No description available.

No description available.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Three major systems participate in the control of the peripheral circulation: the renin-angiotensin, the arginine vasopressin (AVP) and the sympathetic nervous systems. These studies examined the roles of the AVP and the sympathetic nervous systems in the regulation of blood pressure at both the central and the peripheral level. Anatomical studies have revealed that hypothalamic neurons containing AVP extend to the nucleus tractus solitarius (NTS) in the medulla. Since the NTS is the primary site of termination of the afferent neurons of the baroreceptor reflex arc, it suggests that AVP may be involved in central cardiovascular regulation. The effect of central AVP on mean arterial pressure (MAP) and sympathetic nerve activity, estimated from plasma catecholamine levels, was investigated. The injection of AVP into the fourth cerebroventricle and NTS of conscious, unrestrained rats increased MAP and plasma noradrenaline and adrenaline levels, suggesting that AVP may act centrally at the NTS to modulate sympathoadrenal outflow. However, the injection of a selective vascular antagonist of AVP, d(CH₂)₅Tyr(Me)AVP, into the fourth ventricle or NTS did not affect MAP or plasma catecholamine levels, either in normotensive rats, in rats subjected to hypotensive stress, or in neurogenically-stressed rats. This suggests that endogenously-released AVP may not have a tonic influence on central cardiovascular regulation. The role of AVP in the control of MAP, cardiac output (CO) and its distribution was investigated in anesthetized, surgically-stressed rats. The i.v. injection of d(CH₂)₅Tyr(Me)AVP decreased MAP and total peripheral resistance (TPR), did not alter CO, and increased the distribution of blood flow (BF) to the stomach and skin. The vascular role of AVP was found to be greater in the absence of influence from the renin-angiotensin and the sympathetic nervous systems. After blockade of the renin-angiotensin system by the infusion of saralasin the AVP antagonist increased BF to the skin and muscle, while after blockade of the α-adrenergic system with the infusion of phentolamine, the AVP antagonist markedly increased BF to the muscle. Thus, the amount of vasoconstriction produced by AVP in different vascular beds was found to depend on the endogenous vasomotor tone from the renin-angiotensin and α-adrenergic systems. Cross-circulation studies were conducted to concurrently observe the peripheral and central effects of α-agonists in two anesthetized rats, designated rat A and B, respectively. The i.v. injection of clonidine into rat A was found to increase MAP and decrease HR in rat A, and reduce MAP and HR in rat B. Since the stimulation of peripheral α-adrenoceptors in rat A by clonidine increased MAP, it suggests that the effects of peripheral post-junctional α₂-adrenoceptors predominate over those of peripheral pre-junctional α₂-adrenoceptors. In contrast, the i.v. injection of the α₁-agonist, methoxamine, in rat A increased MAP and decreased HR in rat A, and increased both MAP and HR in rat B. This suggests that central α₁-adrenoceptors may mediate responses in the opposite direction to those produced by α₂-adrenoceptors. To verify the results of the cross-circulation studies in animals free of the influence of surgery and anesthesia, and to determine whether the responses to a-agonists were mediated by changes in sympathoadrenal outflow, clonidine and a more selective α₂-agonist, B-HT 920, were injected centrally in conscious rats. The i.e.v. injection of clonidine (1 µg) significantly decreased MAP and HR and slightly decreased plasma noradrenaline and adrenaline levels; however, contrary to expectations, the i.c.v. injection of B-HT 920 (1, 10 µg) increased MAP, decreased HR and slightly increased plasma noradrenaline and adrenaline levels. To determine whether the responses to central injection of clonidine or B-HT 920 were due to the stimulation of α₂-adrenoceptors, i.c.v. injections of these drugs were given after pretreatment with rauwolseine, a selective α₂-antagonist. The i.c.v. injection of rauwolscine in conscious rats increased MAP and plasma noradrenaline and adrenaline levels, suggesting that central α₂-adrenoceptors may mediate tonic inhibition of the cardiovascular system. However, i.c.v. injections of clonidine or B-HT 920 produced the same responses in the absence or presence of rauwolscine. Further studies with different α-adrenergic agonists and antagonists with various selectivities are necessary before we can explain the differential effects of central clonidine and B-HT 920. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate

published_or_final_version / Physiology / Doctoral / Doctor of Philosophy

published_or_final_version / Pharmacology / Master / Master of Philosophy

No description available.

published_or_final_version / abstract / toc / Zoology / Master / Master of Philosophy

No description available.

Made available in DSpace on 2015-05-14T16:53:19Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-02-27Bitstream added on 2015-05-14T16:59:01Z : No. of bitstreams: 1 000828052_20150610.pdf: 305956 bytes, checksum: 7369e2c8e287bd85ed19449e6cb2b2e6 (MD5) Bitstreams deleted on 2015-06-12T11:19:08Z: 000828052_20150610.pdf,. Added 1 bitstream(s) on 2015-06-12T11:19:39Z : No. of bitstreams: 1 000828052.pdf: 458163 bytes, checksum: 8f3277eff5562c7da6c209cf3706a1c0 (MD5) / A imipramina é antidepressivo tricíclico cujo principal mecanismo é a inibição da captura neuronal de noradrenalina e/ou serotonina, aumentando os níveis sinápticos dessas monoaminas. Além disso, a imipramina, bem como outros antidepressivos tricíclicos, antagonizam os adrenoceptores α1 na mesma faixa de concentração em que inibem o transportador de noradrenalina. Por outro lado, estudos recentes mostraram que a imipramina tem afinidades distintas para os três subtipos de adrenoceptores α1, (α1A, α1B e α1D), ou seja, aproximadamente 25 vezes mais seletiva para α1A em relação aos adrenoceptores α1B e 10 vezes para adrenoceptores α1D em relação aos adrenoceptores α1B. Isso sugere que seu mecanismo de ação possa estar relacionado com essa característica, uma vez que, ao aumentar os níveis sinápticos de noradrenalina, antagoniza α1A e α1D, mas deixa relativamente livre α1B. Então, o objetivo desta tese foi investigar a participação dos adrenoceptores α1A, α1B e α1D no efeito anti-imobilidade da imipramina no teste de suspensão pela cauda em camundongos. Para isso, camundongos foram submetidos ao teste de suspensão pela cauda, com a administração de diversos antagonistas seletivos e não-seletivos para subtipos α1. Os testes foram realizados utilizando a imipramina associada ao prazosin, antagonista não-seletivo para adrenoceptores α1, RS-100329, antagonista seletivo pra α1A, L-765314, seletivo par α1B e BMY-7378, seletivo para α1D. Os animais também foram avaliados com administrações únicas dos antagonistas. Esta tese mostrou que a administração concomitante de prazosin ou o L-765314 reverteram o efeito anti-imobilidade da imipramina. Por outro lado, nem o RS-100329 ou BMY-7378 modificaram o efeito anti-imobilidade da imipramina. Além disso, a administração de apenas o RS-100329 ou BMY-7378 apresentou efeito anti-imobilidade no teste de suspensão pela cauda. Isso indica que o efeito ... / Imipramine is a tricyclic antidepressant inhibitor of norepinephrine and serotonin neuronal reuptake. In addition, the imipramine antagonizes α1-adrenoceptors in the same concentration range that inhibited norepinephrine transporter. However, the imipramine has different affinity to α1-adrenoceptor subtypes presenting higher affinity (10-25-fold) towards α1A- and α1D-adrenoceptors compared to α1B-adrenoceptors. This study investigates the α1-adrenoceptor subtypes involved in the anti-immobility effect of imipramine in the tail suspension test in mice. The anti-immobility effect of imipramine was significantly antagonized by the non-subtype-selective α1-adrenoceptor antagonist prazosin. Neither the selective α1A adrenoceptor antagonist RS-100329 nor the selective α1D-adrenoceptor antagonist BMY-7378 changed the anti-immobility effect of imipramine. However, the selective α1B-adrenoceptor antagonist L-765314 antagonized the anti-immobility effect of imipramine. In addition, mice treated only with RS-100329 or BMY-7378 showed reduced immobility time in comparison to mice treated with vehicle, whereas L-765314 increased the immobility time. These results suggests that the α1B-subtype is the main target for the increased levels of norepinephrine caused by imipramine, and that the selective antagonism of α1A- and α1D-adrenoceptors results in anti-immobility effects