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Université De Montréal Contribution of Tachykinin and Kinin Receptors In Université de Montréal Contribution of tachykinin and kinin receptors in central autonomic control of blood pressure and behavioural activity in hypertensive rats par Helaine De Brito Pereira Département de physiologie Faculté de Médecine Thèse présentée à la Faculté des études supérieures et postdoctorales en vue de l’obtention du grade de Philosophia Doctor (Ph.D.) en Physiologie Mai, 2010 © Helaine De Brito Pereira, 2010 ii Université de Montréal Faculté des études supérieures et postdoctorales Cette thèse intitulée: Contribution of tachykinin and kinin receptors in central autonomic control of blood pressure and behavioural activity in hypertensive rats Présentée par : Helaine De Brito Pereira a été évaluée par un jury composé des personnes suivantes : Dr. Jean-Louis Schwartz, président-rapporteur Dr. Réjean Couture, directeur de recherche Dr. Madhu B. Anand-Srivastava, membre du jury Dr. Pedro D'Orléans-Juste, examinateur externe Dr. Hélène Girouard, représentant de la FESP iii I want officially thank God, for giving me the patience, health, strength, and intelligence to do my doctoral studies. I am thankful for the kindest, most understanding and loving husband in the world. I cannot even put into words the kind of man he is. I am blessed that God brought him into my life and thankful for the almost six years that we have shared so far. I would like to thank my siblings Renato and Karina, and my brother-in-law Fabio for treasured memories and loving support throughout my education and graduation. iv Aos meus pais, Que me deram a vida e me ensinaram a vivê-la com dignidade, não bastaria um obrigado. Que iluminaram os caminhos obscuros com afeto e dedicação para que os trilhássemos sem medo e cheios de esperanças, não bastaria um muito obrigado. Que se doaram inteiros e renunciaram aos seus sonhos, para que, muitas vezes, pudésse realizar os meus. Pela longa espera e compreensão durante minha longa ausência, não bastaria um muitíssimo obrigado. A vocês, pai e mãe por natureza, por opção e amor, não bastaria dizer, que não tenho palavras para agradecer tudo isso. Mas é o que me acontece agora, quando procuro arduamente uma forma verbal de exprimir uma emoção incomparavel. Uma emoção que jamais seria traduzida por palavras. Amo vocês v Acknowledgements I want first to thank my reseach director, Dr. Rejean Couture, for welcoming me in Canada and in his laboratory. During more than a decade of knowing him, he has helped me to see life and science in their full depth, and taught me how to appreciate the good scientific work that helps other researchers to build on it. I warmly thank my laboratory friends and colleagues, Sébastien Talbot, Dr. Brice Ongali, Dr. Frank Cloutier, Jenny Pena-Dias, Mahmud Ismael, Emna Chahmi, Nejla Tidjane, Dr. Karim Lahjouji, and Jacques Sénécal. Thank you to all members of the Physiology department, and especially to Johanne Payette and Marjolaine Homier, for their help and support. I would like to say thank you to Paula Jansen Santana and Claude Gauthier for the graphic and artistic work on the figures. In addition, I thank my Brazilian friends who encouraged, supported me and have always been present in hard times, Janaina Suckow, Simone Carrer, Angela Piovesan, Billa Furlanetto, THANK YOU and I love you girls! Finally, I thank the Quebec Society of Hypertension (SQHA) and the Faculty of Graduate Studies (FESP), which have offered me travel grants and awards of excellence, respectively. The financial support of this work was provided by research grants from the Canadian Institutes of Health Research (CIHR) to Dr. Réjean Couture and National Council of Technological and Scientific Development (CNPq) (proc. 201428/2003-2) Brazil to H. De Brito Pereira. vi Abstract This work aims at studing the role of tachykinin NK-3 receptor (R) and kinin B1R in central autonomic regulation of blood pressure (BP) and to determine whether the B1R is overexpressed and functional in rat models of hypertension by measuring the effect of a B1R agonist on behavioural activity. Assumptions: (1) NK-3R located in the ventral tegmental area (VTA) modulates the mesolimbic dopaminergic system and has a tonic activity in hypertension; (2) B1R is overexpressed in the brain of hypertensive rats and has a tonic activity, which contributes to hypertension via a dopamine mechanism; (3) the inhibition of NK-3R and B1R with selective antagonists, reduces central dopaminergic hyperactivity and reverses hypertension. A model of genetic hypertension and a model of experimental hypertension were used: spontaneously hypertensive rats (SHR, 16 weeks) and Wistar-Kyoto (WKY) rats infused for 14 days with angiotensin II (Ang II) (200 ng / kg / min, subcutaneous (s.c.) with Alzet mini pump). The age-matched untreated WKY rats served as common controls. In the first study (article # 1), the cardiovascular response in SHR was evaluated following intracebroventricular (i.c.v.) and/or intra-VTA injection of an agonist (senktide) and antagonists (SB222200 and R-820) of NK-3R. These responses have also been characterized using selective dopamine antagonists DA-D1R (SCH23390), DA-D2R (raclopride) or non- selective dopamine DA-D2R (haloperidol). Also the VTA has been destroyed by ibotenic acid. The pressor response induced by senktide and the anti-hypertensive response induced by SB222200 or R-820 were more pronounced by intra-VTA. These responses were prevented by pre- treatment with raclopride and haloperidol. The lesion of the VTA has prevented the pressor response relayed by senktide (i.c.v.) and the anti- hypertensive effect of R-820 (i.c.v.). In addition, SB222200 (intra-VTA) prevented the pressor response of senktide (i.c.v.) and conversely, senktide (i.c.v.) prevented the antihypertensive effect of SB222200 (intra-VTA). The second study (article # 2) showed that the B1R antagonist (SSR240612) vii administered by gavage or i.c.v. reverses hypertension in both models. This anti-hypertensive effect was prevented by raclopride and haloperidol. In contrast, the two B1R antagonists (R-715 and R-954) injected s.c., which do not cross the blood-brain barrier reduced weakly blood pressure in hypertensive rats. In the third study (article # 3), the i.c.v. injection of a selective kinin B1R agonist Sar[DPhe8][des-Arg9]BK caused behavioural responses in SHR and Ang II-treated rats and had no effect in control WKY rats . The responses elicited by B1R agonist were blocked by an antagonist of NK-1 (RP67580), an antagonist of NMDA glutamate receptor (DL-AP5), an inhibitor of nitric oxide synthase (NOS) (L -NNA) as well as raclopride and SCH23390.The responses were modestly affected by the inhibitor of inducible NOS (iNOS). The B1R mRNA (measured by RT-PCR) was significantly increased in the hypothalamus, the VTA and the nucleus accumbens of hypertensive animals (SHR and treated with Ang II) compared with control rats. These neuropharmacological studies suggest that: (1) the NK-3R from the VTA is involved in the maintenance of hypertension in SHR by increasing DA transmission in the midbrain; (2) the B1R in SHR and Ang II-treated rats contributes to hypertension via a central mechanism involving DA- D2R; (3) the central B1R increases locomotor activity and nocifensive behaviours via the release of substance P (NK-1), DA and nitric oxide in both rat models of hypertension. Thus, the brain tachykinin NK-3R and kinin B1R represent potential therapeutic targets for the treatment of hypertension. The modulation of the mesolimbic/mesocortical dopaminergic pathway by these receptors suggests their involvement in other physiological functions (pleasure, motor activity, coordination of the response to stress) and pathophysiology (anxiety, depression). Keywords: Tachykinin NK-3R, kinin B1R, dopamine, ventral tegmental area, hypertension, behavior. viii Résumé Ce travail vise à étudier le rôle du récepteur NK-3 des tachykinines (NK- 3R) et du récepteur B1 des kinines (B1R) dans la régulation autonomique centrale de la pression artérielle et de déterminer si le B1R est surexprimé et fonctionnel chez le rat hypertendu en mesurant l’effet d’antagoniste B1R sur l’activité comportementale. Hypothèses: (1) le NK-3R localisé dans l’aire tegmentale ventrale (VTA) module l’activité dopaminergique du système mésolimbique et possède une activité tonique dans l’hypertension; (2) le B1R est surexprimé dans le cerveau du rat hypertendu et possède une activité tonique qui contribue à l’hypertension via un mécanisme dopaminergique; (3) l’inhibition des NK-3R et B1R avec des antagonistes sélectifs réduit l’hyperactivité dopaminergique centrale et renverse l’hypertension. Un modèle d’hypertension génétique et un modèle d’hypertension expérimentale ont été utilisés: le rat spontanément hypertendu (SHR, 16 sem) et le rat Wistar Kyoto (WKY) infusé pendant 14 jours avec l’angiotensine II (Ang II) (200 ng/kg/min, s.c. avec mini pompe Alzet). Le rat WKY non traité du même âge a servi de témoin commun. Dans la première étude (article # 1), la réponse cardiovasculaire des SHR a été évaluée à la suite de l’injection i.c.v. et/ou intra-VTA d’un agoniste (senktide) et d’antagonistes (SB222200 et R-820) du NK-3R. Ces réponses ont aussi été caractérisées en utilisant des antagonistes sélectifs des récepteurs DA-D1R (SCH23390), DA-D2R (raclopride) ou non-sélectif DA- D2R (halopéridol). Aussi le VTA a été détruit par l’acide iboténique. La réponse pressive induite par senktide et la réponse anti-hypertensive induite par SB222200 ou R-820 étaient plus marquées par la voie intra- VTA. Ces réponses ont été prévenues par un pré-traitement avec le raclopride et l’halopéridol. La lésion du VTA a prévenu la réponse pressive relayée par le senktide (i.c.v.) ainsi que l’effet anti-hypertenseur du R-820 (i.c.v.). De plus, le SB222200 (intra-VTA) a prévenu la réponse pressive du senktide (i.c.v.) et inversement, le senktide (i.c.v.) a prévenu l’effet anti-hypertenseur du SB222200 (intra-VTA).
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