Interaction with chlorethylclonidine has been used to subdivide populations of α1-adrenoceptors in some tissues. WB 4101 can distinguish high and low affinity states of the receptor. The present study was carried out to determine if different populations or affinity states of α1-adrenoceptors distinguished by either of these compounds, could explain the variation in α1-adrenoceptor agonist affinity found amongst rabbit arteries. Five arteries were studied whose affinity for noradrenaline vary between 4.8 and 6.4. These were the thoracic aorta, renal, superior mesenteric, ear and ovarian arteries. WB 4101 was found to be equally effective in antagonizing noradrenaline on all arteries. Chlorethylclonidine caused a 20-fold rightward shift of the noradrenaline dose-contraction curve in the thoracic aorta; but had little or no effect on the other vessels. Thus, the combination of different proportionsof subsets of α1-adrenoceptors distinguished by WB 4101 or chlorethylclonidine does not explain the variation in α1-adrenoceptor affinity found in these rabbit arteries.

No intuito de avaliar o papel do receptor b2-adrenérgico no processo de regeneração muscular, os músculos tibialis anterior de camundongos knockout para o adrenoceptor b2 (b2KO) foram criolesados e analisados após 1, 3, 10 e 21 dias. Análises de aspectos morfológicos e contráteis, atuação de macrófagos M1 e M2, conteúdo de AMPc e ativação de elementos da via de sinalização TGF-b/smad foram realizadas. Os músculos em regeneração dos animais b2KO apresentaram redução do calibre das fibras musculares, redução na função contrátil em 10 dias após criolesão, atenuado aumento do conteúdo de AMPc nos músculos em 10 dias após criolesão, aumento da inflamação e do número de macrófagos nos músculos em regeneração em 3 e 10 dias após lesão, predominância de macrófagos M1, diminuição da ativação de TbR-I e smad2/3 e da expressão de smad4 em 3 dias após lesão, e aumento na expressão de akirina1 em 10 dias após lesão. Nossos resultados sugerem que o adrenoceptor b2 contribui para a regulação das fases iniciais da regeneração muscular. / In this study, we investigated the role of the b2-adrenoceptor in skeletal muscle regeneration. Tibialis anterior muscles from b2-adrenoceptor knockout (b2KO) mice were cryolesioned and analysed after 1, 3, 10, and 21 days. Analysis of structural and contractile aspects, M1 and M2 macrophage profile, cAMP content, and activation of TGF-b/smad signalling elements. Regenerating muscles from b2KO mice showed diminished calibre of regenerating myofibres, decreased muscle contractile function at 10 days when compared with those from wild-type, attenuated augment in cAMP content in muscles at 10 days post-injury, increase in inflammatory process and in the number of macrophages at 3 and 10 days, prevalence of M1 macrophage phenotype, reduction in TbR-I and smad2/3 activation, and in the smad4 expression at 3 days, and an increase in akirin1 expression at 10 days in muscles from b2KO mice when compared to those from wild-type. Our data suggest that the b2-adrenoceptor contributes to the control of the initial stages of muscle regeneration.

<p>α₁- and α₂-Adrenoceptors are involved in various physiological events in the eye: blood flow regulation, aqueous humor dynamics and pupil regulation. The α₁- and α₂-adrenoceptors can be further subdivided into six subtypes (α_1A, α_1B, α_1D, α_2A , α_2B, and α_2C ). Currently available α1- and α₂-adrenergic drugs are not selective for the different subtypes and some ocular adrenergics have undesirable side-effects, both local and systemic. A better understanding of the subtype distribution in the eye would be useful when designing new drugs with greater efficacy and fewer adverse effects; this applies especially to the treatment of glaucoma. The purpose of the thesis was therefore to identify and localize the different subtypes of α₁- and α₂-adrenoceptors in the eye. </p><p>The identities of the α₁-adrenoceptor subtypes were studied in various parts of pig and albino rabbit eyes by radioligand binding. In the pig retina and in the albino rabbit iris, ciliary body and retina, mixed populations of α_1A- and α_1B-adrenoceptors were localized. In the rabbit choroid only the α_1A-adrenoceptor subtype was detected. </p><p>The α₂-adrenoceptor subtypes were also characterized by radioligand binding, in different parts of the pig eye. In the iris, ciliary body and choroid, only α_2A-adrenoceptors were localized, while in the retina, mostly α_2A-adrenoceptors and a minor population of α_2C-adrenoceptors were identified. High densities of α_2A-adrenoceptors were found in the ciliary body and choroid.</p><p>The effect of α₂-adrenoceptor agonists on the porcine ciliary artery was studied on a small-vessel myograph. α₂-Adrenoceptor agonists proved to be potent vasoconstrictors in the porcine ciliary artery and it was found that the vasoconstriction induced by brimonidine was mediated by the α_A-adrenoceptor.</p>

α1- and α2-Adrenoceptors are involved in various physiological events in the eye: blood flow regulation, aqueous humor dynamics and pupil regulation. The α1- and α2-adrenoceptors can be further subdivided into six subtypes (α1A, α1B, α1D, α2A , α2B, and α2C ). Currently available α1- and α2-adrenergic drugs are not selective for the different subtypes and some ocular adrenergics have undesirable side-effects, both local and systemic. A better understanding of the subtype distribution in the eye would be useful when designing new drugs with greater efficacy and fewer adverse effects; this applies especially to the treatment of glaucoma. The purpose of the thesis was therefore to identify and localize the different subtypes of α1- and α2-adrenoceptors in the eye. The identities of the α1-adrenoceptor subtypes were studied in various parts of pig and albino rabbit eyes by radioligand binding. In the pig retina and in the albino rabbit iris, ciliary body and retina, mixed populations of α1A- and α1B-adrenoceptors were localized. In the rabbit choroid only the α1A-adrenoceptor subtype was detected. The α2-adrenoceptor subtypes were also characterized by radioligand binding, in different parts of the pig eye. In the iris, ciliary body and choroid, only α2A-adrenoceptors were localized, while in the retina, mostly α2A-adrenoceptors and a minor population of α2C-adrenoceptors were identified. High densities of α2A-adrenoceptors were found in the ciliary body and choroid. The effect of α2-adrenoceptor agonists on the porcine ciliary artery was studied on a small-vessel myograph. α2-Adrenoceptor agonists proved to be potent vasoconstrictors in the porcine ciliary artery and it was found that the vasoconstriction induced by brimonidine was mediated by the αA-adrenoceptor.

No intuito de avaliar o papel do receptor b2-adrenérgico no processo de regeneração muscular, os músculos tibialis anterior de camundongos knockout para o adrenoceptor b2 (b2KO) foram criolesados e analisados após 1, 3, 10 e 21 dias. Análises de aspectos morfológicos e contráteis, atuação de macrófagos M1 e M2, conteúdo de AMPc e ativação de elementos da via de sinalização TGF-b/smad foram realizadas. Os músculos em regeneração dos animais b2KO apresentaram redução do calibre das fibras musculares, redução na função contrátil em 10 dias após criolesão, atenuado aumento do conteúdo de AMPc nos músculos em 10 dias após criolesão, aumento da inflamação e do número de macrófagos nos músculos em regeneração em 3 e 10 dias após lesão, predominância de macrófagos M1, diminuição da ativação de TbR-I e smad2/3 e da expressão de smad4 em 3 dias após lesão, e aumento na expressão de akirina1 em 10 dias após lesão. Nossos resultados sugerem que o adrenoceptor b2 contribui para a regulação das fases iniciais da regeneração muscular. / In this study, we investigated the role of the b2-adrenoceptor in skeletal muscle regeneration. Tibialis anterior muscles from b2-adrenoceptor knockout (b2KO) mice were cryolesioned and analysed after 1, 3, 10, and 21 days. Analysis of structural and contractile aspects, M1 and M2 macrophage profile, cAMP content, and activation of TGF-b/smad signalling elements. Regenerating muscles from b2KO mice showed diminished calibre of regenerating myofibres, decreased muscle contractile function at 10 days when compared with those from wild-type, attenuated augment in cAMP content in muscles at 10 days post-injury, increase in inflammatory process and in the number of macrophages at 3 and 10 days, prevalence of M1 macrophage phenotype, reduction in TbR-I and smad2/3 activation, and in the smad4 expression at 3 days, and an increase in akirin1 expression at 10 days in muscles from b2KO mice when compared to those from wild-type. Our data suggest that the b2-adrenoceptor contributes to the control of the initial stages of muscle regeneration.

The presence of an alpha-adrenoceptor--mediated coronary vasoconstrictor reflex during acute systemic hypoxia was examined in thirteen chloralose-anesthetized dogs. Local vasodilator effects were avoided by perfusing the left common coronary artery (LCC) with normoxic blood, while the dogs were ventilated with 5% 02-95% N2 . Left ventricular afterload was held constant and positive cardiac inotropic responses and beta two-adrenoceptor-mediated coronary vasodilation were blocked by propranolol. Parasympatheticmediated bradycardia and coronary vasodilation were blocked with atropine. Systemic hypoxia decreased LCC flow to normoxic myocardium by 19.4+2.6 %. Although myocardial oxygen extraction increased 9.7+2.9 %, myocardial oxygen consumption decreased 16.5+2.6 %. Intracoronary prazosin prevented the reflex vasoconstriction during repeated hypoxia.

Músculos esqueléticos de ratos idosos apresentam uma reduzida capacidade de se regenerar após lesão. No presente estudo, nós lançamos a hipótese de que a estimulação farmacológica de adrenoceptores b2 em músculos de ratos idosos lesados poderia melhorar a regeneração destes. Ratos jovens e idosos foram tratados com injeção subcutânea do agonista b2-adrenérgico formoterol (2 mg/kg/dia) durante 10 e 21 dias após lesão do músculo sóleo. Os músculos de ratos idosos lesados e tratados com formoterol por 10 e 21 dias apresentaram menor processo inflamatório e fibras musculares em regeneração com maior calibre quando comparados aos músculos apenas lesados. O tratamento com formoterol preveniu a queda da força tetânica e aumentou a síntese de proteínas e a fosforilação de mTOR em músculos de ratos idosos lesados e avaliados após 10 dias. Nossos resultados sugerem que o formoterol melhora a capacidade regenerativa estrutural e funcional dos músculos esqueléticos de ratos idosos, e que esse efeito é mediado pelo aumento da síntese protéica através da ativação de mTOR. / Skeletal muscles from old rats fail to completely regenerate following injury. In the present work, we hypothesized that pharmacological stimulation of b2-adrenoceptors in aged muscles following injury could improve their regenerative capacity. Young and aged rats were treated with a subcutaneous injection of b2-adrenergic agonist formoterol (2 mg/kg/day) up to 10 and 21 days after soleus muscle injury. Formoterol-treated muscles from old rats evaluated at 10 and 21 days post-injury showed reduced inflammation and regenerating myofibers of greater caliber when compared to their injured controls. Formoterol minimized the decrease in tetanic force and increased protein synthesis and mTOR phosphorylation in old muscles at 10 days post-injury. Our results suggest that formoterol improves structural and functional regenerative capacity of regenerating skeletal muscles from aged rats by increasing protein synthesis via mTOR activation.

O controle neural da pressão arterial é essencial para a manutenção da homeostase do organismo. Este controle é realizado principalmente por núcleos bulbares e hipotalâmicos. Um dos principais sistemas de neurotransmissão envolvidos no controle da pressão arterial é o catecolaminérgico. Células noradrenérgicas e adrenérgicas estão presentes em todos os centros bulbares reguladores da pressão arterial, enquanto seus receptores, principalmente o receptor &alpha;2 adrenérgico (&alpha;2r), estão presentes nas mesmas regiões além de estarem presentes também nos núcleos hipotalâmicos. Estes receptores, quando ativados nestes núcleos, geram respostas cardiovasculares e atuam em conjunto com outros sistemas de neurotransmissão neste controle. Dentre estes sistemas de neurotransmissão, merecem destaque os sistemas angiotensinérgico e glutamatérgico, não apenas por estarem presentes nestes núcleos, mas também por atuarem no controle da pressão arterial. Contudo, pouco se sabe sobre como o sistema catecolaminérgico interage com estes sistemas. Desta forma, estudamos neste projeto a influência do sistema glutamatérgico e angiotensinérgico sobre o sistema catecolaminérgico no bulbo de ratos. Através de culturas de células bulbares, demonstramos que a ativação de receptores glutamatérgicos do tipo NMDA é capaz de elevar os níveis proteicos do &alpha;2R e que os receptores ionotrópicos do tipo não-NMDA precisam estar desbloqueados para tal. Em ratos adultos, microinjeções repetidas inibem a resposta bradicárdica induzida pela ativação dos &alpha;2rR no NTS. Contudo, o knockdown dos receptores AT1 de angiotensina restaura a resposta bradicárdica. A partir destes resultados, foi demonstrado que o sistema glutamatérgico é capaz de modular o sistema catecolaminérgico, enquanto o knockdown do receptor AT1 de angiotensina no NTS acentua a resposta bradicárdica dos &alpha;2R do NTS. Estes resultados sugerem que os sistemas de neurotransmissão bulbares interagem de diferentes formas e a compreensão deste controle pode vir a ser de grande valia para a compreensão de como se dá o controle da pressão arterial pelo sistema nervoso / The neural control of blood pressure is essential for the maintenance of the homeostasis of the organism. This control is performed mainly by nuclei in the medulla oblongata and in the hypothalamus. One of the main neurotransmitter system involved in this control is the catecholaminergic. Noradrenergic and adrenergic cells are present in all medullary nuclei involved in the arterial pressure regulation, while its receptors, especially the &alpha;2 adrenoceptor, are present in the same region plus hypothalamic nuclei. These receptors, upon activation in these nuclei, generate cardiovascular response, and act with other neurotransmission systems in this control. Among these systems, the glutamatergic and angiotensinergic deserve attention not only for also being present in the same nuclei, but for also acting in the control of the arterial pressure. Both angiotensinergic and glutamatergic systems interact with the catecholaminergic system throughout the nervous system. However, little is known about how the catecholaminergic system interacts with these systems in the modulation of blood pressure. Therefore, we studied in this project the influence of the glutamatergic and angiotensinergic systems over the catecholaminergic system in the medulla oblongata of rats. Through cell cultures of the medulla oblongata, we demonstrated that the activation of glutamatergic NMDA receptors is capable of elevating the proteic levels of &alpha;2-adrenoceptors, and that non-NMDA receptors need to be unblocked for such. In adult rats, repeated microinjections inhibit the bradycardic response elicited by the &alpha;2 adrenoceptors in the NTS. However, the angiotensin AT1 receptors knockdown restored the bradycardic response. Through the chronic knockout of angiotensinergic AT1 receptors in the NTS, we observed bradycardic response elicited by the activation of &alpha;2 adrenoceptors in the NTS of the knock-down rats. These results suggest that the medullary neurotransmission systems interact in different ways, and the comprehension of this control may be of great value for the comprehension of how the neural control of the blood pressure works

<p>The endothelium plays an important part in blood flow regulation by producing the vasodilatory substance nitric oxide (NO). Various studies have shown that commonly accepted risk factors for coronary heart disease, such as hypertension, diabetes, hypercholesterolemia, smoking and mental stress impair endothelium-derived vasodilation by the NO-pathway. This thesis focuses on the effects of mental stress on the endothelium. Furthermore, the effects of epinephrine (E) and norepinephrine (NE) and blockades of adrenergic receptors were studied in the forearm in young healthy subjects.</p><p>Different blockades were given locally in the forearm, not affecting general hemodynamics. β-adrenoceptor blockade impaired endothelium-dependent vasodilation (EDV), while α-adrenoceptor blockade and neurogenic blockade caused a general vasodilation which was not endothelium dependent. Neuropeptide Y did not seem to influence blood flow in the resting forearm.</p><p>A short period of mental stress induced by an arithmetic task, impaired EDV in the forearm. This negative effect could be blocked by β-adrenergic, but not α-adrenergic receptor blockade.</p><p>Local infusions of E and NE in the human forearm induced vasodilation and vasoconstriction, respectively. As both EDV and endothelium-independent vasodilation were affected by both E and NE, the two catecholamines did not seem to affect vascular tone by an endothelium-specific mechanism.</p><p>Both cold pressure stress and mental stress induced impairments in flow-mediated vasodilation (FMD) when normalised for the degree of hyperemic blood flow.</p><p>These findings give us new insights in how mental stress and sympathetic activation affects the endothelium and how the negative effects can be prevented.</p>

The endothelium plays an important part in blood flow regulation by producing the vasodilatory substance nitric oxide (NO). Various studies have shown that commonly accepted risk factors for coronary heart disease, such as hypertension, diabetes, hypercholesterolemia, smoking and mental stress impair endothelium-derived vasodilation by the NO-pathway. This thesis focuses on the effects of mental stress on the endothelium. Furthermore, the effects of epinephrine (E) and norepinephrine (NE) and blockades of adrenergic receptors were studied in the forearm in young healthy subjects. Different blockades were given locally in the forearm, not affecting general hemodynamics. β-adrenoceptor blockade impaired endothelium-dependent vasodilation (EDV), while α-adrenoceptor blockade and neurogenic blockade caused a general vasodilation which was not endothelium dependent. Neuropeptide Y did not seem to influence blood flow in the resting forearm. A short period of mental stress induced by an arithmetic task, impaired EDV in the forearm. This negative effect could be blocked by β-adrenergic, but not α-adrenergic receptor blockade. Local infusions of E and NE in the human forearm induced vasodilation and vasoconstriction, respectively. As both EDV and endothelium-independent vasodilation were affected by both E and NE, the two catecholamines did not seem to affect vascular tone by an endothelium-specific mechanism. Both cold pressure stress and mental stress induced impairments in flow-mediated vasodilation (FMD) when normalised for the degree of hyperemic blood flow. These findings give us new insights in how mental stress and sympathetic activation affects the endothelium and how the negative effects can be prevented.