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

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Effects of Centrally Acting Antihypertensive Drugs on the Microcirculation of Spontaneously Hypertensive Rats 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), rilmeni- dine (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 impor- tant 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 antihyper- tensive 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
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