Journal of Clinical Investigation Vol. 42, No. 12, 1963 PATTERNS OF PRESSOR RESPONSE TO NOXIOUS STIMULI IN NORMAL, HYPERTENSIVE, AND DIABETIC SUBJECTS * By ALVIN P. SHAPIRO, SPERO E. MOUTSOS, AND EMANUEL KRIFCHER (From the Department of Medicine, University of Pittsbuirgh School of Medicinie, Pittsburgh, Pa.) (Submitted for publication April 30, 1963; accepted August 16, 1963) In earlier studies, the influence of various "host factors" affecting the pressor responses to noxi- ous stimuli in hypertensive and normotensive sub- jects was investigated. Information was obtained indicating that intrinsic factors predominate in determining the type and severity of such pressor responses (1). It also was demonstrated that lowering basal blood pressure in the hypertensive patient with therapeutic doses of reserpine and chlorothiazide did not decrease these responses (2). The present studies represent a continuing ef- fort to define the factors determining patterns of pressor response to noxious stimuli, with par- ticular attention to the physiologic mechanisms that mediate these responses. As in previous stud- ies, the cold pressor test was assumed to measure the neurogenic component, and this response was compared to the results with two operationally simple psychological stimuli (1, 2). Synthetic angiotensin II, presently the most potent periph- eral vasoconstrictor known, was used in this ex- periment as a direct humoral vasoconstrictor and was administered as a single intravenous dose, in a constant amount and with a constant technique. An automatic indirect blood pressure recorder that permits an objective recording, obviates the neces- sity of arterial cannulation, and allows the testing of many subjects with minimal inconvenience to them was employed. In addition to normotensive and hypertensive patients, the present study uti- lized diabetic subjects, a population with a tend- ency to neurologic abnormalities that theoretically should affect their pathways of blood pressure responsiveness. * Supported by training (HTS 5467) and research (HE-05711) grants from the U. S. Public Health Serv- ice and by the Health Research and Services Foundation of the United Fund of Allegheny County, Pa. MATERIALS AND METHODS A total of 113 subjects in four groups were studied: 55 were hypertensive (diastolic pressure, 90 mm Hg or above without obvious primary renal or endocrine dis- ease as its cause), and 58 were normotensive. All were patients in either the Presbyterian-University Hospital or the Falk Outpatient Clinic of the University of Pitts- burgh School of Medicine. Twenty of the hypertensive subjects were diabetic as were 25 of the normotensives. Criteria for the presence of diabetes consisted of the demonstration of an elevated fasting blood sugar, an abnormal glucose tolerance curve, or both; many sub- jects had evidence of other diabetic concomitants con- sisting of microaneurysms, neuropathy, or nephropathy. The normotensive nondiabetic controls consisted of pa- tients with diseases not involving the cardiovascular or renal systems. The salient clinical features in the four groups are indicated in Table I. The small differences in ages between the two normotensive groups and the two hypertensive groups were not significant statistically. A slightly higher basal blood pressure was present in the normotensive diabetics as compared to the nondiabetic normotensive group; between the two hypertensive groups, the diabetics had slightly lower basal blood pressure (p=.05 for each). Subjects were included as they became available to the investigators during the course of the study. None were chosen who were receiving therapeutic agents known or suspected to affect autonomic nervous system reactivity. These included all hypotensive drugs,1 steroids, tranquil- izers, sedatives, analgesics, and psychic energizers. Pa- tients who could not cooperate for various reasons, were too ill to undergo the tests, or had priority needs for therapy were not included. Consequently, the groups that were studied cannot be considered random samples of the various populations under consideration. Despite the lack of a systematic technique of sampling, however, which often is impractical in this type of investigation, the clinical characteristics of the subjects indicated the inclusion of the usual range of manifestations of these diseases. Patients were studied usually in the morning, in the 1 A few hypertensive subjects regularly taking thia- zides were included although they were not given the drug on the test day. Our previous studies have indicated that thiazides do not affect the pressor responses to these stimuli (2). 1890
Transcript
Journal of Clinical InvestigationVol. 42, No. 12, 1963
PATTERNSOF PRESSORRESPONSETO NOXIOUSSTIMULI INNORMAL,HYPERTENSIVE, AND DIABETIC SUBJECTS*
By ALVIN P. SHAPIRO, SPEROE. MOUTSOS,AND EMANUELKRIFCHER
(From the Department of Medicine, University of Pittsbuirgh School of Medicinie,Pittsburgh, Pa.)
(Submitted for publication April 30, 1963; accepted August 16, 1963)
In earlier studies, the influence of various "hostfactors" affecting the pressor responses to noxi-ous stimuli in hypertensive and normotensive sub-jects was investigated. Information was obtainedindicating that intrinsic factors predominate indetermining the type and severity of such pressorresponses (1). It also was demonstrated thatlowering basal blood pressure in the hypertensivepatient with therapeutic doses of reserpine andchlorothiazide did not decrease these responses(2).
The present studies represent a continuing ef-fort to define the factors determining patterns ofpressor response to noxious stimuli, with par-ticular attention to the physiologic mechanismsthat mediate these responses. As in previous stud-ies, the cold pressor test was assumed to measurethe neurogenic component, and this response wascompared to the results with two operationallysimple psychological stimuli (1, 2). Syntheticangiotensin II, presently the most potent periph-eral vasoconstrictor known, was used in this ex-periment as a direct humoral vasoconstrictor andwas administered as a single intravenous dose, ina constant amount and with a constant technique.An automatic indirect blood pressure recorder thatpermits an objective recording, obviates the neces-sity of arterial cannulation, and allows the testingof many subjects with minimal inconvenience tothem was employed. In addition to normotensiveand hypertensive patients, the present study uti-lized diabetic subjects, a population with a tend-ency to neurologic abnormalities that theoreticallyshould affect their pathways of blood pressureresponsiveness.
* Supported by training (HTS 5467) and research(HE-05711) grants from the U. S. Public Health Serv-ice and by the Health Research and Services Foundationof the United Fund of Allegheny County, Pa.
MATERIALS AND METHODS
A total of 113 subjects in four groups were studied:55 were hypertensive (diastolic pressure, 90 mmHg orabove without obvious primary renal or endocrine dis-ease as its cause), and 58 were normotensive. All werepatients in either the Presbyterian-University Hospitalor the Falk Outpatient Clinic of the University of Pitts-burgh School of Medicine. Twenty of the hypertensivesubjects were diabetic as were 25 of the normotensives.Criteria for the presence of diabetes consisted of thedemonstration of an elevated fasting blood sugar, anabnormal glucose tolerance curve, or both; many sub-jects had evidence of other diabetic concomitants con-sisting of microaneurysms, neuropathy, or nephropathy.The normotensive nondiabetic controls consisted of pa-tients with diseases not involving the cardiovascular orrenal systems. The salient clinical features in the fourgroups are indicated in Table I. The small differencesin ages between the two normotensive groups and the twohypertensive groups were not significant statistically. Aslightly higher basal blood pressure was present in thenormotensive diabetics as compared to the nondiabeticnormotensive group; between the two hypertensive groups,the diabetics had slightly lower basal blood pressure(p=.05 for each).
Subjects were included as they became available to theinvestigators during the course of the study. None werechosen who were receiving therapeutic agents known orsuspected to affect autonomic nervous system reactivity.These included all hypotensive drugs,1 steroids, tranquil-izers, sedatives, analgesics, and psychic energizers. Pa-tients who could not cooperate for various reasons, weretoo ill to undergo the tests, or had priority needs fortherapy were not included. Consequently, the groupsthat were studied cannot be considered random samplesof the various populations under consideration. Despitethe lack of a systematic technique of sampling, however,which often is impractical in this type of investigation,the clinical characteristics of the subjects indicated theinclusion of the usual range of manifestations of thesediseases.
Patients were studied usually in the morning, in the
1 A few hypertensive subjects regularly taking thia-zides were included although they were not given the drugon the test day. Our previous studies have indicatedthat thiazides do not affect the pressor responses to thesestimuli (2).
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PATTERNSOF PRESSORRESPONSETO NOXIOUS STIMULI 1891
TABLE I
Clinical data
All subjectsFundi
Sex Race Cardiac PretestBUN* hyper- I and III blood Pretest
Age M F Negro White >20 trophy II and IV pressuref pulset
* Blood urea nitrogen.t Average of base lines before all four noxious Stimuli.
group. MBP= mean blood pressure.
fasting state. In a few instances, tests were done in theafternoon, with the patient omitting lunch. Insulin ororal hypoglycemic drugs were omitted on the day oftesting in those diabetics receiving these agents. Bloodpressure was determined indirectly with the Gilford auto-matic blood pressure relorder; a cardiotachometer, op-erating from a photoelectric pickup attached to the earlobe, recorded pulse rate with each blood pressure cycle(1).
Patients were put to bed in a quiet room. After at-tachment of the apparatus they rested, alone in the room,for 15 to 30 minutes while blood pressure and pulsemeasurements were made automatically at 1-minute in-tervals. After the rest period, four stimuli were ad-ministered at 15- to 30-minute intervals; between tests,the investigator again left the room. Three of the stim-uli have been described previously (1): 1) venipunctureand the intravenous injection of 10 ml of normal salinewith a stylized protocol during which the subject isasked to "count backwards from 100 as rapidly as pos-sible" ("saline" test) ; 2) a standard cold pressor test;and 3) the rapid reading of a chart containing the namesof colors, printed in colors other than the color nameitself ("color" test). The fourth stimulus consisted ofthe intravenous injection, over a period of 1 minute, of0.03 jug per kg of angiotensin II 2 (to a maximal dose of2.5 lig in patients weighing over 83 kg) prepared in aconcentration of 0.25 j.Lg per ml. After administration ofthe angiotensin, blood pressures were taken as closely aspossible to every 30 seconds by cycling the machine manu-ally. The maximal systolic and diastolic rises generallyoccurred from 11 to 21 minutes after the start of the in-jection. The maximal change in pulse rate, which usuallywas downward, also was recorded during this period.
The four stimuli were not administered randomly, but
2As synthetic valyl-5-angiotensin II, supplied by CibaPharmaceutical Co., Summit, N. J.
No significant differences among the four base lines for each
in the same order for all subjects, as follows: test 1,saline; test 2, cold pressor; test 3, angiotensin; test 4,color. The response for each test represented the dif-ference between the maximal change and the average offour readings immediately before the particular stimulus.Thus, a new base line was used for each test, but sta-tistical analyses indicated no significant differences amongthese four base lines in any of the four groups of pa-tients. The systolic and diastolic responses were con-verted to a single figure, the calculated mean blood pres-sure [diastolic + (pulse pressure/3)], to simplify latercomputations. Separate analyses of the systolic anddiastolic components of the responses were not per-formed, since it was not felt that these would add sig-nificantly to the interpretation of the data in this study.It was observed, however, that angiotensin produced pri-marily a diastolic response, while the cold pressor, saline,and color tests varied from a predominantly diastolic ele-vation, through a "mixed" response, to a predominantlysystolic elevation, respectively, as in previous studies(1, 2). The average response, in both mean blood pres-sure and pulse rate, was calculated for each of the fourgroups, and compared for each test by analysis of variance(3).
The Clyde Mood Scale, a self-administered, adjective-rating, psychological test, was used with most of thesubjects at the conclusion of the experimental period.This test provides an estimate of the patient's attitudesat the time of testing. The calculated scores deviate froma norm of 50 and estimate the mood of the subject insix categories, i.e., friendly, energetic, clear-thinking,aggressive, jittery, depressed (1).
RESULTS
The average response to all four stimuli and thestatistical analyses are presented in Table II.
ALVIN P. SHAPIRO, SPEROE. MOUTSOS,AND EMANUELKRIFCHER
TABLE lI
Blood pressure and pulse responscs
Blood pressure response Pulse rate response
Angio- Cold Angio- ColdGroup tensin pressor Saline Color tensin pressor Saline Color
Among all groups F 17.52 9.59 3.57 3.89 7.08 1.36 3.42 1.26p <.001* .001* .025* .01* <.01* >.05 .025* >.05
p values for group comparisonsN X N-Dt .001* >.05 >.05 >.05 >.05 >.05NX H <.001* <.001* <.001* .01-.001* >.05 .02*N-D X H-D .01-.001* >.05 >.05 >.05 <.001* >05H X H-D .05* .001* >05 >.05 .02* .01*
* Significant values (p = .05 or less).t N = normotensive; N-D = normotensive-diabetic; H = hypertensive; H-D = hypertensive-diabetic.
These responses are depicted in Figure 1. Asshown in previous studies, the nondiabetic hyper-tensives (H) were significantly more reactive thannormal subjects (N) to both of the psychologicalstimuli and to the cold pressor test. In addition,this study demonstrated that they reacted morevigorously to angiotensin. The diabetic hyper-tensives (H-D) similarly were more reactive to
'5-
5-
01
ii K0A-
angiotensin than normotensive diabetics (N-D)and seemingly more responsive to the cold pres-sor, saline, and color tests, although the differenceswith these latter three tests were not significantstatistically.
Striking contrasts were evident between the di-abetics and nondiabetics, both hypertensive andnormotensive. The diabetics were more respon-
STIMULI IN THE FOUR GROUPSOF PATIENTS INDICATED. The data are arranged inthe figure to show the contrast between diabetic and nondiabetic groups. Signifi-cant differences (p <.05) are indicated by an asterisk. Further statistical com-
parisons, namely, of normotensives vs. hypertensives, are indicated in Table II.
SALINE COLOR
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PATTERNSOF PRESSORRESPONSETO NOXIOUS STIMULI
sive to angiotensin and less reactive to the coldpressor stimulus. These changes were highly sig-nificant with the exception of that between thecold pressor responses in N and N-D (19.6 and16.1 mmHg, respectively, p >.05). The aver-age differences between angiotensin (A) and coldpressor (CP) responses, however, were markedlyincreased in the diabetics (H = 9.5 mmHg, H-D= 26.7 mmHg, p <.001; N = 6.6 mmHg, N-D= 19.4 mmHg, p =.01 >.001). This was em-phasized further when the ratio A/CP was de-termined. The median values of A/CP werehigher for the diabetics (H = 1.30; H-D = 2.62;N = 1.26; N-D = 2.57). The percentages of sub-jects with A/CP values of 2.0 or above (Figure2) were significantly greater (chi square; p <.01)in each of the diabetic groups as compared to itsrespective nondiabetic group.3
3 The mean values of the pressor responses for theten patients in the N-D group with postural hypotension,or other clinical evidence of peripheral neuropathy (im-paired motor reflexes, grossly diminished vibratory sense,or impotence), or both, were 36.1, 15.9, 14.2, and 11.6mm Hg to the angiotensin, cold pressor, saline, andcolor tests, respectively, with 71% having an A/CP ratiogreater than 2.0; these values were not significantly dif-ferent from the remainder of the group. Similarly, forthe seven patients in the H-D group, the mean valueswere 47.8, 15.8, 12.1, and 11.9 mmHg to these fourtests, with 70%o having an A/CP ratio greater than 2.0,again not different from the rest of the group.
F11 NLroftennsive100-
Normotensive iadbetic
O Hypertensive2, 8 *
Hypertensive DiabeticA 7
70.Q.3
40
FIG. 2. COMPARISONOF PERCENTAGEOF SUBJECTS WITHANGIOTENSIN/COLD PRESSOR(A/CP) RATIO GREATERTHAN2.0 IN THE DIABETIC AND NONDIABETIC GROUPS. Differ-ences are significant (p <.01) by chi square analysis as
indicated by an asterisk.
Still further demonstration of the contrastingdifferences in the angiotensin and cold pressorresponses in the diabetics and nondiabetics is pro-vided by the frequency distribution curves setforth in Figures 3 and 4. These demonstrateseparate peaks for diabetics and nondiabetics,within both the normotensive (Figure 3) and thehypertensive (Figure 4) populations. Moreover,the peaks for the diabetics move in opposite di-rections on the curves for the two tests, i.e., tothe left for the cold pressor and to the right forangiotensin.
- Diabetics--- Non-Diabetics
-4.901 10.1 20.1 30) 40.1 50) Wj -4.90.,o 66p 0
mm. Hg (Mean B.e)
FiG. 3. FREQUENCYDISTRIBUTION OF PRESSORRESPONSESIN NORMOTENSIVESTO
ANGIOTENSIN AND COLD PRESSOR.
45.
40.
35-
R 30
Ok 25
k 20-
15
10.
5
0
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ALVIN P. SHAPIRO, SPERO E. MOUTSOS,AND EMANUELKRIFCHER
- DIABETICS--- NON- DIABETICS
65.0 0
mm. Hg (Mean B.P)
FIG. 4. FREQUENCYDISTRIBUTION OF PRESSORRESPONSESIN HYPERTENSIVESTO
ANGIOTENSIN AND COLD PRESSOR.
Comparison of the pattern of responses to thetwo psychological stimuli was noteworthy, sincethese responses did not decline significantly in thediabetics despite their decreased cold pressor re-
activity. This is shown best in Figure 5, whichdemonstrates the percentile change in the re-
120i
110-
.! 100-
S 90-
0
E 80
; 70-E 60-
50-
0, 40-
6 30-
20-
%'- 10-
CQ 0-
10-
sponses to each test in the H, N-D, and H-Dgroups with the responses in the normal group
as the base lines. In the H group, all four re-
sponses were enhanced. In the two diabeticgroups, N-D and H-D, the responses to the twopsychological stimuli, like that to angiotensin, were
FIG. 5. COMPARISONOF THE PRESSORRESPONSESIN THE THREE EXPERI-
MENTAL GROUPSTO THOSE IN THE NORMALSUBJECTS. For each test, thepressor response (mm Hg, mean blood pressure) in the experimental grouphas been expressed as the percentage of- the response to the same test in thenormotensive nondiabetic group.
45
40-
35
30
k 25
k 20
' 5
§ 10
5-
0O
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PATTERNSOF PRESSORRESPONSETO NOXIOUS STIMULI
TABLE III
Clyde Mood Scale scores
Group Friendly Energetic Clear-thinking Aggressive Jittery Depressed
increased, although the cold pressor reactivity wasdepressed.
The pulse responses showed little difference.The only meaningful contrast was between H andH-D in the decline that occurred after the adminis-tration of angiotensin. This decline was less inthe H-D, perhaps indicating that impairment ofthe autonomic nervous system prevented the usualreflex fall in pulse rate to this predominantly dias-tolic rise in pressure. Similarly, the smallerrises to other stimuli in the H-D (p =.01 for thesaline test) might represent impairment of cardio-accelerator mechanisms.
The Clyde Mood Scale scores (Table III) in-dicated no significant differences among the fourgroups in the various categories measured. Thus,insofar as this test is an adequate measure, theattitudes of the subjects in the four groups werefairly uniform.
DISCUSSION
The data confirm that hypertensive patients aremore responsive than normotensive subjects tosimple psychological stimuli as well as to the coldpressor test. In addition, the present study indi-cates that they also react more vigorously to thedirect humoral vasopressor influence of angioten-sin. The latter observation is interesting becauseof current controversy concerning the role of an-gioteinsinase in determining the response to angio-tensin. It has been demonstrated with angioten-sin 1131 (4) and with rat bioassay (5) that the invitro half-life of angiotensin in hypertensiveplasma is shortened. Thus, increased destructionby an angiotensinase in the hypertensive subjecthas been suggested as an adaptive mechanism tochronic angiotensinemia. On the other hand, thein vivo half-life of angiotensin 131 appears to beprolonged in the hypertensive (6), and Wood'sdata from the offspring of hypertensive sub-
jects indicate decreased angiotensin destruc-tion in these individuals (7). Klaus, in fact,found no differences in angiotensinase activity ofsera from normal and hypertensive subjects (8).The evidence from angiotensin I131 can be ques-tioned, since data obtained with tritiated angioten-sin (9) indicate that the fate of the iodinatedcompound may not reflect the true behavior of thepolypeptide. In addition, Khairallah, Bumpus,Page, and Smeby (10) have demonstrated a num-ber of nonspecific angiotensinases. Our presentdata would indicate at least that if angiotensinaselevels are elevated in chronic hypertension, theydo not inhibit the pressor response to an acuteinjection of the synthetic polypeptide. Kaplanand Silah have provided similar evidence ofhyperreactivity to angiotensin in a group of es-sential hypertensives given a more chronic infu-sion of the material (11).
What appears evident is the importance of in-trinsic responsiveness in evaluation of blood pres-sure control as demonstrated in the present studyby hyperresponsiveness in the hypertensive sub-ject to several pressor stimuli, presumably actingby different mechanisms. Gombos and associates(12) have pointed out that such an increased pres-sor response need not imply an increased sensi-tivity of arterioles per se, since the percentile risein blood pressure in the hypertensives essentiallywas unchanged from the normal. Moreover, sinceperipheral resistance increases exponentially withdecrease in the radius of the arteriole, a change ina vessel already narrowed produces a larger in-crease in peripheral resistance than the samechange in a more dilated arteriole. The fact re-mains, however, that the clinically important meas-urement, namely, the actual blood pressure rise inmillimeters of Hg, is greater in the hypertensivesubject. Moreover, we have shown that the re-sponse to these stimuli is not dependent on the
1895
ALVIN P. SHAPIRO, SPEROE. MOUTSOS,AND EMANUELKRIFCHER
base-line pressure in the hypertensive individ-ual; among normotensives it is greater inthose with a family history of hypertension (1).In addition, hypertensive subjects with basal bloodpressures lowered by therapeutic doses of reser-pine and chlorothiazide show no decrease in pres-sor response to noxious stimuli and, in fact, havean enhanced percentile rise (2).
In our previous studies, analysis of systolic,diastolic, and pulse rate relationships permittedsuggestions concerning the proportional changesin peripheral resistance and cardiac output in theproduction of the pressor responses with thestimuli that we have employed (1). Withoutsimultaneous cardiac output measurements, how-ever, these provide only inferences for the under-standing of the hemodynamic mechanisms involvedand have not been attempted in the present study.Moreover, recent data that include the demon-stration of high outputs with normal resistancesin young hypertensives suggest that it may bemore correct to conceive of hypertension hemo-dynamically as an imbalance between output andresistance rather than purely a disease of elevatedresistance (13). Thus, a normal peripheral re-sistance that is unchanged with a rise in cardiacoutput becomes a comparatively high resistance.Such a concept adds importance to increased re-sponsiveness as demonstrated solely by blood pres-sure measurement, independent of the relativecontributions of output and resistance to thechange.
The differences demonstrated between diabeticsand nondiabetics, which are reflected in percentilerise as well as in millimeters of Hg, can be inter-preted in terms of a hypothesis that blood pressureresponses are regulated by two independent yetinterrelated mechanisms: 1) the neurogenic, medi-ated efferently by the sympathetic nervous systemthrough its innervation of vascular structures andterminal release of norepinephrine and 2) the hu-moral, represented by direct effects on arteriolarsmooth muscle by circulating vasoconstrictor ma-terials, among which may be polypeptides whoseprototype is angiotensin II. The concept that thecold pressor response is mediated by efferents inthe sympathetic nervous system, and accordingly,measures the neurogenic component, is supportedby observations that it is reduced or blocked byspinal anesthesia (14) and by ganglion-blocking
(15) and sympatholytic drugs (16). Similarly,although some recent evidence suggests a con-tributing central action (17) and mediationthrough the sympathetic nervous system (18),angiotensin has been primarily established as a di-rect vasoconstrictor of arterioles (19).
Impairment of the circulatory response to thecold pressor test corresponds to previous demon-strations in diabetic subjects of failure of othercirculatory adjustments mediated by the sympa-thetic nervous system (20). Enhanced respon-siveness to humoral agents, e.g., exogenous cir-culating norepinephrine, has been demonstratedpreviously in diabetics (21, 22), and the presentstudy indicates that this occurs with a differenttype of peripheral vasoconstrictor as well, namely,the polypeptide angiotensin. Increased reactivityto humoral materials is typical of denervated ar-terioles. Its presence in the diabetic after adminis-tration of angiotensin argues against any signifi-cant role of the autonomic nervous system in nor-mally mediating responses to angiotensin.
The clinical manifestation of these two con-trasting effects in the diabetics is the increase inthe A/CP ratio, which may indicate autonomicnervous system impairment. The ratio also is in-creased in hypertensive patients after administra-tion of sympatholytic drugs (16). Although theA/CP ratio was usually high, i.e., > 2.0, in thosediabetics with postural hypotension or other obvi-ous evidence of peripheral neuropathy, it is ofconsiderable interest that it was elevated as wellin patients without clinical signs of neurologicalimpairment including some with recent or evenlatent glucose intolerance. \Vhether a change inthe regulation of blood pressure of this type mightoffer an additional guide to early diabetes detec-tion poses a question that merits additional epi-demiological study.
Brust and Ferris have discussed the evidencefor a dual system of blood pressure regulation,neurogenic and humoral, in the organism (23),and Page has suggested that the humoral pathwaysare the more primitive (24). Variability of path-ways of response to noxious stimuli of psychologi-cal origin also was proposed some years ago byFerris, Reiser, Stead, and Brust (25), but "neuro-genic" and "psychogenic" are still often consid-ered synonymous. Further evidence to support aconcept of flexibility of response is provided by
1896
PATTERNSOF PRESSORRESPONSETO NOXIOUS STIMULt
the present data, which indicate the persistance ofresponses to the saline test, a procedure that in-cludes both a venipuncture and mental arithmetic,and the color test in the diabetics, despite the de-creased activity of the cold pressor or autonomicpathway.
SUMMARY
The blood pressure responses to four differentnoxious stimuli were studied in 113 normotensiveand hypertensive patients. Subjects with andwithout diabetes were included in each category.Hypertensives were noted to be more reactive toangiotensin II as well as to the cold pressor testand to simple psychological stimuli. Diabetics dis-played decreased reactivity to the cold pressorstimulus, but enhanced responses to angiotensin,as compared with nondiabetics; their responses tothe psychological stimuli were not decreased sig-nificantly in spite of evidence of impairment ofthe cold pressor response. The results are dis-cussed in terms of the pertinence of intrinsic re-sponsiveness to pressor stimuli in evaluation of therenal pressor mechanism and the interrelationshipsbetween neurogenic and humoral pathways inblood pressure regulation.
ACKNOWLEDGMENTS
Mrs. Jean Small, Miss Jacqueline MeArdle, and MissEileen Tyrrell provided valued technical assistance. Thehelp of Dr. James Bonessi of the Diabetic Clinic of theFalk Outpatient Department in obtaining diabetic sub-jects for study is acknowledged. Support for hospitali-zation of several of the patients included in the studywas from Clinical Research Center grant FR-56 fromthe U. S. Public Health Service.
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13. Brod, J. Haemodynamic response to stress and itsbearing on the haemodynamic basis of essentialhypertension ill Symposium on the Pathogenesis ofEssential Hypertension. Prague, State MedicalPublishing House, 1962, p. 256.
14. Brust, A. A., M. F. Reiser, and E. B. Ferris, Jr.Evaluation of neurogenic control of blood pressurein hypertension 'with tetraethylammonium andspinal anesthesia. J. dlin. Invest. 1951, 30, 925.
15. Reiser, M. F., and E. B. Ferris, Jr. The nature ofthe cold pressor test and its significance in relationto neurogenic and humoral mechanisms in hyper-tension. J. dlin. Invest. 1948, 27, 156.
16. Shapiro, A. P., and E. Krifcher. Pressor responsesto noxious stimuli in hypertensive patients; effectof guanethidine sulfate and a-methyl DOPA. Tobe published.
17. Bickerson, R. K., and J. P. Buckley. Evidence for acentral mechanism in angiotensin induced hyper-tension. Proc. Soc. exp. Biol. (N. Y.) 1961, 106,834.
18. Zimmerman, B. G. Effect of acute sympathectomyon responses to angiotensin and norepinephrine.Circulat. Res. 1962, 11, 780.
19. Page, I. H., and F. M. Bumpus. Angiotensin.Physiol. Rev. 1961, 41, 331.
20. Sharpey-Schafer, E. P., and P. J. Taylor. Absentcirculatory reflexes in diabetic neuritis. Lancet1960, 1, 559.
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