Pressor Responses Noxious Stimuli in Hypertensive Patients · Pressor Responses to Noxious Stimuli in Hypertensive Patients Effects of Guanethidine Sulfate and Alpha Methyldopa By

Pressor Responses to Noxious Stimuli inHypertensive Patients

Effects of Guanethidine Sulfate and Alpha Methyldopa

By ALVIN P. SHAPIRO, M.D., AND EMANUEL KRIFCHER, M.D.

IN previous studies, pressor reactivity toseveral standardized noxious stimuli was

evaluated quantitatively, and increased re-sponsiveness was demonstrated in hyperten-sive as compared with normotensive sub-jects." 2 The stimuli employed in thesestudies included simple psychologic provoca-tion as well as the cold pressor test and theintravenous injection of a small dose of angio-tensin II. Differences in the physiologicmechanisms of response were suggested fromexamination of the influence of diabetes mel-litus on pressor reactivity to these stimuli.2Since alteration by hypotensive drugs of theblood pressure response to noxious stimulirepresents a clinically important but usuallyundetermined pharmacologic function, eval-uation of the effect of several of these agentsalso was undertaken. In an earlier study itwas reported that chlorothiazide and reser-pine, in their usual therapeutic doses in hy-pertensive patients, failed to diminish the de-gree of pressor response to several of theaforementioned stimuli, despite lowering ofthe basal pressure.3 The present study wasdesigned to test the reactivity of hypertensivepatients before and during therapy with twomore potent hypotensive agents, guanethi-dine sulfate and alpha methyldopa. The dataalso were examined for information pertinentto the questions of the clinical pharmacologyand mechanism of action of these com-pounds.

From the Department of Medicine, University ofPittsburgh School of Medicine, Pittsburgh, Pennsyl-vania.

Supported by Training Grant HTS-5467 (Dr. Krif-cher) and Research Grant HE-05711 from the U. S.Public Health Service and by a grant from theHealth Research and Services Foundation of theUnited Fund of Allegheny County.

Methods and MaterialsTwenty-eight studies were done in subjects

with moderate to severe hypertensive vasculardisease, before and during therapy. Thirteen werein patients receiving guanethidine sulfate and 15in patients on alpha methyldopa. The severityof the hypertensive disease and the average doseand duration of therapy in each group are indi-cated in table 1.

Patients were either ambulatory and seen reg-ularly in the Hypertension-Renal Clinic or werehospitalized on the Clinical Research Unit * ofthe Presbyterian-University Hospital. All were re-ceiving the medications for therapeutic indica-tions.

Four noxious stimuli that have been describedin detail previously 1-3 were administered tostudy pressor responses. They consisted of (1)the intravenous injection of 10 ml. of normalsaline during which the patient is asked "to countbackwards from 100 as rapidly as possible" (sa-line); (2) a standard cold pressor test; (3) thereading of a confusing color chart (color); (4)the intravenous injection of 0.03 jgg./Kg. bodyweight of angiotensin II over a period of 1 min-ute. In the group of 13 patients receivingguanethidine sulfate, only the last eight weretested with angiotensin. Of the 15 on alphamethyldopa, one was not tested with angiotensin.The four tests were administered at 15-minuteintervals after an initial rest period of 15 to 30minutes.The order of administration of the stimuli was

the same in all subjects, as follows: saline, coldpressor, angiotensin, color. In most subjects, thefirst testing was before therapy. In a few, thefirst set of tests was performed while subjectswere receiving medication and, in these instanc-es, a minimum of 2 weeks was allowed to elapsebefore re-testing. Tests were done in the morning,usually with the patients in a fasting state, butat least 1 hour after the most recent dose ofmedication. All blood pressures were recordedwith the patient supine during the rest periodsand the tests, but at the end of the study the

*Supported by Clinical Research Center GrantFR-56.

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SHAPIRO, KRIFCHER

patients were tilted to the upright position andan erect blood pressure was determined when ithad stabilized (i.e., after 3 to 5 minutes inthe erect posture).

Blood pressures were determined on the Gil-ford automatic indirect recorder; pulse rates wereregistered simultaneously by means of a Gilfordcardiotachometer operating from a photoelectriccell attached to the ear of the subject.' Thepretest baselines and the maximum responses ofblood pressure and pulse rate for each test weredetermined as described previously.1 2 Systolicand diastolic values were converted to a cal-culated mean blood pressure

(diastolic ±pulse pressure3

to simplify subsequent ~statistical calculation.

Clinical Data

Therapy

ResultsThe resting blood pressures and pulse rates

(pretest baselines) and the responses to eachtest, before and during therapy with eitherguanethidine sulfate or alpha methyldopa,are presented in tables 2 and 3. Comparisonof the responses to each test are depicted infigure 1 (guanethidine sulfate group) andfigure 2 (alpha methyldopa group). The de-clines in pretest baselines and erect bloodpressures are also illustrated in these figures.The method of paired differences was usedto test the significance of the changes in bothpretest levels and responses.

Table 1

Number of patients Average

Male Female II

Guanethidine sulfateAlpha methyldopa

9 4

9 6

7

5

Grade of fundi Cardio-III IV megaly

3 3 12

)' 8 2 14

Baseline Blood Pressures andTable 2

Pressor Responses Before and During Therapy

Test

Saline

Cold pressor

Angiotensin t(0.03 jug./Kg.)

Color

Erectblood pressure

Before RxDuring RxDifference

pBefore RxDuring RxDifference



.P


p

Guanethidine sulfate(n 13)

Mean blood pressure(mm. Hg)

Pre-testbaseline Response

150.0 18.4144.0 13.5-6.0 -5.0

0.1 > 0.05 0.02 *

150.5 31.8145.2 19.9-5.3 -11.8> 0.05 <0.01 *150.5 36.7139.1 37.5-11.4 +0.8< 0.01* >0.05153.7 15.7147.0 10.8-6.6 -5.0> 0.05 0.05*

153.4119.9-33.4< 0.001 *

Alpha methyldopa(n-- 15)

Mean blood pressure(mm. Hg)


152.5 15.3136.8 10.0-15.7 -5.3< 0.01 * 0.02 *

154.1 24.8136.8 16.5-17.3 -8.3<0.01* <0.01*156.3 36.9140.0 43.1-16.3 +6.2

0.01 * 0.05 *

159.4 11.7138.7 7.5-20.7 -4.2

0.01 * > 0.05

157.6116.8-40.8< 0.001 *

* Significant difference.t With angiotensin test; n 8 for guanethidine sulfate, n 14 for alpha methyldopa.

Circulation, Volume XXX, November 1964

672

Age(years)

45.046.8

Bloodurea

nitrogen(mg.%)

19.320.0

Drugdose

(mg. / day)

62.51370

Durationof

therapy(weeks)

5.22.8



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PRESSOR RESPONSES IN HYPERTENSION

Table 3Baseline Pulse Rates and Responses Before and During Therapy

Guanethidine sulfate(n = 13)

Pulse rate(beats / minute)

Pre-testbaselinie Response


pBefore RxDuring RxDiff-erence



p

68.459.1-9.3< 0.01 *

69.158.0

-11.1< 0.01 *

74.060.4

-13.6< 0.01 *

68.257.9

-10.30.01 *

15.06.2

-8.80.015 *

14.18.8

-5.20.05 *

-1.3-5.4+4.1>0.0510.15.9

-4.20.05 *

Alpha methyldopa(n - 15)

Pulse rate(beats/ mllinute)


69.3 10.964.8 6.7-4.5 -4.2> 0.05 0.02*70.8 11.364.4 8.1-6.4 -3.2> 0.05 > 0.0570.6 -1.362.7 -1.1-7.9 -0.2

0.05* >0.0573.2 11.764.4 4.2-8.8 -7.50.05* 0.1 > .05

* Significant difference.t With angiotensin test; n = 7 for guanethidine sulfate, n = 10 for

a

.50i 99~~~~~~~~~

40

, 30

20

Q 10

Q

- 20

E -20-

-30-

- 40-

-50Mean PulseBP Rate

alpha methyldopa.

Response before FcResponse during FR

Decline in resting (supine)level E Fc

Decline in erect level c Rx* .05

** .05- 01*** <.01

MBP PR MBP PR MBP PR MBP

Saline Cold Pressor Angiotensin Color Erect

Figure 1Effects of therapy with guanethidine sulfate on the resting (pre-test baseline) pressures andpulse rates, and the responses to noxious stimuli before and during therapy. The last column inthe chart (MBP erect) indicates the fall in erect pressure produced by therapy. The vertical

lines indicating pulse rates are all depicted in solid black, but refer to response before, decline

in restIng, and response during, respectively, in the same order from left to right as for the

larger bars preceding them which indicate mean blood pressures.


673

'rest

Saline

Cold pressor

Angiotensin t(0.03 gg./Kg.)

Color



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SHAPIRO, KRIFCHER

It is apparent that both drugs caused onlya modest decline in the supine pretest base-line pressures. In fact, with guanethidine sul-fate, the average fall was of questionable sig-nificance. The erect blood pressures,however, were lowered significantly withboth compounds.The effect of therapy on pressor respon-

siveness essentially was similar with bothdrugs. The most striking feature was the con-trast between the cold pressor response,which was decreased markedly with therapy,and the angiotensin response, which was un-affected by guanethidine and indeed signifi-cantly increased, albeit a modest amount, inthe subjects receiving alpha methyldopa. Theresponses to the venipuncture (saline test)and to the color test tended to follow thepattern of the cold pressor response in thisstudy, both showing a decline during therapywith each compound.The contrast between the effects of therapy

on the responses to angiotensin and to thecold pressor stimulus also can be shown bythe device of comparing the ratio, angioten-sin to cold pressor (A/CP), before and dur-

50-

40

c 30

6 20

10-

E-20--30-

-40-

-50- Mean PulseB P Rote

ing therapy.2 The median * A/CP ratios be-fore therapy were 1.31 for guanethidine sul-fate and 1.57 for alpha methyldopa; duringtherapy, they rose to 2.41 and 3.18, respec-tively. With use of the Wilcoxon rank test,4the increases in ratio were highly significant(p - 0.01). Similarly, the average differencesbetween angiotensin and cold pressor re-sponses (A - CP) were 8.3 and 12.1 mm.Hg before therapy for guanethidine sulfateand alpha methyldopa, respectively, increase-ing to 19.7 and 26.0 mm. Hg during therapy;these differences also were highly significant(p= 0.02).A dose-dependent relationship of the fall

in cold pressor response was noted with al-pha methyldopa; this was suggested by thedata for guanethidine sulfate, but was not asclear-cut (fig. 3).The patterns of the changes in pulse rate

were similar to those for blood pressure. Pre-test baseline rates declined during therapy

* The median was determined rather than themean because these are ratios and accordingly donot follow a normal distribution.

* Response before RcE Response during RA

2 Decline in resting (supine)level U F<

R Decline in erect level U F,

* .05**.05 - 01

*** <.01

MBP PR MBP PR MBP PR MNBP

Saline Cold Pressor Angiotensin Color ErectFigure 2

Effects of therapy with alpha methyldopa. See figure 1 for explanation.

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674

*



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100-

90-

80-

n=5

<I.U <?.U*>1.0

nI8

I-

<50 > 50,<100

gms. DOSE n

Figure 3Effect of treatment with alpha methyldopa (left) and guanethidine (right)pressure response to cold pressor test. The per cent decline is calculatedResponse before therapy - Response during therapy

Response before therapy1

with both compounds but this effectappeared greater with guanethidine sulfatethan with alpha methyldopa. With guanethi-dine, the pulse rate increments with the sa-

line, cold pressor, and color tests were sig-nificantly less during therapy. With alphamethyldopa, the differences in pulse rate re-

sponses to these three stimuli were small andsignificant statistically only for the saline test.Angiotensin produced a slight fall in pulserate, unaffected by therapy with either com-

pound.

DiscussionIn contrast to the results achieved in our

previous study with chlorothiazide and re-

serpine in therapeutic doses,3 the two more

potent agents, guanethidine sulfate and al-pha methyldopa, caused a decline in reactiv-

Circulation, Volum.e XXX, November 1964

ng.

on mean bloodfrom the ratio:

ity to the cold pressor test. The response toangiotensin, the result of a direct vasocon-

stricting effect on the peripheral vascularbed,5 was not reduced by treatment and in-deed was increased in some subjects. Sincethe effector arc of the cold pressor response

is probably the sympathetic nervous system.these findings are in keeping with the conceptof sympatholysis by the drugs and hyper-sensitivity of the denervated arterioles to hu-moral vasoconstrictors. Preservation of angio-tensin response after sympatholysis also hasbeen observed by Brown and Wood, whoused a ganglion-blocking agent,7 and argues

against any significant role of the autonomicnervous system in the pressor response toangiotensin. Likewise, Dollery, Harington,and Hodge recently have demonstrated an

increased responsiveness to norepinephrine in

C.S(i

Q)

70-

60-

50-

40-

30-

20-

10-

0-

n=2

Xff]999

U

.

100>am~L-

675

n=3



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SHAPIRO, KRIFCHER

patients receiving alpha methyldopa.8 As sug-gested in our report of angiotensin and coldpressor reactivity in normal and diabetic sub-jects,2 an elevation of the "A/CP ratio" above2.0, although this is an empirically derivedfigure dependent on conducting both testsaccording to the described protocol, mayserve clinically to indicate impairment of sym-pathetic innervation of peripheral vasculature.A significant decline was noted in both the

saline and color responses with guanethidine,and in the saline test only with alpha methyl-dopa. In the previous study with chlorothia-zide and reserpine, these responses, as wellas the cold pressor response, did not decline.3In diabetic subjects with sympathetic impair-ment, however, in whom the cold pressorresponse was decreased, responses to thesepsychological stimuli also were not dimin-ished and it was proposed that they couldoperate alternatively through humoral or"angiotensin-like" mechanisms.2 The data inthe present study, indicating that with thesympatholysis induced by these potent com-pounds the psychophysiologic responses weredepressed, would suggest that our previousobservation in diabetic subjects was dose de-pendent, i.e., a less complete sympathetic de-nervation was present in the diabetic subjectsthan in the present group of patients ondrugs. On the other hand, the difference be-tween the two groups could be interpretedas time dependent, i.e., alternative responsepathways may represent a gradually develop-ing adaptive mechanism to spontaneous ac-quisition of sympathetic impairment, andthus may be absent with the relatively acutesympatholysis produced by drugs. Such con-cepts, however, are inferred from hemody-namic measurements that are influenced by avariety of factors and remain speculative.The hypothesis that peripheral mechanismsalternative to the autonomic nervous system,such as the elaboration of vasoactive poly-peptides, could mediate cardiovascular re-sponsiveness, is attractive, but its explorationrequires the development of technics formeasuring the humoral biochemical changes

acutely accompanying responses to noxiousstimuli.The study was not designed and the pa-

tients were not selected specifically to com-pare differences between the effects ofguanethidine sulfate and alpha methyldopa,but several observations can be noted. Phar-macologically the two compounds act differ-ently on the autonomic nervous system.Guanethidine sulfate appears to deplete nor-epinephrine stores or to interfere with nor-epinephrine release at peripheral sites, pos-sibly by blocking acetylcholine.9 Alphamethyldopa theoretically could interferewith norepinephrine synthesis by competitiveinhibition at the decarboxylase step. Someinvestigators have reported a decrease in theexcretion of the urinary metabolite vanilman-delic acid,10 but others have not.11 12 Tissuedepletion of norepinephrine occurs, but nei-ther the persistence of this depletion nor thehypotensive effects of the compound corre-late with the duration of decarboxylase in-hibition.12 It has been suggested, therefore,that the amine metabolites of alpha methyl-dopa themselves are responsible directly fornorepinephrine depletion.12 Alternatively,Dacty and Rand have argued that alphamethylnorepinephrine, itself a pressor ma-terial but less potent than norepinephrine,becomes a "false transmitter" after administra-tion of alpha methyldopa and hence re-sponses to sympathetic stimulation are damp-ened.13 The situation remains uncertain as isemphasized by a comprehensive recent studyof the metabolism of alpha methyldopa inman by Buhs and co-workers. The data ofthese investigators indicate no apparent corre-lation between the variations in the metabolicfate of the drug and its degree of hypotensiveaction.14

Clinically, however, the two drugs pro-duced qualitatively similar effects in the pres-ent study, effects that demonstrate at least afunctional sympatholysis. The effect of guan-ethidine sulfate on the pulse rate seemedmore pronounced, a finding which may in-dicate that although both drugs deplete car-diac tissue of catecholamines,l. the clinical


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effect on the heart is more pronounced withguanethidine than with alpha methyldopa.Alpha methyldopa lowered the supine pres-sure to a greater extent than did guanethidinesulfate, which is in keeping with the impres-sion that this drug has a greater potential tolower blood pressure by actually decreasingperipheral resistance.8 Nevertheless, as theseobservers, and others,'16 17 pointed out, anadditional and quite significant postural hy-potension is present, as usually occurs withdrugs that are operationally sympatholytic,and is the result of fall in cardiac output inthe erect position. The dose-dependent rela-tionship of the depression of the cold pressorresponse with alpha methyldopa was indica-tive of increasing sympatholysis with increas-ing dosage.The results, as did those with chlorothia-

zide and reserpine,3 hcLve certain therapeuticimplications. Obviously, a decrease in theblood pressure "ceiling" in response to stimu-lation occurred; this may have therapeuticvalue, since hypertensive patients are rarelyin a basal state but are exposed continuallyto noxious stimuli of various types. It isequally clear, however, that increments inblood pressure during any particular periodof observation may occur despite effectivetherapy with potent drugs, and in some in-stances reactivity may be enhanced. Eleva-tions of blood pressure during drug therapythus can represent reactive responses ratherthan therapeutic failures. Accordingly, theyshould suggest search for sources of suchstimulation, which are frequently psycho-physiologic,18 rather than constitute immedi-ate indications for changes in type or dose ofmedication.

SumnmaryThe pressor and pulse rate responses to

several standardized stimuli were determinedin hypertensive patients receiving guanethi-dine sulfate or alpha methyldopa in thera-peutic doses. Despite differences between thetwo compounds in their mode of action, bothdemonstrated functionally sympatholytic ef-fects. Both drugs produced a greater bloodpressure fall in the erect posture than in theCirculation, Volume XXX, November 1964

supine and impaired the pressor response tothe cold pressor test. The pressor reactivityto intravenous angiotensin, however, persist-ed. Responses to psychophysiologic stimuliwere decreased. The implications of thesefindings for both therapy and for understand-ing of physiologic mechanisms of pressor re-activity are discussed.

AcknowledgmentGuanethidine sulfate and angiotensin II (as valyl-

5-angiotensin-II) were supplied by Ciba Pharma-ceutical Company; alpha methyldopa was obtainedfrom Merek, Sharp and Dohme, Inc. The assist-ance of Miss Eileen Tyrrell in the statistical analysesof the data is gratefully acknowledged.

References1. SHAPIRO, A. P.: An experimental study of com-

parative responses of blood pressure to differ-ent noxious stimuli. J. Chron. Dis. 13: 293,1961.

2. SHAPIRO, A. P., MOUTSOS, S. E., AND KRIFCHER,E.: Patterns of pressor response to noxiousstimuli in normal, hypertensive and diabeticsubjects. J. Clin. Invest. 42: 1890, 1963.

3. SHAPIRo, A. P.: Pressor responses to noxiousstimuli in hypertensive patients; effects ofreserpine and chlorothiazide. Circulation 26:242, 1962.

4. EDWARDS, A. L.: Statistical Methods for theBehavioral Sciences. New York, Rinehart &Co., 1960, p. 291.

5. PAGE, I. H., AND BUMPUS, F.: Angiotensin.Physiol. Rev. 41: 331, 1961.

6. REISER, M. F., AND FERRIS, E. B., JR.: The na-ture of the cold pressor test and its signifi-cance in relation to neurogenic and humoralmechanisms in hypertension. J. Clin. Invest.27: 156, 1948.

7. BROWN, W. J., JR., AND WOOD, J. E.: The effectof acute autonomic blockade upon peripheralarteriolar and venous responses to angiotensinin man. Clin. Res. 11: 163, 1963.

8. DOLLERY, C. T., HARINGTON, M., AND HODGE,J. V.: Hemodynamic studies with methyl-dopa: Effect on cardiac output and responseto pressor amines. Brit. Heart J. 25: 670, 1963.

9. SHORE, P. A.: Release of serotonin and cate-cholamines by drugs. Pharmacol. Rev. 14:531, 1963.

10. TYCE, G. M., SHEPS, S. G., AND FLOCK, E. V.:Determination of urinary metabolites of cate-cholamines after the administration of methyl-dopa. Proc. Staff Meet., Mayo Clin. 38: 571,1963.

11. CANNON, P. J., WHITLOCK, R. T., MoRRis, R. C.,

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ANGER, M., AND LARAGH, J. H.: Effects ofalpha methyldopa in severe and malignanthypertension. J.A.M.A. 179: 673, 1962.

12. SJOERDSMA, A., VENDSALU, A., AND ENGELMAN,K.: Studies on the metabolism and mecha-nism of action of methyldopa. Circulation 28:492, 1963.

13. DAY, M. D., AND RAND, M. J.: An hypothesisfor the mode of action of alpha methyldopain relieving hypertension. J. Pharm. & Phar-macol. 15: 221, 1963.

14. BuHs, R. P., BECK, J. L., SPETH, 0. C., SMITH,J. L., TRENNER, N. R., CANNON, P. J., ANDLARAGH, J. H.: The metabolism of methyl-dopa in hypertensive human subjects. J.Pharmacol. & Exper. Therap. 143: 205, 1964.

15. STONE, C. A., Ross, C. A., WENGER, H. C.,LUDDEN, C. T., BLESSING, J. A., TOTARO, J. A.,

AND PORTER, C. C.: Effect of a-methyl-3,4-dehydroxyphenylalanine (methyldopa), reser-pine and related agents on some vascular re-sponses in the dog. J. Pharmacol. & Exper.Therap. 136: 80, 1962.

16. SANNERSTEDT, R., Bojs, G., VARAUSKAS, E.,AND WERK6, L.: Alpha methyldopa in arteri-al hypertension; clinical, renal, and hemody-namic studies. Acta med. Scandinav. 174: 54,1963.

17. VINCENT, W. A., KASHEMSANT, V., CUDDY, R.P., SMULYAN, H., AND EICH, R. H.: Theacute hemodynamic effects of alpha methyl-dopa. Am. J. M. Sc. 246: 558, 1963.

18. SHAPIRO, A. P.: Psychophysiologic mechanismsin hypertensive vascular disease. Ann. Int.Med. 53: 715, 1960.

Observations on TreatmentBy Richard Bright-1827

One of the most important questions in the treatment of this class of dropsies, is thepropriety of employing Mercury. It is consistent with the most successful treatment ofmany forms of inflammatory disease, that we should have recourse to the valuablecombination of Calomel with Opium; and iit is consistent with what is generally deemedgood practice, that by the cautious use of mercury we should endeavour to producemore healthy action, and to piromote absorption when there is reason to believe thatdisease has left any chronic morbid action tending to produce unhealthy deposit inglandular structures. Still however, the.cases which have proved most successful in myown practice, have generally been those in which I have rigidly abstained from theuse of mercury. In some cases I have seen the good effects of other remedies entirelyinterrupted by the mercurial action; and I have likewise seen several instances in whichthe cure, when mercurials have formed part of the plan, has been protracted to a greatlength; and a great many in which the full action of mercury has not prevented theregular progress of the disease, and its fatal termination.-Original Papers of RichardBright on Renal Disease. Edited by A. ARNOLD OSMAN. London, Oxford UniversityPress, 1937, pp. 74-75.

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ALVIN P. SHAPIRO and EMANUEL KRIFCHERGuanethidine Sulfate and Alpha Methyldopa

Pressor Responses to Noxious Stimuli in Hypertensive Patients: Effects of

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