Altered vasoreactivity and mechanical properties of skeletal muscle arterioles could impact peripheral insulin resistance and hypertension observed in type 2 diabetes. The purpose was to determine if increased vasoconstrictor reactivity, decreased vasodilator reactivity and alterations in the structural properties of 1A arterioles from both high-oxidative and low-oxidative glycolytic skeletal muscles is present during prediabetes as well as acute and chronic diabetes, and to determine if this dysfunction precedes the development of elevated arterial pressure in type 2 diabetes. Zucker Diabetic Fatty (ZDF) rats and lean age-matched controls were studied at 7 (prediabetes), 13 (acute diabetes) and 20 (chronic diabetes) weeks of age. Following measurement of arterial pressure, vasoconstrictor responsiveness to norepinephrine (NE), potassium chloride (KCl), and increasing intraluminal pressure (MYO), vasodilator responsiveness to acetylcholine (ACh), sodium nitroprusside (SNP) and intraluminal flow and passive mechanical properties were examined in arterioles from soleus and gastrocnemius muscles. Vasoconstriction to NE was enhanced in gastrocnemius muscle arterioles during prediabetes and preceded elevated arterial pressure. Alterations in the passive mechanical properties of arterioles from both muscles were observed throughout the progression of diabetes. Flow-induced vasodilation was decreased in the high-oxidative muscle arterioles during acute diabetes, and was coincident with the emergence of elevated arterial pressure. During chronic diabetes, vasodilation to ACh and flow were reduced in soleus muscle arterioles. The reduced vasodilation to ACh was the result of a loss of NO. Although the vasodilator capacity of low-oxidative glycolytic skeletal muscle arterioles was not diminished throughout the progression of diabetes, the contribution of NO to AChinduced dilation was lost in the prediabetic and acute diabetic rats. The data demonstrate that alterations in both the vasoconstrictor and passive properties of low-oxidative glycolytic skeletal muscle arterioles are present during prediabetes, and precede the development of type 2 diabetes, and that although endothelial dysfunction does not become manifest in these skeletal muscle arterioles, alterations in the signaling mechanisms to achieve that vasodilation are present in prediabetes. Moreover, overt type 2 diabetes results in endothelial dysfunction and altered mechanical properties in high-oxidative skeletal muscle arterioles.

Aging is associated with increases in regional and systemic vascular resistance and impaired ability to increase blood flow to active muscles during exercise. Aging enhances vasoconstrictor responsiveness in both humans and animals, and an increase in Angiotensin II-induced vasoconstriction is one possible mechanism for old age-associated increase in muscle vascular resistance. The purpose of this study was to determine 1) whether aging alters Ang II-induced vasoconstriction, 2) whether exercise training attenuates the age-associated alteration in Ang II-mediated vasoconstriction, and 3) the mechanism(s) through which aging and exercise training alter Ang II-induced vasoconstriction in rat skeletal muscle arterioles. Male Fischer 344 rats were assigned to 4 groups: Young sedentary (YS; 4 months), old sedentary (OS; 24 months), young trained (YT) and old trained (OT). Exercise-trained groups performed treadmill exercises for 60 min/day at 15 m/min, on a 15º incline for 5 days/week for 10-12 weeks. First-order (1A) arterioles were isolated from soleus and gastrocnemius muscles for in vitro experimentation. Intraluminal diameter changes were determined in response to the cumulative addition of Ang II (3×10-11 - 3×10-5 M). Ang II dose responses were then determined following the removal of endothelium and treatment with NG-nitro-L-arginine methyl ester (L-NAME, 10-5 M), a nitric oxide synthase (NOS) inhibitor. Ang II-induced vasoconstriction was augmented in the aged skeletal muscle arterioles, both in soleus and gastrocnemius muscles, and age-associated increases in Ang II-induced vasoconstriction were abolished with the removal of endothelium and with L-NAME. Exercise training ameliorated the age-induced increase in Ang II-vasoconstriction, and this alteration was eliminated by the removal of endothelium and with NOS inhibition. These findings suggest that aging enhances Ang II-induced vasoconstrictor responses in the arterioles from both soleus, high oxidative, and white portion of gastrocnemius, low oxidative glycolytic muscles, and this age-associated change occurs through an endothelium-dependent NOS signaling pathway. These results also demonstrated that exercise training can ameliorate the age-associated increase in Ang II vasoconstriction in the arterioles from both high oxidative and low oxidative glycolytic muscles through an endothelium-mediated NOS mechanism.

Aging is associated with increases in regional and systemic vascular resistance and impaired ability to increase blood flow to active muscles during exercise. Aging enhances vasoconstrictor responsiveness in both humans and animals, and an increase in Angiotensin II-induced vasoconstriction is one possible mechanism for old age-associated increase in muscle vascular resistance. The purpose of this study was to determine 1) whether aging alters Ang II-induced vasoconstriction, 2) whether exercise training attenuates the age-associated alteration in Ang II-mediated vasoconstriction, and 3) the mechanism(s) through which aging and exercise training alter Ang II-induced vasoconstriction in rat skeletal muscle arterioles. Male Fischer 344 rats were assigned to 4 groups: Young sedentary (YS; 4 months), old sedentary (OS; 24 months), young trained (YT) and old trained (OT). Exercise-trained groups performed treadmill exercises for 60 min/day at 15 m/min, on a 15º incline for 5 days/week for 10-12 weeks. First-order (1A) arterioles were isolated from soleus and gastrocnemius muscles for in vitro experimentation. Intraluminal diameter changes were determined in response to the cumulative addition of Ang II (3×10-11 - 3×10-5 M). Ang II dose responses were then determined following the removal of endothelium and treatment with NG-nitro-L-arginine methyl ester (L-NAME, 10-5 M), a nitric oxide synthase (NOS) inhibitor. Ang II-induced vasoconstriction was augmented in the aged skeletal muscle arterioles, both in soleus and gastrocnemius muscles, and age-associated increases in Ang II-induced vasoconstriction were abolished with the removal of endothelium and with L-NAME. Exercise training ameliorated the age-induced increase in Ang II-vasoconstriction, and this alteration was eliminated by the removal of endothelium and with NOS inhibition. These findings suggest that aging enhances Ang II-induced vasoconstrictor responses in the arterioles from both soleus, high oxidative, and white portion of gastrocnemius, low oxidative glycolytic muscles, and this age-associated change occurs through an endothelium-dependent NOS signaling pathway. These results also demonstrated that exercise training can ameliorate the age-associated increase in Ang II vasoconstriction in the arterioles from both high oxidative and low oxidative glycolytic muscles through an endothelium-mediated NOS mechanism.

Altered vasoreactivity and mechanical properties of skeletal muscle arterioles could impact peripheral insulin resistance and hypertension observed in type 2 diabetes. The purpose was to determine if increased vasoconstrictor reactivity, decreased vasodilator reactivity and alterations in the structural properties of 1A arterioles from both high-oxidative and low-oxidative glycolytic skeletal muscles is present during prediabetes as well as acute and chronic diabetes, and to determine if this dysfunction precedes the development of elevated arterial pressure in type 2 diabetes. Zucker Diabetic Fatty (ZDF) rats and lean age-matched controls were studied at 7 (prediabetes), 13 (acute diabetes) and 20 (chronic diabetes) weeks of age. Following measurement of arterial pressure, vasoconstrictor responsiveness to norepinephrine (NE), potassium chloride (KCl), and increasing intraluminal pressure (MYO), vasodilator responsiveness to acetylcholine (ACh), sodium nitroprusside (SNP) and intraluminal flow and passive mechanical properties were examined in arterioles from soleus and gastrocnemius muscles. Vasoconstriction to NE was enhanced in gastrocnemius muscle arterioles during prediabetes and preceded elevated arterial pressure. Alterations in the passive mechanical properties of arterioles from both muscles were observed throughout the progression of diabetes. Flow-induced vasodilation was decreased in the high-oxidative muscle arterioles during acute diabetes, and was coincident with the emergence of elevated arterial pressure. During chronic diabetes, vasodilation to ACh and flow were reduced in soleus muscle arterioles. The reduced vasodilation to ACh was the result of a loss of NO. Although the vasodilator capacity of low-oxidative glycolytic skeletal muscle arterioles was not diminished throughout the progression of diabetes, the contribution of NO to AChinduced dilation was lost in the prediabetic and acute diabetic rats. The data demonstrate that alterations in both the vasoconstrictor and passive properties of low-oxidative glycolytic skeletal muscle arterioles are present during prediabetes, and precede the development of type 2 diabetes, and that although endothelial dysfunction does not become manifest in these skeletal muscle arterioles, alterations in the signaling mechanisms to achieve that vasodilation are present in prediabetes. Moreover, overt type 2 diabetes results in endothelial dysfunction and altered mechanical properties in high-oxidative skeletal muscle arterioles.

Aging is associated with increases in regional and systemic vascular resistance and arterial blood pressure. One possible mechanism through which these age-associated alterations occur is enhanced vasoconstrictor responsiveness, or alterations in the structural properties of the resistance vasculature. We hypothesized that stiffness and vasoconstriction would be greater in skeletal muscle arterioles from old rats, and that endurance exercise training would ameliorate the associated with aging alterations. METHODS: Young sedentary (YS; 4 months), old sedentary (OS; 24 months), young trained (YT) and old trained (OT) male Fischer 344 rats were used. Training modality was treadmill exercise at 15 m/min up a 15o incline, 5 days/wk for 12wks. Skeletal muscle first-order arterioles were isolated for in vitro experimentation. Intraluminal diameter was measured in response to the cumulative addition of endothelin-1, norepinephrine, KCl, and isoproterenol. Stiffness was measure by examining the arterioles' stress and strain relation to increased luminal pressure in Ca++ free solution. RESULTS: Skeletal muscle arterioles had augmented vasoconstriction to endothelin-1 and norepinephrine. Adrenergic vasodilation was diminished in aged rat arterioles. Stiffness increased with age. Exercise training ameliorated the age-associated changes in stiffness and norepinephrine vasoconstriction. Exercise training did not alter endothelin-1 vasoconstriction or adrenergic vasodilation. CONCLUSIONS: These findings suggest that enhanced vascular sensitivity to vasoconstrictors and increased arteriole stiffness may play a role in the increase in skeletal muscle and systemic vascular resistance and, thus, contribute to the elevated blood pressure which occurs in aging humans. These results also demonstrate some of the cardioprotective effects of exercise training.

The cardiovascular system helps maintain blood pressure and blood flow to the different organ systems through many elaborate mechanisms. These mechanisms include the different blood vessels, each with their own properties, as well as both neural and humoral factors. The vessels that are most relevant here are arterioles, also known as resistance vessels, as they play a significant role in regulating organ blood flow, vascular resistance, and blood pressure in many different physiological conditions, such as exercise. More specifically, the focus of this paper is the endothelial layer of the arteriolar wall and its role in attenuating sympathetic adrenergic vasoconstriction, or sympatholysis. Exercising skeletal muscle cells require an increase in blood flow to adequately meet their oxygen and nutrient demands. In order to accomplish this, there is an increase in cardiac output by the heart and also a redistribution of blood flow away from inactive regions towards active muscle cells. This critical redistribution of blood flow depends on the sympathetic nervous system, which increases in activity during contraction to cause vasoconstriction of the arterioles that supply other inactive organs except the brain. Despite this increase in sympathetic nerve activity, there is also profound vasodilation in the microvasculature of active skeletal muscle cells. It is this paradox that helps match the increase in metabolism with an increase in blood flow during exercise, and it is also this mechanism that has been coined ‘functional sympatholysis.’ Although much effort has been put into studying the mechanism through which functional sympatholysis occurs, the existing data and evidence are not sufficient to deduce a clear picture at this time. There are inconsistencies regarding the functional distribution of alpha-adrenergic receptors, the role of non-adrenergic receptors, the impact of many different metabolic factors, and finally also the contribution of non-metabolic factors. Due to such contrasting data, it is clear that further research will need to be conducted in order to obtain a concrete explanation for sympatholysis. A recent study has postulated that the process of sympatholysis may primarily involve the endothelium. This study used various manipulations that involved endothelium-dependent vasodilatory responses as well as endothelium-independent vasodilatory responses intersected with sympathetic adrenergic nerve activity to determine that only those vasodilatory agents that functioned using the endothelium were able to attenuate sympathetic adrenergic vasoconstriction. This compelling evidence has made way for further inquiry into the endothelium’s role in this very important process. Due to the fact that the greatest amount of research has been devoted to studying the contraction-related attenuated responsiveness of alpha-adrenergic receptors, a hypothetical study and its various methods are proposed in this paper. This hypothesis states that both adenosine triphosphate and flow-mediated dilation, two vasodilatory stimuli that rely on a functional endothelium, are sympatholytic agents, whereas adenosine, which acts on vascular smooth muscle to cause vasodilation, is not sympatholytic. The conclusions that might be drawn from such a study and their various implications are also discussed. Finally, the major relevancy in this topic relates to the fact that sympatholysis or impaired sympatholysis may be a factor in many metabolic and cardiovascular diseases along with exercise. Some of the diseases discussed here are type II diabetes, hypertension, and chronic myocardial infarction. A concrete understanding of the mechanism by which this process occurs would potentially help invent new treatment plans and prevention. At this point, it seems probable that the endothelium does play a significant role in sympatholysis, but whether it is the primary dictator and whether there are also other influences that are absolutely essential still remains relatively uncertain.

La prise en charge d’une hypertension artérielle est un enjeu majeur dans certaines situations à risque telles que la pré-éclampsie ou chez les patients avec une pathologie respiratoire pour lesquels la vasoconstriction hypoxique pulmonaire est bénéfique. L’urapidil est un antihypertenseur d’action mixte associant une action antagoniste sur les récepteurs alpha-1 adrénergiques post synaptiques périphériques et une baisse du tonus sympathique par action centrale qui pourrait impliquer à la fois un blocage des récepteurs alpha-1 et une activité agoniste sérotoninergique sur les récepteurs 5HT1A qui limite la survenue d’une tachycardie reflexe. La première étude indique que les récepteurs 5HT1A périphériques ne semblent pas impliqués dans les effets vasculaires périphériques de l’urapidil, qui seraient principalement le résultat du blocage des récepteurs alpha 1 adrénergiques. La deuxième étude montre que l’urapidil préserve la VHP contrairement à la nicardipine et la clévidipine qui l’inhibent. / Urapidil, a vasodilator, is widely used in the treatment of hypertension mostly due to better patient tolerance. Urapidil has a dual action: firstly it works as a selective alpha1- adrenoreceptor antagonist and secondly as an agonist of 5-HT1A receptors in the central nervous system. Thus, the present findings, while confirming that urapidil is a potent inhibitor of alpha 1-adrenoceptor-induced contraction targeting preferentially arteries with an endothelial dysfunction, do not support the role of 5-HT1A receptor activation in the control of the vascular tone in response to urapidil in the three types of blood vessels studied. In conclusion, this trial showed that in our experimental setting, urapidil preserved the hypoxia triggered vasoconstriction in isolated pulmonary vessels. Conversely, both calcium channel inhibitors nicardipine and clevidipine blunted the vasocontrictor reaction to hypoxia. These findings may have important clinical consequences that deserve further evaluation.

Made available in DSpace on 2017-07-24T19:22:02Z (GMT). No. of bitstreams: 1 Priscila de Camargo Smolarek.pdf: 1803284 bytes, checksum: d41ae9900eb30eddbfaa74a5d2ac7233 (MD5) Previous issue date: 2016-02-18 / Local anesthetics are drugs widely used by dentists. The objective of this doubleblind, crossover clinical trial was to evaluate the efficacy of articaine 4% (Ar4) compared to mepivacaine 2% (Me2) both associated with epinephrine 1: 100,000. The local anesthetics were applied to sound soft tissue (lower lip mucosa) in a model without surgical trauma. After sample size calculation, 72 healthy volunteers were randomly divided in two groups that received local anesthesia with Ar4 and Me2. A initial evaluation was performed to identify the physiological profiles of the volunteers. Then, they were blindfolded and subjected to baseline tests for sensitivity (A-alpha fibers A - beta, A - delta and fiber type C) and vascularization of the lower lip. Computerized anesthesia was subsequently performed. A total volume of 0.3 ml of anesthetic was injected in the central region of the lower lip. Pain during anesthesia was evaluated through the visual analogue scale (VAS). At different periods after anesthesia (3, 10, 20 and 30 min), all the tests were repeated. In addition to that, the diameter of the anaesthetized area was measured in mm, the residual effect of the anesthesia was assessed with the VAS (after 30, 40, 50 and 60 min), and the anesthesia recovery time in minutes (a self-assessment record). After 7 days, the cross-over was performed and the entire sequence of the tests was repeated. When considering the local vasoconstriction after anesthesia, the highest values were achieved after anesthesia with Me2, regardeless the evaluation period. The best anesthetic effect was observed for Me2, 20 and 30 minutes after anesthesia (p<0.001). Recovery from anesthesia was faster for Ar4 (average time of recovery = 81.51 ± 29.08 min) compared to Me2 (92.38 ± 26.82 min) (p = 0.001, Wilcoxon Signed Rank Test). In conclusion, the data collected in this research showed that the use of mepivacaine promoted a longer lasting anesthetic effect when compared with articaine. / Os anestésicos locais são drogas amplamente utilizadas por cirurgiões - dentistas. O objetivo deste estudo duplo-cego e cruzado foi avaliar a eficácia da articaína 4% (Ar4) comparada a mepivacaína 2% (Me2) ambas associadas com epinefrina 1:100.000, aplicadas ao tecido rico em receptores sensoriais e vascularização, em modelo sem trauma cirúrgico. Uma amostra de 72 voluntários saudáveis foi dividida aleatoriamente em dois grupos que receberam anestesia local com Ar4 e Me2. Foi realizada uma avaliação para identificação do perfil fisiológico dos voluntários, em seguida, eles foram vendados e submetidos a testes de linha de base para a vascularização e sensibilidade do lábio inferior, referentes às fibras A- alpha, A – beta, A – delta e fibra tipo C. A anestesia computadorizada foi realizada posteriormente com volume total de 0,3 mL, na região central do lábio inferior. A dor à anestesia foi avaliada segundo a escala visual analógica (VAS). Após 3, 10, 20 e 30 min do término da anestesia, os testes de vascularização local e sensibilidade das fibras nervosas foram repetidos e medidos segundo a VAS; a área anestesiada foi medida em mm. O efeito residual em 30, 40, 50 e 60 min após a anestesia foi avaliado com VAS, e tempo total de anestesia em min, por uma ficha de auto- avaliação. Após 7 dias o cruzamento foi realizado e toda a sequência do experimento foi repetida. A Me2 demonstrou maior efeito vasoconstritor local, em todos os tempos, em comparação com a Ar4. A Me2 demonstrou melhor efeito anestésico em T20 e T30 (p<0,001). A recuperação da anestesia foi mais rápida para a Ar4 com tempo total médio de anestesia de 81,51±29,08 min contra a Me2 que demonstra 92,38±26,82 min (p=0,001, teste Wilcoxon Signed Rank). Conclui-se que Me2 demonstra efeito anestésico mais duradouro que a Ar4, pois o maior efeito vasoconstritor da Me2 confere analgesia mais eficaz por maior tempo.

Ascent to altitude presents a significant challenge to the human body. Specifically, it is associated with an increased ventilation and pulmonary vasoconstriction. In healthy subjects these are related such that a high ventilatory drive is associated with blunted pulmonary vasoconstriction. Adults born prematurely and given supplemental oxygen at birth have a blunted ventilatory response to hypoxia. We hypothesized that the hypoxic ventilatory and pulmonary vasoconstrictor responses would be unrelated following perinatal supplemental oxygen exposure. To test our hypothesis, we used a well-established rat model of 80% O2 (80%) exposure for 14 days post-natally, with 21% O2 exposure as a control (21%). We assessed the ventilatory response to graded hypoxia using barometric plethysmography 6-9 months post hyperoxia exposure. The left and right ventricles were catheterized to evaluate the hemodynamic response to 10 minutes of 12% O2 (hypoxia). To our surprise we found that 80% animals did not demonstrate a depressed ventilatory response to hypoxia. However, these animals experienced increased right ventricular systolic pressure in response to 12% O2. An increase in cardiac output was the primary driving force behind the increase in right ventricular end systolic pressure, not an increase in vascular resistance. We found no relationship between the hypoxic ventilatory drive and right ventricular pressure. In 21% animals exposed to hypoxia, the increase in right ventricular pressure was driven primarily by vasoconstriction and, as previous studies have shown, there was a relationship between the ventilatory and pressure responses. These data suggest that neonatal supplemental oxygen alters the hemodynamic response to hypoxia, possibly through enhanced sympathetic drive. The relationship between ventilation and pulmonary pressure may not translate to individuals born prematurely.

Obesity is associated with increased sympathoactivation that elevates arterial pressure. However, the mechanism linking sympathetic activation to arterial pressure is unclear. Specifically, it has never been demonstrated unequivocally that sympathetically mediated vasoconstriction is increased in obesity. This project tested the hypothesis that sympathetic vascular tone is increased in obese normotensive and hypertensive subjects. The effect of weight loss on sympathetic vascular tone was also assessed. Sympathetic vascular tone was assessed as forearm vasodilatation to intra-arterial phentolamine (?1/2-adrenergic receptor antagonist). Pharmacological responses were correlated with skeletal muscle sympathetic nerve activity (mSNA). Obese subjects with and without hypertension had increased mSNA. However, the vasodilatator response to phentolamine was not augmented in obese normotensive and hypertensive subjects versus lean controls. Additionally, weight loss did not alter phentolamine's vasodilatator response, despite reducing mSNA and arterial pressure in obese groups. These results indicate that sympathetic vascular tone is not increased in obesity despite higher mSNA. These studies also assessed forearm resistance vessel function using intra-arterial nitroprusside (nitric oxide donor) and isoproterenol (?2-adrenergic receptor agonist). The effects of weight loss on these responses were studied in the obese groups. The response to both vasodilators was blunted, but only in obese hypertensive subjects. Weight loss normalized the response to nitroprusside but not to isoproterenol. This result suggests that obesity-related hypertension is associated with vascular smooth muscle dysfunction, which can be improved by weight loss. Blunted vasodilatation to isoproterenol suggests an abnormality on ?2-adrenergic receptor-dependent mechanisms that may or may not depend on the endothelium. Also, mental stress-induced forearm vasodilatation was blunted in obese normotensive subjects, which was not normalized by weight loss. In conclusion, increased sympathetic nerve activity does not augment forearm sympathetic vascular tone. This dissociation could be due to opposing local factors (e.g. insulin, leptin) or to a different target of limb sympathoactivation (e.g. adipocytes vs. vascular). Sympathetic drive to tissues other than the peripheral circulation may play a more important role in arterial pressure elevation in obesity, either directly or indirectly.