Pressor Responses to Noxious Stimuli in Hypertensive Patients

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1 Downloaded from htt://ahajournals.org by on October 2, 2018 Pressor Resonses to Noxious Stimuli in Hyertensive Patients Effects of Guanethidine Sulfate and Alha Methyldoa By ALVIN P. SHAPIRO, M.D., AND EMANUEL KRIFCHER, M.D. IN revious studies, ressor reactivity to several standardized noxious stimuli was evaluated quantitatively, and increased resonsiveness was demonstrated in hyertensive as comared with normotensive subjects." 2 The stimuli emloyed in these studies included simle sychologic rovocation as well as the cold ressor test and the intravenous injection of a small dose of angiotensin II. s in the hysiologic mechanisms of resonse were suggested from examination of the influence of diabetes mellitus on ressor reactivity to these stimuli.2 Since alteration by hyotensive drugs of the blood ressure resonse to noxious stimuli reresents a clinically imortant but usually undetermined harmacologic function, evaluation of the effect of several of these agents also was undertaken. In an earlier study it was reorted that chlorothiazide and reserine, in their usual theraeutic doses in hyertensive atients, failed to diminish the degree of ressor resonse to several of the aforementioned stimuli, desite lowering of the basal ressure.3 The resent study was designed to test the reactivity of hyertensive atients before and during theray with two more otent hyotensive agents, guanethidine sulfate and alha methyldoa. The data also were examined for information ertinent to the questions of the clinical harmacology and mechanism of action of these comounds. From the Deartment of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. Suorted by Training Grant HTS-5467 (Dr. Krifcher) and Research Grant HE from the U. S. Public Health Service and by a grant from the Health Research and Services Foundation of the United Fund of Allegheny County. Circulation, Volume XXX, November Methods and Materials Twenty-eight studies were done in subjects with moderate to severe hyertensive vascular disease, before and during theray. Thirteen were in atients receiving guanethidine sulfate and 15 in atients on alha methyldoa. The severity of the hyertensive disease and the average dose and duration of theray in each grou are indicated in table 1. Patients were either ambulatory and seen regularly in the Hyertension-Renal Clinic or were hositalized on the Clinical Research Unit of the Presbyterian-University Hosital. All were receiving the medications for theraeutic indications. Four noxious stimuli that have been described in detail reviously 1-3 were administered to study ressor resonses. They consisted of (1) the intravenous injection of 10 ml. of normal saline during which the atient is asked "to count backwards from 100 as raidly as ossible" (saline); (2) a standard cold ressor test; (3) the reading of a confusing color chart (color); (4) the intravenous injection of 0.03 jgg./kg. weight of angiotensin II over a eriod of 1 body minute. In the grou of 13 atients receiving guanethidine sulfate, only the last eight were tested with angiotensin. Of the 15 on alha methyldoa, one was not tested with angiotensin. The four tests were administered at 15-minute intervals after an initial rest eriod of 15 to 30 minutes. The order of administration of the stimuli was the same in all subjects, as follows: saline, cold ressor, angiotensin, color. In most subjects, the first testing was before theray. In a few, the first set of tests was erformed while subjects were receiving medication and, in these instances, a minimum of 2 weeks was allowed to elase before re-testing. Tests were done in the morning, usually with the atients in a fasting state, but at least 1 hour after the most recent dose of medication. All blood ressures were recorded with the atient suine during the rest eriods and the tests, but at the end of the study the Suorted by Clinical Research Center Grant FR-56.

2 672 SHAPIRO, KRIFCHER atients were tilted to the uright osition and an erect blood ressure was determined when it had stabilized (i.e., after 3 to 5 minutes in the erect osture). Blood ressures were determined on the Gilford automatic indirect recorder; ulse rates were registered simultaneously by means of a Gilford cardiotachometer oerating from a hotoelectric cell attached to the ear of the subject.' The retest baselines and the maximum resonses of blood ressure and ulse rate for each test were determined as described reviously.1 2 Systolic and diastolic values were converted to a calculated mean blood ressure (diastolic ±ulse ressure 3 to simlify subsequent ~statistical calculation. Clinical Data Theray Guanethidine sulfate Alha methyldoa Male Female II Table 1 Results The resting blood ressures and ulse rates (retest baselines) and the resonses to each test, before and during theray with either guanethidine sulfate or alha methyldoa, are resented in tables 2 and 3. Comarison of the resonses to each test are deicted in figure 1 (guanethidine sulfate grou) and figure 2 (alha methyldoa grou). The declines in retest baselines and erect blood ressures are also illustrated in these figures. The method of aired differences was used to test the significance of the changes in both retest levels and resonses. Number of atients Average 7 )' Grade of fundi Cardio- III IV megaly Age (years) Blood urea nitrogen (mg.%) Drug dose (mg. / day) Duration of theray (weeks) Downloaded from htt://ahajournals.org by on October 2, 2018 Baseline Test Saline Cold ressor Angiotensin t (0.03 jug./kg.) Color Erect blood ressure Blood Pressures and.p Table 2 Pressor Resonses Before and During Theray Guanethidine sulfate (n 13) Mean blood ressure (mm. Hg) Pre-test baseline Resonse > > 0.05 < < 0.01 > > < Alha methyldoa (n-- 15) Mean blood ressure (mm. Hg) Pre-test baseline Resonse < <0.01 < > < Significant difference. t With angiotensin test; n 8 for guanethidine sulfate, n 14 for alha methyldoa. Circulation, Volume XXX, November 1964

3 PRESSOR RESPONSES IN HYPERTENSION Table 3 Baseline Pulse Rates and Resonses Before and During Theray 'rest Saline Cold ressor Angiotensin t (0.03 gg./kg.) Color Diff-erence Guanethidine sulfate (n = 13) Pulse rate (beats / minute) Pre-test baselinie Resonse < < < > Alha methyldoa (n - 15) Pulse rate (beats/ mllinute) Pre-test baseline Resonse > > 0.05 > > >.05 Significant difference. t With angiotensin test; n = 7 for guanethidine sulfate, n = 10 for alha methyldoa. 673 Downloaded from htt://ahajournals.org by on October 2, , Q 10 Q - 20 E Mean BP Pulse Rate.50i 99~~~~~~~~~ Decline in resting (suine) level E Fc Decline in erect level c Rx a Resonse before Fc Resonse during FR <.01 MBP PR MBP PR MBP PR MBP Saline Cold Pressor Angiotensin Color Erect Figure 1 Effects of theray with guanethidine sulfate on the resting (re-test baseline) ressures and ulse rates, and the resonses to noxious stimuli before and during theray. The last column in the chart (MBP erect) indicates the fall in erect ressure roduced by theray. The vertical lines indicating ulse rates are all deicted in solid black, but refer to resonse before, decline in resting, and resonse during, resectively, in the same order from left to right as for the larger bars receding them which indicate mean blood ressures. Circulation, Volume XXX, November 1964

4 674 SHAPIRO, KRIFCHER Downloaded from htt://ahajournals.org by on October 2, 2018 It is aarent that both drugs caused only a modest decline in the suine retest baseline ressures. In fact, with guanethidine sulfate, the average fall was of questionable significance. The erect blood ressures, however, were lowered significantly with both comounds. The effect of theray on ressor resonsiveness essentially was similar with both drugs. The most striking feature was the contrast between the cold ressor resonse, which was decreased markedly with theray, and the angiotensin resonse, which was unaffected by guanethidine and indeed significantly increased, albeit a modest amount, in the subjects receiving alha methyldoa. The resonses to the veniuncture (saline test) and to the color test tended to follow the attern of the cold ressor resonse in this study, both showing a decline during theray with each comound. The contrast between the effects of theray on the resonses to angiotensin and to the cold ressor stimulus also can be shown by the device of comaring the ratio, angiotensin to cold ressor (A/CP), before and dur- 40 c E ing theray.2 The median A/CP ratios before theray were 1.31 for guanethidine sulfate and 1.57 for alha methyldoa; during theray, they rose to 2.41 and 3.18, resectively. With use of the Wilcoxon rank test,4 the increases in ratio were highly significant ( ). Similarly, the average differences between angiotensin and cold ressor resonses (A - CP) were 8.3 and 12.1 mm. Hg before theray for guanethidine sulfate and alha methyldoa, resectively, increaseing to 19.7 and 26.0 mm. Hg during theray; these differences also were highly significant (= 0.02). A dose-deendent relationshi of the fall in cold ressor resonse was noted with alha methyldoa; this was suggested by the data for guanethidine sulfate, but was not as clear-cut (fig. 3). The atterns of the changes in ulse rate were similar to those for blood ressure. Pretest baseline rates declined during theray The median was determined rather than the mean because these are ratios and accordingly do not follow a normal distribution. Resonse before Rc E Resonse during RA 2 Decline in resting (suine) level U F< R Decline in erect level U F, < Mean B P Pulse Rote MBP PR MBP PR MBP PR MNBP Saline Cold Pressor Angiotensin Color Erect Figure 2 Effects of theray with alha methyldoa. See figure 1 for exlanation. Circulation, Volune XXX, November 1964

5 PRESSOR RESPONSES IN HYPERTENSION C.S (i n=2 Q) n=5 n=3 ni8 Xff ]9 9 U Downloaded from htt://ahajournals.org by on October 2, I- <I.U <?.U <50 > 50, 100> >1.0 <100 gms. DOSE nng. Figure 3 Effect of treatment with alha methyldoa (left) and guanethidine (right) on mean blood ressure resonse to cold ressor test. The er cent decline is calculated from the ratio: Resonse before theray - Resonse during theray Resonse before theray1 with both comounds but this effect aeared greater with guanethidine sulfate than with alha methyldoa. With guanethidine, the ulse rate increments with the saline, cold ressor, and color tests were significantly less during theray. With alha methyldoa, the differences in ulse rate resonses to these three stimuli were small and significant statistically only for the saline test. Angiotensin roduced a slight fall in ulse rate, unaffected by theray with either comound. Discussion In contrast to the results achieved in our revious study with chlorothiazide and reserine in theraeutic doses,3 the two more otent agents, guanethidine sulfate and alha methyldoa, caused a decline in reactiv- Circulation, Volum.e XXX, November 1964 ity to the cold ressor test. The resonse to angiotensin, the result of a direct vasoconstricting effect on the eriheral vascular bed,5 was not reduced by treatment and indeed was increased in some subjects. Since the effector arc of the cold ressor resonse is robably the symathetic nervous system. these findings are in keeing with the concet of symatholysis by the drugs and hyersensitivity of the denervated arterioles to humoral vasoconstrictors. Preservation of angiotensin resonse after symatholysis also has been observed by Brown and Wood, who used a ganglion-blocking agent,7 and argues against any significant role of the autonomic nervous system in the ressor resonse to angiotensin. Likewise, Dollery, Harington, and Hodge recently have demonstrated an increased resonsiveness to noreinehrine in

6 Downloaded from htt://ahajournals.org by on October 2, atients receiving alha methyldoa.8 As suggested in our reort of angiotensin and cold ressor reactivity in normal and diabetic subjects,2 an elevation of the "A/CP ratio" above 2.0, although this is an emirically derived figure deendent on conducting both tests according to the described rotocol, may serve clinically to indicate imairment of symathetic innervation of eriheral vasculature. A significant decline was noted in both the saline and color resonses with guanethidine, and in the saline test only with alha methyldoa. In the revious study with chlorothiazide and reserine, these resonses, as well as the cold ressor resonse, did not decline.3 In diabetic subjects with symathetic imairment, however, in whom the cold ressor resonse was decreased, resonses to these sychological stimuli also were not diminished and it was roosed that they could oerate alternatively through humoral or "angiotensin-like" mechanisms.2 The data in the resent study, indicating that with the symatholysis induced by these otent comounds the sychohysiologic resonses were deressed, would suggest that our revious observation in diabetic subjects was dose deendent, i.e., a less comlete symathetic denervation was resent in the diabetic subjects than in the resent grou of atients on drugs. On the other hand, the difference between the two grous could be interreted as time deendent, i.e., alternative resonse athways may reresent a gradually develoing adative mechanism to sontaneous acquisition of symathetic imairment, and thus may be absent with the relatively acute symatholysis roduced by drugs. Such concets, however, are inferred from hemodynamic measurements that are influenced by a variety of factors and remain seculative. The hyothesis that eriheral mechanisms alternative to the autonomic nervous system, such as the elaboration of vasoactive olyetides, could mediate cardiovascular resonsiveness, is attractive, but its exloration requires the develoment of technics for measuring the humoral biochemical changes SHAPIRO, KRIFCHER acutely accomanying resonses to noxious stimuli. The study was not designed and the atients were not selected secifically to comare differences between the effects of guanethidine sulfate and alha methyldoa, but several observations can be noted. Pharmacologically the two comounds act differently on the autonomic nervous system. Guanethidine sulfate aears to delete noreinehrine stores or to interfere with noreinehrine release at eriheral sites, ossibly by blocking acetylcholine.9 Alha methyldoa theoretically could interfere with noreinehrine synthesis by cometitive inhibition at the decarboxylase ste. Some investigators have reorted a decrease in the excretion of the urinary metabolite vanilmandelic acid,10 but others have not Tissue deletion of noreinehrine occurs, but neither the ersistence of this deletion nor the hyotensive effects of the comound correlate with the duration of decarboxylase inhibition.12 It has been suggested, therefore, that the amine metabolites of alha methyldoa themselves are resonsible directly for noreinehrine deletion.12 Alternatively, Dacty and Rand have argued that alha methylnoreinehrine, itself a ressor material but less otent than noreinehrine, becomes a "false transmitter" after administration of alha methyldoa and hence resonses to symathetic stimulation are damened.13 The situation remains uncertain as is emhasized by a comrehensive recent study of the metabolism of alha methyldoa in man by Buhs and co-workers. The data of these investigators indicate no aarent correlation between the variations in the metabolic fate of the drug and its degree of hyotensive action.14 Clinically, however, the two drugs roduced qualitatively similar effects in the resent study, effects that demonstrate at least a functional symatholysis. The effect of guanethidine sulfate on the ulse rate seemed more ronounced, a finding which may indicate that although both drugs delete cardiac tissue of catecholamines,l. the clinical Circulation, Volume XXX, November 1964

7 Downloaded from htt://ahajournals.org by on October 2, 2018 PRESSOR RESPONSES IN HYPERTENSION effect on the heart is more ronounced with guanethidine than with alha methyldoa. Alha methyldoa lowered the suine ressure to a greater extent than did guanethidine sulfate, which is in keeing with the imression that this drug has a greater otential to lower blood ressure by actually decreasing eriheral resistance.8 Nevertheless, as these observers, and others,'16 17 ointed out, an additional and quite significant ostural hyotension is resent, as usually occurs with drugs that are oerationally symatholytic, and is the result of fall in cardiac outut in the erect osition. The dose-deendent relationshi of the deression of the cold ressor resonse with alha methyldoa was indicative of increasing symatholysis with increasing dosage. The results, as did those with chlorothiazide and reserine,3 hclve certain theraeutic imlications. Obviously, a decrease in the blood ressure "ceiling" in resonse to stimulation occurred; this may have theraeutic value, since hyertensive atients are rarely in a basal state but are exosed continually to noxious stimuli of various tyes. It is equally clear, however, that increments in blood ressure during any articular eriod of observation may occur desite effective theray with otent drugs, and in some instances reactivity may be enhanced. Elevations of blood ressure during drug theray thus can reresent reactive resonses rather than theraeutic failures. Accordingly, they should suggest search for sources of such stimulation, which are frequently sychohysiologic,18 rather than constitute immediate indications for changes in tye or dose of medication. Sumnmary The ressor and ulse rate resonses to several standardized stimuli were determined in hyertensive atients receiving guanethidine sulfate or alha methyldoa in theraeutic doses. Desite differences between the two comounds in their mode of action, both demonstrated functionally symatholytic effects. Both drugs roduced a greater blood ressure fall in the erect osture than in the Circulation, Volume XXX, November suine and imaired the ressor resonse to the cold ressor test. The ressor reactivity to intravenous angiotensin, however, ersisted. Resonses to sychohysiologic stimuli were decreased. The imlications of these findings for both theray and for understanding of hysiologic mechanisms of ressor reactivity are discussed. Acknowledgment Guanethidine sulfate and angiotensin II (as valyl- 5-angiotensin-II) were sulied by Ciba Pharmaceutical Comany; alha methyldoa was obtained from Merek, Shar and Dohme, Inc. The assistance of Miss Eileen Tyrrell in the statistical analyses of the data is gratefully acknowledged. References 1. SHAPIRO, A. P.: An exerimental study of comarative resonses of blood ressure to different noxious stimuli. J. Chron. Dis. 13: 293, SHAPIRO, A. P., MOUTSOS, S. E., AND KRIFCHER, E.: Patterns of ressor resonse to noxious stimuli in normal, hyertensive and diabetic subjects. J. Clin. Invest. 42: 1890, SHAPIRo, A. P.: Pressor resonses to noxious stimuli in hyertensive atients; effects of reserine and chlorothiazide. Circulation 26: 242, EDWARDS, A. L.: Statistical Methods for the Behavioral Sciences. New York, Rinehart & Co., 1960, PAGE, I. H., AND BUMPUS, F.: Angiotensin. Physiol. Rev. 41: 331, REISER, M. F., AND FERRIS, E. B., JR.: The nature of the cold ressor test and its significance in relation to neurogenic and humoral mechanisms in hyertension. J. Clin. Invest. 27: 156, BROWN, W. J., JR., AND WOOD, J. E.: The effect of acute autonomic blockade uon eriheral arteriolar and venous resonses to angiotensin in man. Clin. Res. 11: 163, DOLLERY, C. T., HARINGTON, M., AND HODGE, J. V.: Hemodynamic studies with methyldoa: Effect on cardiac outut and resonse to ressor amines. Brit. Heart J. 25: 670, SHORE, P. A.: Release of serotonin and catecholamines by drugs. Pharmacol. Rev. 14: 531, TYCE, G. M., SHEPS, S. G., AND FLOCK, E. V.: Determination of urinary metabolites of catecholamines after the administration of methyldoa. Proc. Staff Meet., Mayo Clin. 38: 571, CANNON, P. J., WHITLOCK, R. T., MoRRis, R. C.,

8 678 ANGER, M., AND LARAGH, J. H.: Effects of alha methyldoa in severe and malignant hyertension. J.A.M.A. 179: 673, SJOERDSMA, A., VENDSALU, A., AND ENGELMAN, K.: Studies on the metabolism and mechanism of action of methyldoa. Circulation 28: 492, DAY, M. D., AND RAND, M. J.: An hyothesis for the mode of action of alha methyldoa in relieving hyertension. J. Pharm. & Pharmacol. 15: 221, BuHs, R. P., BECK, J. L., SPETH, 0. C., SMITH, J. L., TRENNER, N. R., CANNON, P. J., AND LARAGH, J. H.: The metabolism of methyldoa in hyertensive human subjects. J. Pharmacol. & Exer. Thera. 143: 205, STONE, C. A., Ross, C. A., WENGER, H. C., LUDDEN, C. T., BLESSING, J. A., TOTARO, J. A., SHAPIRO, KRIFCHER AND PORTER, C. C.: Effect of a-methyl-3,4- dehydroxyhenylalanine (methyldoa), reserine and related agents on some vascular resonses in the dog. J. Pharmacol. & Exer. Thera. 136: 80, SANNERSTEDT, R., Bojs, G., VARAUSKAS, E., AND WERK6, L.: Alha methyldoa in arterial hyertension; clinical, renal, and hemodynamic studies. Acta med. Scandinav. 174: 54, VINCENT, W. A., KASHEMSANT, V., CUDDY, R. P., SMULYAN, H., AND EICH, R. H.: The acute hemodynamic effects of alha methyldoa. Am. J. M. Sc. 246: 558, SHAPIRO, A. P.: Psychohysiologic mechanisms in hyertensive vascular disease. Ann. Int. Med. 53: 715, Downloaded from htt://ahajournals.org by on October 2, 2018 Observations on Treatment By Richard Bright-1827 One of the most imortant questions in the treatment of this class of drosies, is the roriety of emloying Mercury. It is consistent with the most successful treatment of many forms of inflammatory disease, that we should have recourse to the valuable combination of Calomel with Oium; and iit is consistent with what is generally deemed good ractice, that by the cautious use of mercury we should endeavour to roduce more healthy action, and to iromote absortion when there is reason to believe that disease has left any chronic morbid action tending to roduce unhealthy deosit in glandular structures. Still however, the.cases which have roved most successful in my own ractice, have generally been those in which I have rigidly abstained from the use of mercury. In some cases I have seen the good effects of other remedies entirely interruted by the mercurial action; and I have likewise seen several instances in which the cure, when mercurials have formed art of the lan, has been rotracted to a great length; and a great many in which the full action of mercury has not revented the regular rogress of the disease, and its fatal termination.-original Paers of Richard Bright on Renal Disease. Edited by A. ARNOLD OSMAN. London, Oxford University Press, 1937, Circulation, Volumne XXX, November 1964