Methylprednisolone-Induced Hypertension - Role for the Autonomic and Renin Angiotensin Systems
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Methylprednisolone-Induced Hypertension Role for the Autonomic and Renin Angiotensin Systems OSVALDO KOHLMANN JR., M.D., ARTUR B. RIBEIRO, M.D., ODAIR MARSON, M.D., MANOEL A. SARAGO£A, M.D., AND OSWALDO L. RAMOS, M.D. SUMMARY The role of the autonomic nervous system (ANS) in the pathogenesis of hypertension induced by methylprednisolone (20 mg/kg/week subcutaneously) was studied in rats before and during chronic renin angiotensin system (RAS) blockade with captopril (20 mg/kg/erery 8 hrs by mouth). Sympathetic nervous system (SNS) blockade was accomplished by the intravenous (i.v.) administration of propranolol (0.20 mg/lOOg) plus phentolamine (1.25 mg/lOOg/i.r.) and ganglionlc (G) blockade by the use of pentollnium tar- tarate (0.5 mg/100g/i.v.). After 4 weeks, methylprednlsolone-treated animals'showed significant decreases in mean arterial pressure (MAP) with both SNS (-34 ± 2 ram Hg) and G (-56 ± 3 mm Hg) blockades; during chronic RAS blockade, even greater falls in MAP were observed (SNS = -43 ± 2 mm Hg and G = -75 ± 3 mm Hg). Nevertheless, for both groups the levels of MAP obtained during SNS and G blockades were higher than those observed in their control groups. At the end of second week, however, in captopril-treated hyper- tensive rats the values of MAP obtained during ANS blockade were lower than those observed in the control group. An increased responsiveness to exogenous administration of norepinephrine (NE) was observed in animals receiving methylprednisolone and captopril. It is concluded that methylprendisolone hypertension in the rat may be initially explained by activation of RAS and ANS. At later phases, a third mechanism has to be postulated to explain the hypertensive state. (Hypertension 3 (suppl II): II-107—11-111, 1981) KEY WORDS * glucocorticoid-hypertension • autonomic nervous system • renin angiotensin system • norepinephrine responsiveness • captopril • saralasin S EVERAL mechanisms have been proposed to explain the pathogenesis of excess glucocorti- coid hypertension. They include: salt reten- tion,1 activation of the renin angiotensin system, 1 '' increased plasma and extracellular volumes,4 and al- Methods Induction of the Hypertensive State Male Wistar rats receiving regular rat chow and tap water were used. Four groups of rats were prepared: 1) terations in various components of the autonomic ner- Group M (n = 20), receiving a long-acting prepara- vous system (ANS).6"7 tion of soluble methylprednisolone (Depo-Medrol, We have recently confirmed that hypertension in- Upjohn) at a dose of 20 mg/kg/week subcutaneously; duced by methylprednisolone in the rat is accom- 2) Group M + C (n = 20), receiving methyl- panied by activation of the renin-angiotensin system.' prednisolone as in Group M plus concomitant cap- However, this hypertension may occur even during topril (Squibb and Sons') at a dose of 20 mg/kg/every chronic renin angiotensin system blockade with cap- 8 hours by gavage; 3) Group N (n = 20), receiving dis- topril," leading to the conclusion that other mech- tilled water by the same route and same frequency as anism^) may participate in the pathogenesis of this Group M; 4) Group N + C (n = 20), receiving dis- hypertension. In this study we tested the role of the tilled water as Group N plus concomitant daily cap- ANS in hypertension induced by methylprednisolone topril given as in Group M + C. All groups were in the rat. Special emphasis is placed upon the interac- followed for 4 weeks, and tail arterial pressure was tion of the autonomic and renin angiotensin systems in registered every week using a tail microphonic this type of experimental hypertension. method' in unanesthetized animals. From the Department of Medicine, Division of Nephrology, Pharmacological Blockade of the Sympathetic Nervous Escola Paulista de Mcdicina, SSo Paulo, Brazil Dr Ribeiro is an Established Investigator from the Brazilian System (SNS) Council for the Development of Science and Technology (CNPq) At the end of the fourth week, 10 animals of each Address for reprints Artur B. Ribeiro, M D, Associate Professor of Medicine, Division of Nephrology, Escola Paulista de experimental group (M; M + C; N, and N + C) had Medicina, Rua Botucatu, 720-04023 S3o Paulo, Brazil catheters placed into the carotid artery and jugular 11-107 Downloaded from http://hyper.ahajournals.org/ by guest on May 20, 2015
11-108 PROCEEDINGS/INTERAMERICAN SOCIETY S U P P II, HYPERTENSION, VOL 3, N o 6, N O V / D E C , 1981 vein under ether anesthesia. On awakening, the rats' TABLE 1. Tail Arterial Pressure (in mm Hg) in groups M, mean arterial pressure (MAP) was continuously M+C,NandN+C recorded with a Beckman physiograph, and the ani- Weeks mals were kept unrestrained with free access to water Groups Control 1 2 3 4 and food. After a 2-hour control period, blockade of M 114 ± 1 126 ±1* 138 ± 1 * 147 ± 1* 155 ± 1* sympathetic nervous system (SNS) was induced by in- M + C 116 ± 1 119 ± 1 122 ±1** 134 ± 1** 140 ±1** travenous administration of propranolol (Inderal, N 114 ± 1 116 ± 1 117 ± 1 117 ± 1 116 ± 1 Ayerst Laboratories) at a dose of 0.20 mg/100 g body weight, followed by phentolamine (Regitine, Ciba N + C 116± 1 114 ± 1 110 ± If 108 ± IT 107 ± IT Geigy Corporation) at a dose of 1.25 mg/100 g body •p < 0.01 compared to groups M + C, N and N + C. weight/i.v. The MAP was recorded for 60 minutes **p < 0.01 compared to group N and N + C. after the initial injection. Results are expressed by tp < 0.01 compared to group N. differences in MAP values before propranolol and 30 minutes after phentolamine administration. Identical procedures as described above were used in animals of Absolute values of direct MAP, as well as changes Groups M + C (n = 12) and N + C (n = 12) studied in MAP induced by SNS and ganglionic blockade, are at the second week. summarized in table 2 and figure 1 respectively. It is apparent that both SNS and ganglionic blockade Ganglionic Blockade and Vascular Responsiveness to evoked significant drops in MAP in all groups. During Norepinephrine (NE) SNS blockade, reductions in MAP of methyl- Four weeks after the initiation of methylpred- prednisolone-treated groups (M = — 34 ± 2 mm Hg nisolone administration, 10 animals of each group (M, and M + C = —43 ± 2 mm Hg) were significantly M + C, N, and N + C) were prepared, as described greater (p < 0.01) than those observed in the control above. After a 30-minute control period, norepineph- groups (N = - 1 5 ± 2 mm Hg and N + C = - 2 4 ± 1 rine (NE) (Noradrenaline, ByK Laboratories) was ad- mm Hg). Similar but greater decreases in MAP were ministered at increasing doses of 50, 100, and 200 observed during ganglionic blockade: M = —56 ± 3 ng/100 g body weight, i.v. Each injection was given mm Hg; M + C = - 7 5 ± 3 mm Hg; N = - 3 4 ± 2 after the MAP had stabilized following the previous mm Hg; and N + C = - 4 8 ± 2 mm Hg. It is also injection, and each dose was given twice. The effect of noteworthy that in the captopril-treated groups (M + NE upon MAP is represented by the mean of the two C and N + C) changes in MAP induced by both maximal elevations observed for each dose used. blockades were significantly greater than those ob- Following a recovery period from the last dose of NE, served in the groups that did not receive that drug (see all animals underwent ganglionic blockade by the ad- figure 1). Furthermore, during autonomic nervous ministration of pentolinium tartarate (Ansolysen, system blockade MAP values in the M + C group Wyeth Laboratories) given as a single intravenous dose of 0.5 mg/100 g body weight. The MAP was registered continuously, and after stabilization, TABLE 2. Mean Arterial Pressure (MAP) m mm Hg Before responses to NE were evaluated as before pento- and During Sympathetic Nervous System (SNS, Proprano- linium. Vascular responsiveness to NE was also tested lol + Phentolamine) and Ganglionic (Pentolinium Tartar- ate) Blockade m Groups M, M + C, N and N + C Studied at in eight animals of Group M + C and N + C studied the 4th week (X ± SEM) at the second week. Groups Before SNS Ganglionic Results are expressed as mean ± standard error of the mean. Statistical analysis were obtained by Stu- M 154 ±2* 118 ±2* 100 ±4* dent / test or analysis of variance when appropriate. M+C 136 ± IT 93±2t 60±3T N 115 ±3TT 100±3TT 81 ±2TT Results N+C 98 ± 1 73 ± 2 50±l Table 1 shows the values of tail arterial pressure *p < 0.01 — compared to groups M + C, N and N + C. (TAP) observed in the four groups studied. As can tp < 0.01 — compared to group N + C. be seen, in animals receiving only methylpredniso- ftp < 0.01 — compared to group N + C. lone TAP was significantly elevated by 1 week, and reached a maximal elevation of 41 ± 1 mm Hg at 4 weeks. In the group receiving captopril methyl- prednisolone (M + C), a progressive rise in TAP was TABLE 3. Mean Arterial Pressure (MAP) m mm Hg Before and During Sympathetic Nervous System (SNS, Proprano- observed only after the first week, and a maximal lol + Phentolamine) and Ganglionic (Pentolinium Tartar- change of 24 ± 1 mm Hg was observed at the fourth ate) Blockade in Groups M+C, and N+C Studied at the week. These values were significantly lower than those 2nd Week (X ± SEM) observed in Group M (p < 0.01). No significant Before SNS Ganglionic Groups changes in TAP were noted in Group N, whereas a small but statistically significant decrease (ATAP = M+C 112 ± 1 * 76 ±2* 50 ±3* - 9 ± 1 mm Hg, p < 0.01) was observed in Group N N+C 98 ± 2 85±3 61 ± 2 + C at the fourth week. *p < 0.01 compared to group N + C. Downloaded from http://hyper.ahajournals.org/ by guest on May 20, 2015
METHYLPREDNISOLONE-INDUCED HYPERTENSION/Kohlmann et al. 11-109 fiMAP 0 AMAP (mriHg} (mmHg) -10 - -10 - -20 - N+C N+C -20 - -30 - -40 - -30 - M+C -50 - M+C -40 - SNS -60 - D 0 GANGLIONIC -50 • -70 - Q SNS -80 - GANGLIONIC -60 - J FIGURE 1. Decreases in mean arterial pressure (AMAP), -70 in mm Hg, during sympathetic nervous system (propranolol FIGURE 2. Decreases in mean arterial pressure (AMAP), + phentolamine) and ganglionic (pentolinium tartarate) in mm Hg, during sympathetic nervous system (propranolol blockades in Groups M, M + C, N and N + C studied at + phentolamine) and ganglionic (pentolinium tartarate) fourth week. *p < 0.01 compared to Group M, **p < 0 01 blockades in Groups M + C and N+C studied at second compared to Group N week *p < 0 01 compared to Group N + C. reached levels that were significantly lower than those observed in the M group, and similar to those of the N group. However, MAP in the M + C group re- mained significantly higher than in the N + C group (see table 2). AMAP Values of MAP in the groups studied at the second (mmHg) week (M + C and N + C) before and during SNS and 120 - BEFORE ganglionic blockade are shown in table 3 and figure 2. DURING GANGLIONIC * • Basal MAP values in M + C group were significantly BLOCKADE higher than those of N + C. Also, both blockade 100 - procedures resulted in evident decreases in MAP *T* values for both groups. However, drops in MAP were of greater magnitude in M + C animals ( - 3 2 ± 2 and —59 ± 2 mm Hg, figure 2) as compared to those ob- 80 - ]lc tained in Group N + C ( - 1 3 ± 1 mm Hg and - 3 6 ± ** ...-'"' . ', • 2 mm Hg) {p < 0.01 for both procedures). Thus, dur- 60 - ing both blockades, MAP was lower in Group M + C I . - - ' ' . - - ' • ' ^ , - ' ' as compared to Group N + C. 1' ___J^ + C Figure 3 shows the increments in MAP obtained TM 40 • =S3 N with NE injections before and during ganglionic - ^ ^ N+C blockade. It is evident that the NE-induced incre- ments in MAP were greatly enhanced by ganglionic 20 • ? blockade. Both before and during ganglionic block- ade, elevations in MAP induced by NE were greater in Group M + C as compared to the other groups (p < 0.05, M + C vs M or N or N + C). 50 100 200 NE(ng/IOOg) Figure 4 shows elevations of MAP induced by NE before and during ganglionic blockade in Groups M + C and N + C studied at the end of second week. For FIGURE 3. Mean arterial pressure elevations (AMAP) all but the first NE dose tested, elevations in MAP for with increasing doses of norepinephrtne (NE) before and both groups were significantly greater during gan- during ganglionic blockade at the fourth week. *p < 0 05 glionic blockade. Again, greater elevations in Group compared to Groups M, N, and N+C before ganglionic M + C were observed before and during ganglionic blockade **p < 0 05 compared to Groups M, N, and N + blockade for all three NE doses tested. C during ganglionic blockade. Downloaded from http://hyper.ahajournals.org/ by guest on May 20, 2015
11-110 PROCEEDINGS/INTERAMERICAN SOCIETY SUPP II, HYPERTENSION, VOL 3, N o 6, N O V / D E C , 1981 A MAP Thus, methylprednisolone hypertension cannot be ex- mmHg) plained only by hyperactivity of the ANS. These eo - results agree with a previous report from our labora- tory which documented a role for the RAS in the BEFORE maintenance of this type of hypertension.' In the DURING GANGLIONIC group receiving captopril and methylprednisolone (M 100 - BLOCKADE + C), ANS blockade caused decreases in MAP that V M+C were greater than those of Group M. Also, the levels of M A P attained during ganglionic and SNS 60 - y blockades were lower in M + C as compared to M. This fact helps to corroborate the hypothesis of a N+C simultaneous activation of the RAS and SNS in the •• methylprednisolone-induced hypertension. However, 60 - the fact that, during ANS blockade, the blood pres- ^y M+C sure levels of the captopril-treated group (M + C) were still higher than those of its appropriate control (N + C) suggests that a third factor, in addition to 40 - N+C ANS and RAS, must be involved to explain the hy- •P pertension following methylprednisolone adminis- tration. 20 - r" ^-^^^ In contrast, at the second week of glucocorticoid administration, both SNS and ganglionic blockades completely reversed elevations of MAP observed in Group M + C. Actually, during these blockades, 50 100 200 NE MAP levels were even lower in Group M + C com- (ng/IOOg) pared to those of Group N + C. Thus, it is apparent that in the earlier phases of methylprednisolone ad- ministration the elevations in blood pressure may be FIGURE 4. Mean arterial pressure elevations (LMAP) explained by simultaneous activation of the RAS and with increasing doses of norepinephnne (NE) before and ANS only. during ganglionic blockade at the second week *p < 0 05 compared to Group N + C before ganglionic blockade. **p Whereas the role of the renin-angiotensin system in < 0 05 compared to Group N + C during ganglionic this type of hypertension is well established,2' ' • ' the blockade. effect of glucocorticoid administration on SNS func- tion remains controversial. 1 ' 6 ' '• '• 10 Some others have suggested alterations in tissue metabolism of cate- cholamines" and others, an increase in vascular sensi- tivity to exogenous NE.' 1 7 In our work we observed that methylprednisolone alone did not significantly alter vascular responsiveness to the three doses of ex- Discussion ogenous norepinephrine used, since MAP elevations A role for the renin angiotensin system (RAS) in were similar in Group M and N both before and dur- the pathogenesis of methylprednisolone hypertension ing ganglionic blockade. Comparable results were pre- in the rat has been previously demonstrated.*• *• * viously reported in the same species studied at 2 However, we have reported previously that RAS weeks.2 However, when methylprednisolone was asso- blockade with captopril does not prevent the develop- ciated with captopril (Group M + C), a significant in- ment of this type of hypertension." This observation is crease in responsiveness to these doses of NE was ob- confirmed in the present work, since elevations in arte- served before and particularly during ganglionic rial pressure were evident at the fourth week in the blockade. This was observed already at the second and group treated with methylprednisolone and captopril was still present at the fourth week. This increased (M + C). Thus, other mechanism(s) must have come responsiveness to NE cannot be attributed to captopril into play to explain the elevations of MAP during alone since the increments in blood pressure observed chronic RAS blockade. in Group N + C are not different from those of Group Our results clearly show that administration of N (fig. 3). Thus, we could observe an increased respon- methylprednisolone for 4 weeks causes hypertension siveness to three exogenously administered doses of accompanied by an increase in SNS activity. Accord- NE only with the association of methylprednisolone ingly with both pharmacological blockade procedures and captopril. Although interpretation of these results used, significantly greater drops were observed in is difficult, one might speculate that a diminished methylprednisolone-treated rats. In the group of endogenous liberation of catecholamines induced by animals receiving only methylprednisolone (M), both the diminution of angiotensin II caused by captopril11 blockades elicited significant drops in MAP; however, could unmask the reported hypersensitivity of the levels of MAP attained were still greater than adrenergic receptors caused by corticosteroid.7 The those observed in the appropriate control (Group N). enhanced responsiveness observed in the Group Downloaded from http://hyper.ahajournals.org/ by guest on May 20, 2015
METHYLPREDNISOLONE-INDUCED HYPERTENSION/Kohlmann el al. 11-11 M + C after ganglionic blockade could help to sup- 3 Elijovich F, Krakoff LR Effect of converting enzyme inhibition on glucocorticoid hypertension in the rat. Am J Physiol 238: port this hypothesis. H844, 1980 In conclusion, it is possible to detect the participa- 4 Haack D, MBhnng J, M5hnng B, Petnm M, Hackental E tion of both the renin-angiotensin system and the Comparative study on development of corticostcrone and autonomic nervous system in the pathogenesis of glu- DOCA hypertension in rats Am J Physiol 233: F403, 1977 5 Kalsner S Mechanism of hydrocortisone potentiation of re- cocorticoid hypertension. In the early stages (second sponse to cpinephnne and norepinephnne in rabbit aorta Circ week) of hypertension, these two factors seem to be Res 24: 383, 1969 responsible for the elevated blood pressure. Subse- 6 Mendlowitz M, Naftchi N, Weinreb HL, Gitlow SE' Effects of quently (fourth week) a third factor must be predmsolone on digital vascular reactivity in normotensive and postulated to explain the raised arterial pressure. The hypertensive subjects J Appl Physiol 16: 89, 1961 7 SchCmig A, Lflth B, Dietz R, Gross F Changes in vascular apparent role of the ANS hyperactivity in this type of smooth muscle sensitivity to vasoconstrictor agents, induced by hypertension may be, at least in part, explained by an corticosterone, adrenalectomy and differing salt intake in rats. increased responsiveness to catecholamines. Clin Sci Mol Med 51: 61s, 1976 8 Kohlmann O Jr, Marson O, Ramos OL, Ribeiro AB Effect of captopril on glucocorticoid excess hypertension. Clin Res 28: 333A, 1980 9 Friedman M, Freed C Microphone manometer for indirect determination of systolic blood pressure in the rat Proc Soc References Exp Biol Mcd 70: 670, 1949 10 Sambhi MP, Weill MH, Udhoji VN Pressor responses to 1. David SD, Gneco MH, Cushman P Adrenal glucocorticoids norepinephrine in humans before and after corticosteroid Am J after twenty years' a review of their clinically relevant conse- Physiol 203: 961, 1962 quences. J Chron Dis 22: 637, 1970 11 Antonaccio ML, Kerwin L' Pre and Post junctional inhibition 2 Krakoff LR, Selvadurai R, Sutter E Effect of methyl- of vascular sympathetic function by captopnl in SHR Implica- prednisolone upon arterial pressure and the renin angiotensin tion of vascular angiotensin II in hypertension and anti- system in the rat Am J Physiol 228: 613, 1975 hypertensive actions of captopnl Hypertension 3: 54, 1981 Downloaded from http://hyper.ahajournals.org/ by guest on May 20, 2015
Methylprednisolone-induced hypertension. Role for the autonomic and renin angiotensin systems. O Kohlmann, Jr, A B Ribeiro, O Marson, M A Saragoça and O L Ramos Hypertension. 1981;3:II-107 doi: 10.1161/01.HYP.3.6_Pt_2.II-107 Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 1981 American Heart Association, Inc. All rights reserved. Print ISSN: 0194-911X. Online ISSN: 1524-4563 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://hyper.ahajournals.org/content/3/6_Pt_2/II-107 Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: http://www.lww.com/reprints Subscriptions: Information about subscribing to Hypertension is online at: http://hyper.ahajournals.org//subscriptions/ Downloaded from http://hyper.ahajournals.org/ by guest on May 20, 2015
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