Effects of Centrally Acting Antihypertensive Drugs on the Microcirculation of Spontaneously Hypertensive Rats

Home , Rilmenidine

Brazilian Journal of Medical and Biological Research (2004) 37: 1541-1549 Effects of rilmenidine on microcirculation 1541 ISSN 0100-879X

Effects of centrally acting antihypertensive drugs on the microcirculation of spontaneously hypertensive rats

V. Estato1, 1Departamento de Fisiologia e Farmacodinâmica, Instituto Oswaldo Cruz, C.V. Araújo1, FIOCRUZ, Rio de Janeiro, RJ, Brasil P. Bousquet2 and 2Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire, E. Tibiriçá1 Faculté de Médecine, Université Louis Pasteur, Strasbourg, France

Abstract

Correspondence We investigated the acute effects of centrally acting antihypertensive Key words E. Tibiriçá drugs on the microcirculation of pentobarbital-anesthetized spontane- • Mesenteric microcirculation Departamento de Fisiologia e ously hypertensive rats (SHR). The effects of the sympatho-inhibitory • Arterial hypertension Farmacodinâmica • Clonidine agents clonidine and rilmenidine, known to activate both α2-adreno- Instituto Oswaldo Cruz, FIOCRUZ • Rilmenidine ceptors and nonadrenergic I1-imidazoline binding sites (I1BS) in the Av. Brasil, 4365 • central nervous system, were compared to those of dicyclopropyl- Baclofen 21045-900 Rio de Janeiro, RJ • LNP 509 Brasil methyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl)-amine hydrochlo- Fax: +55-21-2598-4451 ride (LNP 509), which selectively binds to the I1BS. Terminal mesen- E-mail: [email protected] teric arterioles were observed by intravital microscopy. Activation of the central sympathetic system with L-glutamate (125 µg, ic) induced Research supported by CNPq and marked vasoconstriction of the mesenteric microcirculation (27 ± 3%; FAPERJ, as well as FIOCRUZ N = 6, P < 0.05). In contrast, the marked hypotensive and bradycardic (Fundação Oswaldo Cruz). effects elicited by intracisternal injection of clonidine (1 µg), rilmenidine (7 µg) and LNP 509 (60 µg) were accompanied by significant increases in arteriolar diameter (12 ± 1, 25 ± 10 and 21 ± 4%, Received January 21, 2004 respectively; N = 6, P < 0.05). The vasodilating effects of rilmenidine Accepted June 24, 2004 and LNP 509 were two-fold higher than those of clonidine, although they induced an identical hypotensive effect. Central sympathetic

inhibition elicited by baclofen (1 µg, ic), a GABAB receptor agonist, also resulted in vasodilation of the SHR microvessels. The acute administration of clonidine, rilmenidine and LNP 509 also induced a significant decrease of cardiac output, whereas a decrease in systemic vascular resistance was observed only after rilmenidine and LNP 509. We conclude that the normalization of blood pressure in SHR induced by centrally acting antihypertensive agents is paralleled by important vasodilation of the mesenteric microcirculation. This effect is more pronounced with substances acting preferentially (rilmenidine) or

exclusively (LNP 509) upon I1BS than with those presenting important α2-adrenergic activity (clonidine).

Braz J Med Biol Res 37(10) 2004 1542 V. Estato et al.

Introduction quently accompanied by important central side effects such as sedation and dry mouth result- Chronic elevation of peripheral vascular ing in a loss of interest in its clinical use (11). resistance is considered to be the major he- Since then, the existence of specific bind- modynamic alteration in the established phase ing sites for these drugs characterized by their of human essential hypertension (1). It is lack of sensitivity to catecholamines has been also well known that most of this increased demonstrated in the CNS, i.e., the nonadrener-

vascular resistance is determined at the mi- gic I1-imidazoline binding sites (I1BS) (12,13). crovascular level, resulting mainly from func- The dissociation of the pharmacological tional (changes in vascular reactivity) and/or mechanisms involved in the hypotensive ef- structural (increased arteriolar wall-to-lumen fect of clonidine-like drugs (imidazoline bind- ratio) abnormalities (2,3). Moreover, several ing sites in the ventrolateral medulla) (14-16) lines of evidence suggest that a reduction in and the one responsible for their sedative ac-

the density per volume of tissue (rarefaction) tion (α2-adrenoceptors in the locus coeruleus) of small arterioles and capillaries contri- (14,17) was also established. As a result, a butes significantly to the elevation of resis- second generation of centrally acting antihy- tance and consequently of blood pressure in pertensive drugs has been developed. In fact, essential hypertension (4,5). new drugs such as rilmenidine and moxoni- Although the microcirculation plays a dine have proved to be effective in the treat- causative role in certain forms of hyperten- ment of mild to moderate arterial hypertension sion, it may also represent a preferential without significant sedative effects (18). In the target of this disease (6). Thus, in addition to present study we also used a new pharmacolo- the apparent blood pressure lowering ef- gical tool, dicyclopropylmethyl-(4,5-dimethyl- fects, which are similar between the differ- 4,5-dihydro-3H-pyrrol-2-yl)-amine hydrochlo- ent classes of drugs used in the treatment of ride (LNP 509), which has been shown to bind

high blood pressure, antihypertensive thera- selectively to the I1BS, having no affinity for py should also be able to prevent and/or α2- and α1-adrenoceptors or activity on α2- reverse functional and structural changes of adrenoceptors (19,20). the microcirculation (7,8). The present study was designed to inves- The central sympathetic nervous system tigate the in vivo microcirculatory modifica- plays a major role in the control of vascular tions induced by centrally acting antihyper- resistance (9). Moreover, several experimen- tensive agents in anesthetized spontaneously tal and clinical evidence support the hypo- hypertensive rats (SHR). We hypothesized thesis that an elevated sympathetic control of that the antihypertensive effects of these vascular tone is one of the major causal factors drugs could be associated to significant va- in the development of hypertension, as well as sodilation of the SHR microvessels, result- in the induction of trophic effects such as ing from the inhibition of sympatho-excita- cardiac and vascular hypertrophy/remodeling tory neurons in the brainstem. Intravital video (for a review, see Ref. 10). Sympathetic hyper- microscopy was used to assess the microcir- activity can be effectively modulated by drugs culatory parameters of the rat mesentery dur- acting directly on its site of origin, i.e., the ing central administration of drugs. central nervous system (CNS). In this context, first generation centrally acting antihyperten- Material and Methods sive drugs such as clonidine have long been used in the treatment of essential arterial hy- General procedures pertension (11). Nevertheless, the antihypertensive effect of this class of drugs was fre- All procedures were approved by the

Braz J Med Biol Res 37(10) 2004 Effects of rilmenidine on microcirculation 1543

Animal Welfare Committee of the Oswaldo that the mesentery came to lie over a trans- Cruz Foundation and were consistent with parent plate set, exactly above the window the USA National Institutes of Health Guide light source of the microscope. To prevent for the Care and Use of Laboratory Animals drying of the exposed mesentery, we used a (NIH Publication No. 85-23, revised 1996). plate support containing a continuous water Twelve- to 16-week-old male SHR derived circulating system inside at 37ºC and cov- from the Okamoto-Aoki strain (UNIFESP, ered it with plastic film. São Paulo, SP, Brazil) were housed 4 per cage with a 12-h light/dark cycle and had Cardiac output measurements free access to tap water and standard pellet food. Before the experiment, animals were In separate groups of animals a thora- fasted overnight but given water ad libitum cotomy was performed via a left intercostal in order to minimize peristaltic movements incision between the second and third ribs. of the intestine. The animals were anesthe- The heart was exposed by incising the peri- tized with sodium pentobarbital (50 mg/kg, cardium and the aorta was isolated from ip), tracheostomized, immobilized with pan- contiguous structures and freed from adven- curonium bromide (1 mg/kg, iv), and artifi- titia and adipose tissue at the site of the flow cially ventilated with room air (tidal volume, measurements. An electromagnetic flow 10 ml/kg, stroke rate 45/min); anesthesia probe was then placed around the ascending was complemented hourly with ip injections aorta and connected to a blood flowmeter of 5 mg/kg pentobarbital. The rats were then (Skalar model MDL 1401, Litchfield, Ca- placed on a surgical table and a rectal ther- nada) and cardiac output (CO, ml/min) was mometer was inserted. The thermometer recorded continuously with the above-men- was connected to a temperature monitor tioned recorder. Systemic vascular resistance (Effenberger, Kirchheim, Germany), which (SVR) was calculated as the quotient of the maintained temperature constant at 37ºC with MAP and the CO multiplied by a conversion a thermal pad during all procedures. The factor (80) and reported as dyn s-1 (cm5)-1. right femoral vein was catheterized to permit ip injections. Arterial pressure was continu- Intravital microscopy ously monitored with a catheter placed in the right carotid artery connected to a Hewlett After surgery, the animal was transferred Packard (Palo Alto, CA, USA) quartz trans- to a fixed-stage upright intravital videomi- ducer (1290 A), which in turn was connected croscopy (Olympus BX5-1WL, Melville, to a pressure processor and recorder (Hewlett NY, USA) coupled to a CCD video camera Packard 7754 system with 8805B amplifier). (Samsung BW 273A, Seoul, Korea). Obser- Systolic (SAP) and diastolic (DAP) arterial vations were made using conventional trans- pressures were obtained directly from the illumination with a 10X eyepiece and 10X recordings. The mean arterial pressure (MAP) objectives (Olympus) with final magnifica- was calculated as diastolic pressure plus one tion of 100X. Video images were displayed third of the differential pressure; heart rate on a video monitor (National, Tokyo, Japan) (HR) was counted from the blood pressure coupled to a time-date generator and stored waves by rapid running of the pressure re- in a videocassette recorder (VHS VC 1694- cording. The abdomen was carefully opened B; Sharp, Manaus, AM, Brazil) for off-line by a small midline incision, the rat was then analyses. The selected pictures (six images placed on its side on a plate support and the for each time point) were captured and pro- ileojejunal part of the mesentery was exteri- cessed for static display with a specialized orized carefully and arranged in such a way software (Ecoview ImagePro, Media Cyber-

Braz J Med Biol Res 37(10) 2004 1544 V. Estato et al.

netics Inc., Silver Springs, MD, USA), and USA). Rilmenidine (2-[N-(dicyclopropyl- suitable unbranched arterioles with diam- methyl)amino]oxazoline) was kindly provid- eters between 15 and 30 µm were selected. ed by Institut de Recherches Internationales Arteriolar diameters were measured as the Servier (Courbevoie, France). LNP 509 (dicy- distance between the two clearly defined clopropylmethyl-(4,5-dimethyl-4,5-dihydro- muscular walls and expressed in µm. The 3H-pyrrol-2-yl)-amine hydrochloride was data were automatically transferred to the from the Laboratoire de Neurobiologie et Microsoft® Excel for calculations. Pharmacologie Cardiovasculaire (LNPCV), Université Louis Pasteur (Strasbourg, Intracisternal injections France). Drugs were dissolved in saline (0.9% (w/v) NaCl). The head of the animal was fixed in a stereotaxic apparatus (Stoelting, Wood Dale, Statistical analysis IL, USA). A craniotomy was performed, the cisterna magna was localized with stereo- All data are reported as mean ± SEM for taxic coordinates and the needle was fixed each group of 6 rats. Comparisons between on the skull with dental cement for drug the groups were made with one-way ANOVA administration (10 µl). At the end of the and within-group variations with time were experiment, the same volume of Evans blue analyzed by repeated measures ANOVA. dye was injected under the same conditions. When an overall difference was detected by The brain was removed post mortem and ANOVA, the Student-Newman-Keuls test dissected to determine if the drugs had dif- was used to localize the statistically signifi- fused properly and which structures were cant differences. P values of less than 0.05 reached. were considered to be significant. All calculations were made by computer-assisted Experimental protocol analyses using a commercially available statistical package (Graphpad Instat, Graphpad After completion of the surgical proce- Software, University of London, UK). dures, the animals were allowed to equili- brate for 30 min or until a stable tracing had Results been obtained (control period). Before drug injection, the means of three arterial pres- Central cardiovascular effects of clonidine, sure measurements (SAP, DAP and MAP), rilmenidine and LNP 509 HR and CO, recorded at 5-min intervals, were calculated and considered as the basal There were no significant differences in hemodynamic values. The microvascular baseline blood pressure, HR or CO between parameters of the arterioles and venules were experimental groups, as shown by ANOVA recorded for 2 min at 10-min intervals (P > 0.05). The intracisternal (ic) injection of throughout the experimental period (≈120 1 µg clonidine and 7 µg rilmenidine elicited min). marked and long-lasting antihypertensive effects characterized by a maximum decrease Drugs on MAP of 53 ± 3 and 50 ± 8%, respectively (N = 6, P < 0.05; Figure 1 and Table 1). HR The following drugs were used: sodium was significantly reduced by both drugs, pentobarbital, pancuronium bromide, L-glu- reaching a maximum of 30 ± 2 and 19 ± 5%, tamate, baclofen, and clonidine hydrochlo- respectively (N = 6, P < 0.05). The central ride, purchased from Sigma (St. Louis, MO, administration of clonidine and rilmenidine

Braz J Med Biol Res 37(10) 2004 Effects of rilmenidine on microcirculation 1545 also induced a significant decrease of CO reduction being of 56 ± 4% (N = 6, P < 0.05). (50 ± 10 and 39 ± 2%, respectively; N = 6, P The effects of LNP 509 on CO (-22 ± 3%, N < 0.05) whereas there was a significant de- = 6, P < 0.05) and on SVR (-28 ± 6%; N = 6, crease in SVR of 24 ± 7% (N = 6, P < 0.05) P < 0.05) were significantly different from only after rilmenidine (Figure 1 and Table those observed after clonidine treatment (Fig- 1). The central administration of 60 µg LNP ure 1 and Table 1). On the other hand, 60 µg 509 evoked effects similar to those of cloni- ic LNP 509 had no significant effect on HR dine and rilmenidine on MAP, the maximum (Figure 1 and Table 1).

Figure 1. Time course of the hemodynamic changes in re- 125 125 sponse to intracisternal injection of saline (SAL, control group), 100 100 clonidine (CLO, 1 µg), rilmenidine (RIL, 7 µg), or LNP 509 * * * ** (LNP, 60 µg) in anesthetized 75 * 75 * * spontaneously hypertensive rats. * * * * * * * * * Each set of points represents (% variation) * * 50 + the mean ± SEM for 6 experi- 50 * + * * ments. *P < 0.05 compared to Mean arterial pressure * * * * * +

Cardiac output (% variation) + the control group. P < 0.05 25 25 *+ * compared to the clonidine- treated group (ANOVA).

125 125

100 100 * * *+ + 75 * * * * 75 * *+ * * * * *+ + * * *+ *+ (% variation) 50 50 Heart rate (% variation)

25 Systemic vascular resistance 25 -20 -10 0 10 20 30 40 50 60 70 -20 -100 10203040506070 Time (min) Time (min)

SAL CLO RIL LNP

Table 1. Maximum effects of the intracisternal injection of clonidine (1 µg), or LNP 509 (60 µg) on the macrohemodynamic parameters of pentobarbital-anesthetized spontaneously hypertensive rats.

Saline Clonidine Rilmenidine LNP 509

Before After Before After Before After Before After

MAP (mmHg) 150 ± 6 147 ± 7 157 ± 10 74 ± 7* 146 ± 7 74 ± 16* 153 ± 8 68 ± 8* HR (bpm) 424 ± 11 405 ± 9 405 ± 9 281 ± 7* 451 ± 19 365 ± 15* 417 ± 33 380 ± 29* CO (ml/min) 191 ± 20 191 ± 19 229 ± 11 129 ± 11* 222 ± 30 137 ± 16* 156 ± 22 122 ± 16* SVR (dyn s-1 (cm5)-1 52 ± 2 55 ± 4 46 ± 3 45 ± 2 52 ± 7 40 ± 6* 69 ± 6 49 ± 4*

CO = cardiac output; HR = heart rate; MAP = mean arterial pressure; SVR = systemic vascular resistance. Each value represents the mean ± SEM for 6 experiments. *P < 0.05 compared to basal values (ANOVA).

Braz J Med Biol Res 37(10) 2004 1546 V. Estato et al.

Microcirculatory effects induced by ic µg L-glutamate was accompanied by mesen- injection of clonidine, rilmenidine and LNP teric arteriolar vasoconstriction, reaching the 509 maximum of 27 ± 3% (N = 6, P < 0.05) from the basal value of 19.6 ± 1.4 µm (Figure 2). The hypotensive effect induced by ic injection of 1 µg clonidine, 7 µg rilmenidine Discussion and 60 µg LNP 509 was accompanied by mesenteric arteriolar vasodilation, charac- The present study is the first to demon- terized by a maximum increase in arteriolar strate that acute administration of centrally diameter of 12 ± 1% (N = 6, P < 0.05), 25 ± acting antihypertensive drugs such as cloni- 10% (N = 6, P < 0.05) and 21 ± 4% (N = 6, P dine and rilmenidine significantly dilates the < 0.05; Figure 2) from the basal values of 19 microcirculation of SHR. It is noteworthy ± 1.9, 18.8 ± 1.8 and 22 ± 1 µm, respectively. that both drugs were injected directly into the CNS (intracisternally) in doses that do Cardiovascular and microcirculatory effects not present significant cardiovascular effects of ic injection of baclofen and L-glutamate when administered systemically (21,22). Thus, although the activation of peripheral

The central ic injection of 1 µg baclofen α2-adrenoceptors in SHR also induces dila- elicited marked and long-lasting decreases tion of terminal arterioles (23), the arteriolar in MAP, with a maximum of 63 ± 8% (from vasodilation observed in the present study 155 ± 7 to 62 ± 8 mmHg; N = 6, P < 0.05; data cannot be due to the peripheral effects of not shown). HR decreased by 18 ± 5% (from clonidine. 390 ± 11 to 316 ± 27 bpm; N = 6, P > 0.05; The small arteries and arterioles of the data not shown). The hypotensive effect of microcirculation are well known to be the baclofen was accompanied by significant most important site of the increased vascular vasodilation of the mesenteric microcircula- resistance in hypertensive patients (7). In tion (Figure 2). The maximum increase of SHR, the progressive development of hyper- arteriolar diameter after baclofen was 11 ± tension is associated with an increase in 4% (from 30 ± 5 to 33.5 ± 5 µm; N = 6, P > arteriolar tone in different vascular beds (24) 0.05). On the other hand, the central ic ad- that reaches even the terminal arterioles (lu- ministration of 125 µg L-glutamate evoked a men diameter of about 20 µm) (25,26). More- marked but short-lasting increase in MAP, over, compared to normotensive control rats reaching a maximum of 24 ± 5% (from 161 ± (Wistar-Kyoto), the vascular tone of SHR is 9 to 198 ± 9 mmHg; N = 6, P < 0.05; data not set at a higher steady-state level (27). In this Figure 2. Maximum changes shown). HR increased only by 6 ± 2% (from context, it has already been shown that a (percent of baseline) of mesenteric arteriolar diameter. Varia- 432 ± 9 to 458 ± 5 bpm; N = 6, P > 0.05; data decrease of only 13% in arteriolar diameter tions observed after intracister- not shown). The hypertensive effect of 125 is sufficient to produce an increase in sys- nal injection of saline (SAL, con- temic blood pressure of about 50 mmHg trol group), clonidine (CLO, 1 µg), (26). Moreover, since sympathetic hyperac- rilmenidine (RIL, 7 µg), LNP 509 140 * (LNP, 60 µg), baclofen (BAC, 1 130 + tivity is implicated in the development of 12345 * µg), or L-glutamate (GLU, 125 1234512345 arterial hypertension (28), modulation of the 120 1234152345

µg) in anesthetized spontane- 12345* 12341523451234*

110 1234152341523415234 central sympathetic activity with centrally ously hypertensive rats. Each 12345123451234512345123412345GLU set of points represents the 100 12345 acting antihypertensive agents turns out to SAL CLO RIL LNP BAC12345 mean ± SEM for 6 experiments. 90 12345 12345 be a reasonable therapeutic target in the *P < 0.05 compared to the con- 80 12345 12345 + treatment of this disease. trol group. P < 0.05 compared 70 to the clonidine-treated group We evaluated the microcirculatory be- 60 * (ANOVA). Arteriolar diameter (% variation) havior of SHR using the microcirculation of

Braz J Med Biol Res 37(10) 2004 Effects of rilmenidine on microcirculation 1547 the mesentery, which is known to respond to The central acute administration of anti- peripheral or central sympathetic stimula- hypertensive drugs also induced significant tion (29,30). In fact, the mesenteric micro- decreases in CO, which were of greater mag- vascular network appears to have a dense nitude in response to clonidine than rilmeni- sympathetic innervation (31), which is in- dine or LNP 509. As a result, only rilmeni- creased in arterioles of SHR (32). Functional dine and LNP 509 produced a significant fall studies in the rat demonstrated that the elec- in systemic vascular resistance. These re- trical stimulation of the posterior hypothala- sults are consistent with those reported by mus induces an increase in MAP accompa- Azevedo et al. (34), who showed that acute nied by a significant vasoconstrictor response intravenous administration of clonidine elic- of mesenteric arterioles (31), thus demon- its negative inotropic effects associated with strating that this particular vascular bed is the inhibition of cardiac-specific sympathetic under sympathetic control. Moreover, Le outflow, evaluated by cardiac norepineph- Noble et al. (33) showed that pentobarbital is rine spillover in patients with congestive the anesthetic of choice to be used in exper- heart failure. The acute hypotensive effect of imental studies assessing the mesenteric mi- clonidine in anesthetized rats had been at- crocirculation of the rat, since it does not tributed mainly to a reduction in CO rather interfere with microvascular reactivity to than in total peripheral resistance (35). On adrenergic stimulation. Our results are con- the other hand, in conscious and freely mov- sistent with these observations, since the ing SHR, clonidine-induced hypotension pharmacological activation of the central seems to depend mainly on reduction of sympathetic nervous system with intracis- vascular resistance (36). The greater selec- ternal glutamate, the main excitatory neuro- tivity of rilmenidine for the I1BS, when com- transmitter in the mammalian CNS, elicited pared to the α2-adrenergic receptors (11,15), marked arteriolar constriction in the mesen- could explain this preferential action on vas- tery. cular resistance since LNP 509, which is

Our results also demonstrate that the clas- devoid of α2-adrenergic-mediated cardiovas- sical acute hemodynamic effects of centrally cular activity (19,20), elicited a hemody- acting antihypertensive drugs (i.e., hypoten- namic profile similar to that of rilmenidine sion and bradycardia) are accompanied by after intracisternal administration. significant dilatation of terminal arterioles in Our results also showed that the central

SHR. It is noteworthy that the vasodilating administration of baclofen, a GABAB recep- effects of rilmenidine and LNP 509 were tor agonist which inhibits the neuronal re- much more pronounced than that of cloni- lease of excitatory neurotransmitters such as dine, thus supporting the view that different glutamate (37), also induced significant di- mechanisms might be involved in the antihy- lation of the SHR microvessels. Moreover, it pertensive effects of first- and second-gen- has already been demonstrated that the cen- eration drugs (11). Nevertheless, we did not tral GABA-ergic system exerts a tonic inhib- investigate the pharmacological mechanisms itory effect on the central sympathetic sys- involved in the microcirculatory effects of tem, and consequently on cardiovascular these drugs, which could be clarified by the function (38). These findings confirm the use of selective antagonists. In fact, the pres- hypothesis that the inhibition of the central ent study was designed to test our hypothesis sympathetic drive results in vasodilation of that the inhibition of the central sympathetic the microcirculation of hypertensive animals. system could be accompanied by a signifi- Finally, previous studies using the mes- cant dilation of the microcirculation in hy- enteric vascular bed have shown that hemor- pertensive animals. rhagic hypotension in rats induces signifi-

Braz J Med Biol Res 37(10) 2004 1548 V. Estato et al.

cant vasoconstriction of the microcircula- preferentially (rilmenidine) or exclusively tion (39,40), thus suggesting that the arteri- (LNP 509) upon nonadrenergic imidazoline olar vasodilation in the mesentery observed binding sites than with those presenting im-

in the present study did not result from the portant α2-adrenergic selectivity (clonidine). large drop in arterial pressure induced by the Since important functional and structural antihypertensive drugs. alterations of the microcirculation are involved in the pathophysiology of primary Perspectives arterial hypertension, new therapeutic ap- proaches should be able to prevent or even The results of the present study show that reverse these major features of the disease. the reduction of blood pressure in the ge- netic model of arterial hypertension induced Acknowledgments by centrally acting antihypertensive agents is paralleled by important vasodilation of the The authors gratefully acknowledge Mr. mesenteric microcirculation. This effect is R. Cavalheiro-Silva for skillful technical as- more pronounced with substances acting sistance.

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