consis-tent changes in stroke volume (table 3). Al-though the magnitude of the changes in allthree parameters was essentially similar inboth groups of subjects, the time course oftheir response was significantly different(figs. 1 to 4). Whereas in the majority of thenormal subjects the maximum changes inheart rate and cardiac output occurred with-in one minute of the injection, in the hyper-tensive subjects the corresponding maximumvalues were not achieved until the thirdminute after the drug. The average maxi-mum increase in heart rate was 21 beats per

minute (range of increase 12 to 24;p < 0.001) and 25 beats per minute (rangeCirculation, Volume XXXl, May 1965

of increase 20 to 35; p < 0.001) in the normaland hypertensive groups of subjects, respec-

tively. The corresponding average maximumincreases in cardiac output in the two groups

were 0.779 L./min./M.2 (range of increase0.340 to 1.472; p <0.010) and 0.911 L./min./M.2 (range of increase 0.725 to 1.184; p <0.001), respectively. The attainment of thepeak increase in heart rate and cardiac outputwas immediately followed by a gradual re-

duction in these values toward preinjectionlevels in both groups of subjects. However,whereas the heart rate and cardiac output hadreturned to preinjection control values in allof the normal subjects within 30 minutes, andin all but one (M.N.) within 20 minutes, thereturn toward normal values was much lessrapid in the majority of the hypertensive pa-

tients. Both values were still appreciably ele-vated in four of the six hypertensive patientsat 30 minutes after the injection.

Changes in Systemic Vascular Resistance

The systemic vascular resistance was

abruptly reduced by phentolamine in all sub-jects. The maximum fall occurred within thefirst minute after injection of the drug in allof the normal subjects. In the hypertensivepatients the attainment of the maximum fallwas slower; in two patients it had occurred

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TAYLOR ET AL.

by the end of the first minute, in two by theend of the second minute, and in the remain-ing two by the end of the third minute. Atthe end of the first minute after injection theaverage reduction in systemic vascular re-sistance was 750 dyne sec. cm.-5 M.2 (rangeof reduction 406 to 961) and 1581 dyne sec.cm.-5 M.2 (range of reduction 1205 to 2250)in the normal subjects and hypertensive pa-tients, respectively. However, expressed as apercentage of the initial mean preinjectionvalue, the reductions in systemic vascular re-sistance were very similar, namely, 29 percent (p < 0.001) and 34 per cent (p < 0.001),respectively. The pattern of return of the sys-temic vascular resistance toward preinjectioncontrol values was variable but in generalparalleled the pattern of recovery of the sys-temic arterial pressure. The systemic vascularresistance had returned to control values with-in 30 minutes of the phentolamine injection inall of the normal subjects but in three of thesix hypertensive patients it was still apprecia-bly reduced at this time.

Changes in Oxygen UptakeThe changes in minute oxygen uptake fol-

lowing the injection of phentolamine werefairly consistent within each group of sub-jects. In both groups of subjects the oxygen

uptake during the control preinjection periodwas within normal limits; the average valueswere 145 ml./min./M.2 (range 129 to 165)and 148 ml./min./M.2 (range 127 to 177) inthe normal and hypertensive groups of pa-tients, respectively. In all of the normal sub-jects the injection of phentolamine was im-mediately followed by a rapid reduction inoxygen uptake (fig. 5). The maximum reduc-tion occurred at the second or third minuteafter the injection; the average maximum re-duction was 30 ml./min./M.2 (range of re-duction 16 to 62; p <0.001). Thereafter theoxygen uptake progressively increased towardpreinjection levels, which were attained inall six normal subjects within 20 minutes ofthe injection. The average total oxygen deficitdue to the drug in these subjects comparedto the preinjection levels of oxygen uptakewas 208 ml./M.2 (range of deficit 63 to 451).In none of the subjects was a subsequent in-crease in oxygen uptake observed within theperiod of observation.

In the group of hypertensive patients thechanges in oxygen uptake following injectionof the drug were more varied (fig. 6). Inthree of the patients (J.W., A.S., and F.E.)reductions in oxygen uptake of 24, 19, and15 ml./min./M.2, respectively, were observed

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TIME- MIN

Figure 5

Efect of an acute injection of phentolamine on theoxygen uptake in six normal subjects.

at the second minute after the injection of thedrug. Subsequently, the oxygen uptake in-creased rapidly to exceed the preinjectioncontrol value in each of these subjects beforegradually returning to prephentolamine lev-els. In the other three patients (E.B., A.A.,and J.N.) the changes in oxygen uptake fol-lowed a biphasic pattern, although the maintrend was an increase. In the hypertensivepatients as a group the net change in oxygenuptake after the drug was an average in-crease of 94 ml./M.2 (range of increase 16to 277; p < 0.001).

Changes in Blood Sugar

The changes in blood glucose before andafter the injection of phentolamine are de-tailed in table 4. There was an immediate,small but sustained reduction in blood glucosefollowing the injection in both the normal

IN

IK

OXYGEN

UPTAKE

mi./min.Nsqm.14

16(

E.MB. 45m9.PHE NTOLAMINE

10 0 0 20 5

TIME Mll

,AA I

iO1 (1 1 0 3

Figure 6

Efect of an acute injection of phentolamine on theoxygen uptake in six hypertensive patients.

subjects and in one (J.N.) of the hyperten-sive patients. However, the magnitude of thechanges were such as to be unlikely to haveresulted in any significant circulatory effects.

Dose-response Relationship

Over the relatively narrow dose range ofphentolamine used (0.215-0.392 mg./Kg. ofbody weight) there was no correlation be-tween the dose of the drug and the systemicarterial pressure response in either group ofsubjects singly or combined (r = 0.213).

DiscussionThese observations indicate that in normal

and hypertensive man the immediate circula-tory action of phentolamine is to cause anabrupt reduction in the general systemic vas-cular resistance, resulting in a rapid fall insystemic blood pressure in spite of an in-crease in the cardiac output. The evidencethat the immediate and predominant hemo-dynamic effect of phentolamine is to reducethe peripheral vascular resistance proportion-ately throughout the majority if not all of theregional vascular territories, has been present-ed elsewhere.23 Parallel studies by the sameauthors have also demonstrated that the cen-tral venous pressure falls rapidly at a timewhen the venous return is very considerablyincreased, suggesting that the drug was alsoprobably responsible for some degree of ve-nous dilatation.24 In the same study certainfindings were also observed suggesting a sim-

Table 4Changes in Blood Glucose (mg./100 ml.) afterPhentolamine*

Time, Normal subjects Hypertensive patientsmins. L.D. J.. AA.A. J.N.

-10 108 120 100 1060 109 116 98 1022.5 101 100 101 865 100 98 100 9110 97 96 98 8715 103 102 104 9020 100 96 106 9225 102 94 103 8830 100 97 101 90

*Five mg. of phentolamine were injected intrave-nously immediately following the sample at 0 minute.

Circulation. Volume XXXI, May 1965

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ilar vasodilator activity of the drug on the

pulmonary circulation. In fact, in these latterstudies it was demonstrated that the acute in-jection of phentolamine also resulted in a

rapid but transient shift of blood volume fromthe systemic to the pulmonary vascular bed.24Such a transfer of blood would certainly po-

tentiate the immediate direct hypotensive ac-

tivities of the drug.The evidence from this and other studies

would suggest therefore that the drug haspotent vasodilator activities. The rapidity andmagnitude of the reduction in the systemicvascular resistance of both normal and hyper-tensive patients equally would likewise sug-

gest that the predominant mode of action ofthe drug involved in this particular response

was due to a direct musculotropic vasodilatoreffect on the resistance vessels of the systemiccirculation. Collateral evidence lends strongsupport to this contention. Phentolamine ap-

pears to have only a weak sympathetic block-ing activity4 which is insufficient to affect ap-

preciably the vasoconstriction of the upper

limbs during supine leg exercise in man25 or

to block the Valsalva response.6 23 However,this weak sympathetic-blocking activity of thedrug is combined with a much greater pro-

pensity to block the hemodynamic effects ofcirculating catecholamines. In animals its ac-

tivities in this respect were 30 times as greatas its sympathetic blocking effects,4 and thepresent authors have demonstrated a similaractivity in man.26 Further, the absence of any

overshoot of the systemic arterial pressure aft-er the injection of the drug, compared to thenot infrequently marked overshoot after a

similar reduction in pressure with histamine,may well be due to antagonism of the cate-cholamines reflexly discharged in response tothe abrupt hypotension. However, this mod-erately powerful antagonism of the circula-tory effects of the endogenous catecholaminesis completely overshadowed by the consid-erably more potent direct vasodilator activi-ties of the drug. It is predominantly to thislatter property that phentolamine owes itshypotensive reputation.

These foregoing considerations would sug-


gest that the mechanism of the hemodynamicchanges that are observed following the intra-venous injection of the drug is threefold: first-ly, by producing a small degree of blockadeof sympathetic nervous activity; secondly, andmore importantly, by producing a moderatedegree of antagonism to circulating catechol-amines; and lastly, and of the greatest pro-portional magnitude, by causing a generalizeddirect vasodilatation of all muscular-walledvessels both small and large in all vascularterritories.

In the studies previously referred to, evi-dence was presented suggesting that the drugnot only caused a considerable dilatation ofthe peripheral arterioles but also possibly ofthe major muscular arteries.23 It is well knownthat the state of contraction and resistance tostretch of the muscular carotid arteries are theprimary factors affecting the receptors respon-sible for reflex regulation of the arterial pres-sure in this region. Under normal conditions,a reduction in blood pressure results in animmediate reflex response from these recep-tors in an attempt to reverse the fall, byperipheral vasoconstriction, tachycardia, andan increase in cardiac output. A drug thatnot only lowers the blood pressure but alsodilates the muscular arterial wall could there-fore be expected to result in an extremelybrisk reflex hemodynamic response. Experi-mental evidence in direct support of this con-tention is forthcoming from two sources. Theintravenous injection of phentolamine in dogsin comparable doses to those used in the pres-ent study caused a marked sensitization andpotentiation of the carotid sinus reflexes.4 Fur-ther, Martini and Rovati27 found that thelocal application of phentolamine to the carot-id sinus of the dog likewise resulted in amarked potentiation of the reflex pressor re-sponse to carotid hypotension. It would ap-pear, therefore, that not only is the afferentpathway of the pressor reflex unaffected, asjudged by the hemodynamic response to ex-ercise,25 but also that the drug certainly doesnot depress the reflex activity of the sinoaorticreceptors. While there is no direct evidencefrom this or other studies of a direct depres-

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TAYLOR ET AL.

sor effect of the drug on the higher centersof vasomotor regulation, such a possibilitywould explain the observed effects. The smallmolecular size of the drug and the rapiditywith which it achieves its circulatory effectswould certainly be consistent with rapid intra-cellular transport throughout the body tissues,including those of the central nervous sys-

tem.In this respect it is of interest to speculate

briefly on the biological cellular activity ofthe drug. A reduction in oxygen uptake dueto phentolamine does not appear to havebeen previously reported. In the present studyall of the normal subjects showed significantif transient reductions in oxygen uptake: it ispossible that a similar effect in the hyperten-sive patients was obscured by the much larg-er increase in cardiac work in these subjectsfollowing the injection of the drug. The rela-tively rapid time course of this depression ofoxygen uptake considered in conjunction withthe fact that under normal resting conditionsthe level of circulating catecholamines is ex-

tremely small28 would tend to exclude cate-cholamine antagonism alone as a reliablecause of this effect. Imidazoles as a group

appear to possess the property of being ableto block a large number of vital esterase re-

actions in vivo.29 The time course of the re-

duction in oxygen uptake in the present studyvould suggest that a generalized but evanes-

cent reduction in cellular oxidative processes

may possibly have resulted from injection ofthe drug.The majority of antihypertensive drugs in

clinical use at the present time exert theirmajor therapeutic effects by blockade of theautonomic nervous system. These drugs have

achieved widespread popularity in spite ofthe fact that they severely compromise thosefundamental circulatory adaptations on whichsuch patients particularly depend. Drugs withan imidazoline ring, among which are includ-ed phentolamine, Priscoline, and histamine,all appear to possess powerful antihyperten-sive effects due to their direct depressor ac-

tivity on vascular smooth muscle. In additionthese drugs appear to leave the sympatheti-

cally mediated compensatory reflexes of thecirculation largely intact. It is somewhat sur-prising, therefore, that their apparently idealantihypertensive properties have not beenmore fully exploited therapeutically.With regard to the diagnostic use of the

drug in clinical practice, its continued popu-larity as a reliable screening test for pheochro-mocytoma depends entirely on the interpreta-tion that can be placed on the immediateblood pressure changes observed in the in-dividual patient. The usually accepted valuesfor positive responses are immediate reduc-tions of 35 and 25 mm. Hg in the systolic anddiastolic pressures, respectively. In the pres-ent study falls in blood pressure considerablyin excess of these figures were observed in 50per cent of the hypertensive patients, noneof whom had a pheochromocytoma or otherevidence of an increased secretion of cate-cholamines. Although such a high proportionof false positive reactions has no bearing onthe reliability of the test in patients with adefinite pheochromocytoma, it seriously im-pedes the validity of the procedure as a re-liable screening test. This is not surprising inview of the in-built fallacy of the test in de-pending on absolute levels of blood pressurereduction. The drug produces a generalizedand relatively nonspecific vasodilatation, sothat the percentage reduction in blood pres-sure was of a comparable order between dif-ferent individuals. Thus, the higher the ab-solute level of blood pressure, the greater isthe fall after the drug.

In view of these findings, the place of phen-tolamine as a valid diagnostic test requiresserious reappraisal. The value of any drugused in a biological test depends entirely onthe precision with which the results can beinterpreted. In the case of phentolamine, itis well known that sedatives, uremia, preg-nancy, a variety of neurologic diseases, andeven a distended urinary bladder all greatlyinfluence the circulatory response to the in-jection of the drug. In addition, the drugnot infrequently causes an unexpectedly largehypotensive response, when none of these fac-tors is apparently operative to explain such


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an exaggerated effect. This, in fact, occurredin two hypertensive patients in a parallelstudy.23 These abnormal and often dangerousreactions are probably due to the fact thatthe diagnostic test, as usually employed, isnot, and often cannot be carried out underconditions of uniform biological baseline sta-bility. Under such varied conditions, it is notso surprising, therefore, that injection of a

drug which not only blocks two of the im-portant factors responsible for the reflex regu-lation of the blood pressure, but also achievesits major hemodynamic effect by a powerfuldirect vasodilator action at arteriolar level,should be instrumental in producing false-positive results. This contention is supportedcircumstantially by the finding of a poor dose-response relationship in terms of blood pres-

sure changes, not only in the present studybut also in other reports.23' 30A further point of considerable relevance is

that the onset of left ventricular insufficiencyis associated with a progressive increase invasoconstriction of the regional territories,partly directly sympathetically mediated andpresumably potentiated by an increased secre-

tion of adrenal medullary catecholamines. Theexhibition of phentolamine under these con-

ditions may produce a profound and mislead-ing fall in blood pressure, due not only to theblockade of these vital compensatory mecha-nisms, but due to the marked potentiationof its hypotensive properties by an im-paired cardiac output responsiveness. Theseconsiderations lead one seriously to questionthe validity of the continued use of the drugas a reliable screening test for the presenceof excessive circulating catecholamines due topheochromocytoma in man.

SummaryCirculatory observations have been made

on six normal subjects and six hypertensivepatients before and after the acute intrave-nous injection of 5 mg. of phentolamine.The drug caused a prompt reduction in sys-

temic vascular resistance which resulted in a

rapid fall in systemic blood pressure in spiteof an increase in heart rate and cardiac out-put.

Circulation, Voliime XXXI, May 1965

Evidence is presented that the predominantvascular activity of the drug is to cause adirect relaxation of vascular smooth muscle,an effect far more potent than its antagonismof circulating catecholamines or its very muchweaker sympathetic-blocking action. This di-rect depressor effect on vascular smooth mus-cle unaccompanied by any but slight sym-pathetic blocking activities endows the drugwith theoretically ideal antihypertensiveproperties.

Phentolamine caused a transient but sig-nificant reduction in oxygen uptake in themajority of individuals. It is suggested thatthis may be due to a direct inhibition ofcellular oxidative mechanisms.An appraisal of the circulatory activities of

the drug with particular regard to its use as adiagnostic test for pheochromocytoma leadsto serious doubts, not only with regard tothe precision with which the results of suchtests can be interpreted, but also to the valid-ity of the use of the drug as a reliable screen-ing test for excessive circulating catechol-amines.

AcknowledgmentThe authors are deeply indebted to Mr. J. Ramsay

and technicians for technical assistance and to SisterMI. C. Mitchell and nursing staff for invaluable helpduring the investigative procedures. The authors alsowish to express their appreciation to the MedicalResearch Council, Moray Endowment Trust, theBoard of Management of the Royal Infirmary andCiba Laboratories Ltd., for financial support withthe investigation. Phentolamine was supplied by CibaLaboratories Ltd., Horsham, Eglannd.

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K. W. DONALDS. H. TAYLOR, G. R. SUTHERLAND, G. J. MACKENZIE, H. P. STAUNTON and

The Circulatory Effects of Intravenous Phentolamine in Man

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The Circulatory Effects of Intravenous Phentolamine in Man