An Octopus-Derived Peptide with Antidiuretic Activity in Rats.

Discovering new drug candidates with high efficacy and few side effects is a major challenge in new drug development. The two evolutionarily related peptides oxytocin (OXT) and arginine vasopressin (AVP) are known to be associated with a variety of physiological and psychological processes via the association of OXT with three types of AVP receptors. Over decades, many synthetic analogs of these peptides have been designed and tested for therapeutic applications; however, only a few studies of their natural analogs have been performed. In this study, we investigated the bioactivity and usefulness of two natural OXT/AVP analogs that originate from the marine invertebrate Octopus vulgaris, named octopressin (OTP) and cephalotocin (CPT). By measuring the intracellular Ca2+ or cyclic AMP increase in each OXT/AVP receptor subtype-overexpressing cell, we found that CPT, but not OTP, acts as a selective agonist of human AVP type 1b and 2 receptors. This behavior is reminiscent of desmopressin, the most widely prescribed antidiuretic drug in the world. Similar to the case for desmopressin, a single intravenous tail injection of CPT into Sprague-Dawley rats reduced urine output and increased urinary osmolality. In conclusion, we suggest that CPT has a significant antidiuretic effect and that CPT might be beneficial for treating urological conditions such as nocturia, enuresis, and diabetes insipidus.

Passive Cigarette Smoking Impact on Blood Pressure Response to Epinephrine and Felypressin in 1K1C Hypertensive Rats Treated or not with Atenolol.

BACKGROUND: Cigarette smoking is usually associated with hypertension and may modify vasoconstrictor response. OBJECTIVE: The present study aimed to analyze and compare the interaction of passive cigarette smoking and hypertension on epinephrine and felypressin blood pressure effects after intravascular injection. METHOD: 45-day male Wistar rats had the main left renal artery partially constricted and the right kidney removed (1K1C model). Rats were placed in the chamber for exposition to passive cigarette smoking (10 cigarettes) during 10 min (6 days a week). Hypertensive rats received atenolol (90 mg/kg/day) by gavage for two weeks. Hypotensive and hypertensive response, response duration and heart rate were recorded from direct blood pressure values. The significance level was 5%. RESULTS: Passive cigarette smoking increased maximal hypertensive response to epinephrine in normotensive and 1K1C-atenolol treated rats and to felypressin only in 1K1C-atenolol treated rats; it also reduced epinephrine hypotensive response. Epinephrine increased heart rate in normotensive and hypertensive passive smokers or non-smoker rats. Comparing the two vasoconstrictors, epinephrine showed greater hypertensive response in normotensive smokers, 1K1C-atenolol treated smokers and non-smokers. However, in normotensive-nonsmoker rats, felypressin showed a greater and longer hypertensive effect. CONCLUSIONS: Our results suggest that passive cigarette smoking may reduce epinephrine vasodilation and increase hypertensive response when compared to felypressin. Therefore, felypressin may be safe for hypertensive patients to avoid tachycardia and atenolol interaction, but for normotensive and non-smoker patients, epinephrine may be safer than felypressin.

Passive Cigarette Smoking Impact on Blood Pressure Response to Epinephrine and Felypressin in 1K1C Hypertensive Rats Treated or not with Atenolol / Impacto do Tabagismo Passivo na Resposta Pressórica à Epinefrina e Felipressina em Ratos Hipertensos 1K1C Tratados ou não com Atenolol

Abstract Background: Cigarette smoking is usually associated with hypertension and may modify vasoconstrictor response. Objective: The present study aimed to analyze and compare the interaction of passive cigarette smoking and hypertension on epinephrine and felypressin blood pressure effects after intravascular injection. Method: 45-day male Wistar rats had the main left renal artery partially constricted and the right kidney removed (1K1C model). Rats were placed in the chamber for exposition to passive cigarette smoking (10 cigarettes) during 10 min (6 days a week). Hypertensive rats received atenolol (90 mg/kg/day) by gavage for two weeks. Hypotensive and hypertensive response, response duration and heart rate were recorded from direct blood pressure values. The significance level was 5%. Results: Passive cigarette smoking increased maximal hypertensive response to epinephrine in normotensive and 1K1C-atenolol treated rats and to felypressin only in 1K1C-atenolol treated rats; it also reduced epinephrine hypotensive response. Epinephrine increased heart rate in normotensive and hypertensive passive smokers or non-smoker rats. Comparing the two vasoconstrictors, epinephrine showed greater hypertensive response in normotensive smokers, 1K1C-atenolol treated smokers and non-smokers. However, in normotensive-nonsmoker rats, felypressin showed a greater and longer hypertensive effect. Conclusions: Our results suggest that passive cigarette smoking may reduce epinephrine vasodilation and increase hypertensive response when compared to felypressin. Therefore, felypressin may be safe for hypertensive patients to avoid tachycardia and atenolol interaction, but for normotensive and non-smoker patients, epinephrine may be safer than felypressin.

Resumo Fundamento: O tabagismo geralmente está associado à hipertensão e pode modificar a resposta vasoconstritora. Objetivo: O presente estudo teve como objetivo analisar e comparar a interação do tabagismo passivo e hipertensão sobre os efeitos da epinefrina e felipressina na pressão arterial após injeção intravascular. Métodos: Ratos Wistar machos de 45 dias tiveram a artéria renal principal esquerda parcialmente obstruída e o rim direito removido (modelo 1K1C). Os ratos foram colocados na câmara para exposição ao tabagismo passivo (10 cigarros) durante 10 minutos (6 dias por semana). Ratos hipertensos receberam atenolol (90 mg/kg/dia) por gavagem durante duas semanas. A resposta hipotensora e hipertensiva, a duração da resposta e a frequência cardíaca foram registradas a partir da medida dos valores diretos da pressão arterial. O nível de significância foi de 5%. Resultados: O tabagismo passivo aumentou a resposta hipertensiva máxima à epinefrina em ratos normotensos e ratos 1K1C tratados com atenolol e à felipressina apenas em ratos 1K1C tratados com atenolol; também reduziu a resposta hipotensiva à epinefrina. A epinefrina aumentou a frequência cardíaca em ratos fumantes passivos ou não-fumantes, normotensos e hipertensos. Comparando os dois vasoconstritores, a epinefrina apresentou maior resposta hipertensiva em fumantes normotensos, ratos 1K1C fumantes e não fumantes tratados com atenolol. No entanto, em ratos normotensos e não fumantes, a felipressina apresentou um efeito hipertensivo maior e mais prolongado. Conclusões: Nossos resultados sugerem que o tabagismo passivo pode reduzir a vasodilatação da epinefrina e aumentar a resposta hipertensiva quando comparado à felipressina. Portanto, a felipressina pode ser segura para pacientes hipertensos, com o objetivo de evitar a interação entre taquicardia e atenolol, mas para pacientes normotensos e não-fumantes, a epinefrina pode ser mais segura que a felipressina.

Increase in pulse pressure on administration of a dental local anesthetic solution, prilocaine hydrochloride with felypressin in male diabetic patients with coronary heart disease.

OBJECTIVES: This study aimed to evaluate pulse pressure fluctuation on dental local anesthetic administration in diabetic patients with and without coronary heart disease undergoing tooth extraction. MATERIALS AND METHODS: This retrospective study in diabetic patients undergoing tooth extraction included 33 patients with coronary heart disease (mean age 79.3 ± 7.4, 64% male) and 49 patients without coronary heart disease (mean age 78.6 ± 6.5, 29% male). The increase in pulse pressure before and after administration of local anesthetics was compared between diabetic patients with and without coronary heart disease. RESULTS: Pulse pressure was increased in male diabetic patients with coronary heart disease compared with those without coronary heart disease following administration of 3% prilocaine hydrochloride with felypressin 0.03 IU/mL (prilocaine) (15.6 ± 15.4 mmHg in those with coronary heart disease (n = 11) versus 4.3 ± 10.9 mmHg in those without coronary heart disease (n = 13), p = 0.03). CONCLUSIONS: Prilocaine administration increased pulse pressure in male diabetic patients with coronary heart disease compared with those without coronary heart disease. Further study is needed to reveal the mechanisms involved in the increase in pulse pressure. CLINICAL RELEVANCE: This is the first study of pulse pressure fluctuation in diabetic patients with and without coronary heart disease following administration of local anesthetics. Our findings can help guide the choice of local anesthetics and serve as a predictor of coronary vascular condition in diabetic patients during dental treatment.

Avaliação dos efeitos vasculares e expressão de mRNA de receptores de drogas vasoconstritoras em leito arterial mesentérico de ratos normotensos, diabéticos, hipertensos renais um-rim, um clip (1R-1C) e 1R-1C diabéticos / Vascular reactivity and vasoconstrictor drugs receptors RNAmexpression on mesenteric artery bed of normotensive, diabetic, 1K-1C hypertensive and 1K-1C hypertensive-diabetic rats

O presente trabalho teve como objetivo avaliar e comparar a reatividade vascular de agentes vasoconstritores presentes nas soluções anestésicas locais (Adrenalina - vasoconstrição e vasodilatação; Felipressina - vasoconstrição), nas doses de 80, 160, 320, 640 e 1280ng (adrenalina) ou 0,25; 0,5; 1; 2 e 4 x10-3UI (felipressina), em leito arterial mesentérico deratos normotensos, diabéticos, hipertensos renais um-rim, um-clip (1R-1C) e hipertensos1R-1C-diabéticos. E correlacionar tal reatividadecom expressão de RNAm dos receptores 1A e 2- adrenérgicos, V1A para vasopressina e AT1A, AT1Be AT2 para angiotensina II visando verificar se a hipertensão arterial e o diabetes mellitus provocam alteração em modelo indutivo e isogênico. Ratos Wistar pesando 110-160g, foram anestesiados com mistura de quetamina e xilazina (50+10mg/ml/kg de peso), tiveram seu abdômen aberto e receberam um clip de prata com abertura 0,25mm na artéria renal esquerda, removendo-se cirurgicamente o rim direito (ratos 1R-1C). Após 14 dias, receberam injeção subcutânea de estreptozotocina (50 e 60mg/kg de peso) para indução do diabetes mellitus sendo a glicemia testada pela veia caudal previamente aos experimentos (diabéticos). Após 30-42 dias da implantação do clip, todos os grupos foram novamente anestesiados e implantou-se cânula de polietileno (PE-50) na artéria carótida esquerda para registro direto da pressão arterial. Após registro da pressão os animais tiveram a artéria principal mesentérica exposta e canulada. O leito arterial mesentérico foi então isolado e colocado em banho com solução nutritiva de Krebs a 37ºC. O cateter foi conectado ao sistema de registro computadorizado (PowerLab®) utilizando software específico (Chart 5Pro ®). Analisaram-se: a pressão máxima (vasoconstrição) e mínima (vasodilatação), o tempo necessário para atingir esse valor, duração total da resposta, integral e integral sobre a linha de base. Os dados foram submetidos à análise de variância de medidas repetidas (ANOVA), seguida do teste de Holm-Sidak (distribuição normal) ou de Mann-Whitney (nãoparamétrico), quando apropriado, nível de significância de 5%. Todas as respostas máximas de vasoconstrição apresentaram comportamento dose-dependente, contudo, para os quatro grupos estudados, a resposta vasoconstritora para adrenalina foi significativamente superior à felipressina (p<0,05). Diabetes e hipertensão reduziram a resposta vasoconstritora da adrenalina e da felipressina, valores de integral sobre a linha de base, respectivamente para grupo controle, diabético, hipertenso e hipertenso-diabético: 2462±465; 1511±236; 2542± 5456 e 3749±819mmHg.s (p<0,05) para adrenalina e 3749 ± 708; 746 ± 103; 1647 ± 422; 1359 ± 591 mmHg.s (p<0,05) para felipressina. Tanto o diabetes quanto a hipertensão, associadas ou não, aumentaram significativamente o tempo para atingir a pressão máxima de vasoconstrição e a duração (p<0,05). As artérias mesentéricas de ratos diabéticos, hipertensos e diabéticos-hipertensos apresentaram expressão significativamente aumentada dos receptores 1Aadrenérgico, AT1B e AT2 para angiotensina II (p<0,05), enquanto receptor AT1A estava com a expressão aumentada apenas nos grupos diabéticos. A expressão do receptor 1A-adrenérgico é discrepante com os achados funcionais, o que pode ser justificado pela fase crônica da doença em que a PCR foi realizada. É possível correlacionar os dados obtidos com a menor atividade vasoconstritora da felipressina observada clinicamente. A maior sensibilidade às moléculas vasoconstritoras pode explicar a maior tendência de pacientes diabéticos desenvolverem hipertensão. A partir dos dados obtidos pode-se concluir que a adrenalina é o vasoconstritor mais potente que a felipressina e ambas as moléculas tem seus efeitos reduzidos em pacientes hipertensos e diabéticos, o que reforça a indicação de se utilizar anestésicos locais associados a vasoconstritores nestas populações.(AU)

The main goal of this study wasto evaluate and compare vasoconstrictor agents present in local anesthetic solutions (Epinephrine - vasoconstriction and vasodilation, Felypressin - vasoconstriction) vascular reactivity on mesenteric artery bed of normotensive, diabetic, renal hypertensive one-kidney-one-clip (1K1C) and hypertensive 1K1C diabetic rats. Dosagesstudied were 80, 160, 320, 640 and 1280ng (epinephrine) or 0,25; 0,5;1; 2 and 4 x 10-3UI (felypressin). Also, we aimed to correlate artery response with RNAm expression of 1A and 2-adrenoceptors, V1A vasopressin receptor and AT1A, AT1B e AT2 angiotensin receptors, in order to verify if arterial hypertension and diabetes can lead to alterations on a inductive and isogenic model. Wistar male rats weighing 110-160g were anaesthetized with a mixture of ketamine and xylazine (50+10mg/ml/kg), had their abdominal cavity opened and a silver clipwith 0.25-mm gap was implanted in the main left kidney artery, the right kidney was surgically removed (1K1C-rats). After 14 days, they received a subcutaneous injection of streptozotocin (50 and 60 mg/ml/kg) for inducing diabetes, whereas the glycemia was tested via the tail vein prior to surgery (diabetic rats). Around 30-42 after the clip was implanted, all the groups were anaesthetized again and a polyethylene (PE-50) cannula was implanted on the left carotid artery for direct arterial pressure register. After registering the pressure, the animals had their main mesenteric artery exposed and cannulated. The mesenteric artery bed was then isolated and transferred to a bath with Krebs nutritive solution at 37ºC. The catheter was connected to the computer register system (PowerLab®) using a specific software (Chart 5Pro ®). The following parameters were analyzed: maximum (vasoconstriction) and minimal pressure (vasodilating), the amount of time necessary to achieve this number, total duration of the reaction, integral and integral over baseline. The data was submitted to analysis of variance of repeated measures (ANOVA), followed by a Holm-Sidak (normal distribution) test or Mann Whitney (parametrics) test when suitable, with a significance level of 5%. All maximum vasoconstriction results presented dosage-dependant behavior, however, for the four groups tested, the vasoconstrictive result for epinephrine was significantly superior to felypressin (p<0,05). Diabetes and hypertension significantly reducedepinephrine and felypressin vasoconstrictor responses, integral above baseline, respectively, for control, diabetic, hypertensive and hypertensive-diabetic groups:2462±465; 1511±236; 2542± 5456 e 3749±819 mmHg.s (p<0.05, epinephrine) and 3749 ± 708; 746 ± 103; 1647 ± 422; 1359 ± 591 mmHg.s (p<0.05, felypressin). Both diabetes and hypertension, associated or not, significantly increased time necessary to achieve maximum vasoconstrictor response and its duration (p<0,05). Diabetic, hypertensive and hypertensive-diabetic mesenteric arteries presented 1A-adrenoceptor, AT1B and AT2 angiotensin II-receptor gene expression significantly increased when compared with control group (p<0,05), while AT1Areceptor presented this pattern only in diabetic groups.1A-adrenoceptor gene expression did not confirm functional data, probably due to chronic disease state in wich PCR was performed. A partir dos dados obtidos pode-se concluir que a adrenalina é o vasoconstritor mais potente que a felipressina e ambas as moléculas tem seus efeitos reduzidos em ratos hipertensos e diabéticos não tratados, o que reforça a indicação de se utilizar anestésicos locais associados a vasoconstritores nestas populações.Its possible to correlate our datawith reducedvasoconstrictor activity of felypressinin clinical use. Increased sensibility and receptor population for vasoconstrictor endogenous molecules could explain diabetic populations tendency to develop arterial hypertension. Our results suggest that epinephrine is more potent than felypressin and both vasoconstrictors presents reduced effects on diabetic and hypertensive patients, what reinforces vasoconstrictor associated with local anesthetic use in this population.(AU)

Comparison of epinephrine and felypressin pressure effects in 1K1C hypertensive rats treated or not with atenolol.

PURPOSE: Epinephrine is considered the gold standard vasoconstrictor for hypertensive patients, but few studies report felypressin's effects. The present study aimed to analyze and compare the effects of these two vasoconstrictors, injected by the intravenous route, on the arterial pressure of normotensive, hypertensive and atenolol-treated hypertensive rats. METHOD: The hypertension model was one-kidney-one-clip (1K1C): the main left renal artery was partially constricted and the right kidney was surgically removed in 45-day-old male Wistar rats. 1K1C hypertensive rats received atenolol (90 mg/kg/day) by gavage for 2 weeks. 28-35 days after hypertension induction, a catheter was inserted into the left carotid artery to record direct blood pressure values. The following parameters were recorded: minimal hypotensive response, maximal hypertensive response, response duration and heart rate. RESULTS: Epinephrine, but not felypressin, exerted an important hypotensive action; non-treated hypertensive rats showed more pronounced vasodilation. Treated and non-treated rats showed hypertensive responses of the same magnitudes in all groups; 1K1C atenolol rats showed reduced hypertensive responses to both vasoconstrictors. Felypressin's response duration was longer than that of epinephrine in all groups. Epinephrine increased heart rate while felypressin reduced this parameter only in the normotensive group. CONCLUSIONS: Our results suggest that felypressin has equipotent pressure responses when compared with epinephrine, showing a greater extent of action. Atenolol's reduction of hypertensive effects surprisingly suggests that atenolol ß-blockade may also be important for felypressin's cardiovascular effect, as is widely known for epinephrine. Our data suggest that felypressin is safe for hypertensive subjects, in particular those receiving atenolol.

Holter ECG assessment of the effects of three different local anesthetic solutions on cardiovascular system in the sedated dental patients with coronary artery disease.

OBJECTIVE: The purpose of the study is to compare the effects of lidocaine alone, epinephrine-combined lidocaine and prilocaine with octapressin on the cardiovascular system during minor oral surgery of sedated cardiac dental patients under local anesthesia. METHODS: Connected to a Holter electrocardiogram (ECG) monitor for a total of 5 hours starting 1 hour before the procedure, twenty patients with high risk of coronary artery disease were included in the prospective cohort study. All the patients had three operations at 3 different appointments with at least one-week intervals and each operation was performed under local anesthesia achieved by 3.6 mL of 3% prilocaine with octapressin, 3.6 mL of 2% lidocaine with 1:80.000 epinephrine and 3.6 mL of 2% lidocaine without a vasoconstrictor. Data of the Holter ECG device assessed at the end of every hour and evaluated statistically. Repeated measures ANOVA, Friedman test, and Wilcoxon signed ranks test were used to perform statistical analysis. RESULTS: Heart-rate showed significant differences between lidocaine with epinephrine and pure lidocaine in an hour following the injection (p<0.05 for all). Cardiac rhythm showed significant differences between prilocaine with octapressin and pure lidocaine at the second hour after its administration (p<0.05 for all). There were no significant differences between 3 local anesthetics in terms of ST segment deviation. CONCLUSION: In minor oral operation on the sedated patients with cardiac disease, the use of 3.6 mL or a less amount of local anesthetic injection containing epinephrine appears to be a predictable and safe method.

Estudo dos efeitos da injeção intravascular de drogas vasoconstritoras associadas a anestésicos locais, sobre a pressão arterial de ratos hipertensos renais e fumantes passivos / Study of the effects of the intravascular injection of vasoconstrictors drugs present in local anesthetics on the arterial pressure of renal hypertensive and passive smoker rats

O anestésico local é o medicamento mais utilizado na Odontologia e sua associação com vasoconstrictores aumenta a duração da anestesia, diminuindo seus efeitos sistêmicos. A hipertensão e o tabagismo são freqüentes na população, sendo responsáveis por complicações sistêmicas. A felipressina, por não interferir com receptores simpáticos, poderia ser um vasoconstrictor indicado para pacientes hipertensos. O objetivo deste trabalho foi estudar a reatividade cardiovascular de animais simultaneamente hipertensos e fumantes passivos aos agentes vasoconstritores associados aos anestésicos locais, verificando também o efeito do tratamento com atenolol. Foram utilizados ratos Wistar machos, divididos em 5 grupos: 1) normotensos não fumantes; 2) normotensos fumantes passivos; 3) hipertensos não fumantes; 4) hipertensos fumantes passivos; 5) hipertensos fumantes passivos tratados com atenolol. A hipertensão renal foi induzida pela remoção do rim direito e instalação de clip de prata (abertura 0,25mm) na artéria renal esquerda, após anestesia com quetamina e xilazina. Os ratos fumantes passivos foram colocados diariamente por 10 minutos, durante 28 dias, em caixa de madeira de 30cmX25cmX15cm dividida em dois compartimentos. Em um deles, eram acesos 10 cigarros e no outro ficavam os animais. A tampa da caixa era fechada e um sistema de ventilação lançava fumaça dos cigarros para o compartimento dos ratos, num fluxo de 10l/min. Após medida indireta da pressão arterial, 14 dias após a cirurgia, o grupo tratado com atenolol foi medicado durante 14 dias seguintes (90 mg/Kg) por gavage. No 28o dia, todos receberam catéter de polietileno na artéria carótida esquerda (para medida de pressão) e outro na veia jugular direita (para injeção de drogas). Para os 5 grupos foram utilizadas: adrenalina (80, 160, 320, 640 e 1280ng) e felipressina (0,125, 0,25, 0,5, 1, 2 e 3 x 10-3UI). O catéter arterial era conectado a transdutor de pressão e o registro realizado por...

The local anesthetic is the most common drug in dentistry and the associated vasoconstrictors increase the duration of anesthesia, decreasing its systemic effects. Hypertension and smoking are problems commonly found in the general population, being responsible for systemic complications. Felypressin, a vasoconstrictor that does not interact with sympathetic receptors, could be indicated to hypertensive patients. This study investigated the cardiovascular reactivity of hypertensive and passive smoker animals under atenolol treatment to epinephrine and felypressin. Male wistar rats were divided into five groups: 1) normotensive and non-smokers, 2) normotensive and passive smokers, 3) hypertensive and non-smokers, 4) hypertensive and passive smokers; 5) hypertensive, passive smokers and treated with atenolol. Renal hypertension was induced by removal of the right kidney and installation of a silver clip (with 0.25-mm opening) in the left renal artery, after anesthesia with ketamine and xylazine. The passive smoker rats were placed, 10 minutes per day, during 28 days in a 30cmX25cmX15cm wood box divided into two compartments. Ten cigarettes were lit in one compartment, and the rats were placed in the other. The box lid was closed and a ventilation system threw the cigarette smoke to the rat compartment. After indirect measurement of blood pressure, 14 days after the surgery, the group of rats treated with atenolol was medicated during the following fourteen days (90 mg/kg) by gavage. On the 28th day, a polyethylene catheter was inserted into the left carotid artery (for direct blood pressure measurements) and into the right jugular vein (for drug injection). The groups received epinephrine (80, 160, 320, 640 and 1280ng) or felypressin (0.125, 0.25, 0.5, 1, 2 and 3 x 10-3UI). The arterial catheter was connected to a pressure transducer and recording was made by a specific computer software. The following parameters were analyzed for all...

Dopamine D1-like receptors play only a minor role in the increase of striatal dopamine induced by striatally applied SKF38393.

We studied the effects of the intra-striatal infusion of Ca(2+)-free medium on the intra-striatal injection of 0.5 µg SKF38393-induced striatal dopamine efflux. It is discussed that the amount of extracellular, striatal dopamine seen after striatally applied SKF38393, is the overall result of the (a) release of dopamine from the alpha-methyl-para-tyrosine-sensitive and Ca(2+)-insensitive pool of newly synthesised dopamine, (b) release of dopamine from the reserpine-sensitive and Ca(2+)-sensitive storage pool, (c) inhibition of uptake of dopamine into nerve terminals and glial cells, and (d) facilitation respectively of the inhibition of uptake into blood vessels: dopamine D1-like receptors play only a very limited role in these processes. The present study underlines our previous notion that the effects of SKF38393 cannot simply be ascribed to the dopamine D1-like receptor stimulation (Saigusa et al., 2009): in fact, the present study clearly reveals that SKF38393 is not at all selective in that respect.

Estudo dos efeitos da injeção intravascular de drogas vasoconstrictoras, presentes nas soluções anestésicas locais, sobre a pressão arterial de ratos normotensos, hipertensos renais um-rim, um clip (1R-1C) e 1R-1C tratados com atenolol / Pressure effects of vasoconstrictors in normotensive, 1K-1C hypertensive and 1K-1C rats treated with atenolol

O presente trabalho teve como objetivo analisar e comparar o efeito de agentes vasoconstrictores presentes nas soluções anestésicas locais, injetados por via intravenosa nas doses de 80, 160, 320, 640 e 1280 ng (adrenalina) ou 0.5, 1, 2, 3 e 4 UI (felipressina), sobre a pressão arterial de ratos, hipertensos renais um-rim, um clip (1R-1C) e 1R-1C tratados com atenolol, comparando com animais nomotensos de mesmo peso e lote. Ratos Wistar machos pesando 150g, foram anestesiados com mistura de igual quantidade de quetamina e xilazina (1mL da mistura/kg), tiveram seu abdômen aberto e receberam um clip de prata com abertura 0,25mm na artéria renal esquerda, removendo-se cirurgicamente o rim direito (ratos 1R-1C). Alguns desses animais, depois de 14 dias, tiveram sua pressão sistólica indireta registrada pela pletsmografia de cauda e começaram a receber tratamento com atenolol (90 mg/kg/dia) por gavage (1R-1C tratados). Após 28 dias da implantação do clip, todos os grupos foram novamente anestesiados e implantaram-se cânulas de polietileno (PE-50) na artéria carótida esquerda e veia jugular direita, para registro direto da pressão arterial e injeção de drogas, respectivamente. Animais de mesmo lote e peso serviram como controle (normotensos). O catéter arterial foi então conectadas ao sistema de registro computadorizado (PowerLab®) utilizando software específico (Chart 5Pro ®). A pressão arterial (PA) e frequência cardíaca (FC) registradas durante os primeiros 5 minutos, foram consideradas como valores basais. Analisaram-se: a menor resposta hipotensora, maior resposta hipertensora, freqüência cardíaca média e duração da resposta, nos três grupos de animais, para cada dose injetada dos dois vasoconstrictores. Os dados foram submetidos à análise de variância de medidas repetidas (ANOVA), seguida do teste de Holm-Sidak ou de Mann-Whitney, quando apropriado, a um nível de significância de 5%. A felipressina, ao contrário da adrenalina, não apresentou ação...

The present study was designed to analyze and compare the effects of some vasoconstrictors, injected by intravenous route in the doses of 80, 160, 320, 640 and 1280 ng (epinephrine) or 0.5, 1, 2, 3 and 4 IU (felypressin) upon the arterial pressure of normotensive, 1K-1C hypertensive and 1K-1C rats treated with atenolol. Male Wistar rats weighting 150g were anesthetized with a mixture of equal proportion of ketamine and xylazine by intraperitonial injection (1mL/kg) and 1K1C hypertension was surgically induced by means of partial constriction of the main left renal artery with a silver clip with a 0.25-mm gap. The right kidney was surgically removed. Fourteen days after surgical procedures arterial pressure (AP) was indirectly measured (tail cuff method) to monitor the development of hypertension. Only 1K1C rats with AP more than 150mm Hg were included in the protocol and received by gavage (1mL/d), for the next 14 days, atenolol (90 mg/kg/day). The treatments were carried out always between 8 and 9 AM. Four weeks after the surgical procedure all rats were anesthetized again with the same mixture and a catheter (PE50) was inserted into the left carotid artery and right jugular vein, respectively to obtain a AP register and to inject drugs. The arterial catheter was then connect to the transducer and to computer register system (PowerLab®) using a Chart 5 Pro® software. The AP and heart rate (HR) registered in the first five minutes were considered basal values. The following parameters were registered: minimal hypotensive response, maximal hypertensive response, mean HR and response lenght (duration), in all animals groups, to every injected dose of epinephrine and felypressin. The data were analyzed by two ways repeated measures ANOVA followed by Holm-Sidak or Mann-Whitney test, when appropriated. The significance level was 5%. Epinephrine, but not felypressin, presents some hypotensive action with the lowest doses. However, both of them present...

Cardiovascular effects of felypressin.

Cardiovascular effects of felypressin (FEL) were studied in Wistar rats. Heart rate and mean arterial pressure measurements were taken in awake rats treated with vasopressin (AVP), FEL, or epinephrine (EPI). Each group received either an intravenous (IV) or an intracerebroventricular V1 receptor antagonist, saline, area postrema removal, or sham surgery. Analysis of variance and Student-Newman-Keuls (P < .05) were applied. Felypressin and AVP induced a pressor effect, and bradycardia was inhibited by IV V1 antagonist. Intracerebroventricular V1 antagonist and area postrema removal enhanced their pressor effects. Epinephrine induced a higher pressor effect and a similar bradycardia that was not affected by the treatments. It was concluded that FEL depends on V1 receptors to induce pressor and bradycardic effects, and that it produces a high relationship between bradycardia and mean arterial pressure variation depending on area postrema and central V1 receptors. These effects are potentially less harmful to the cardiovascular system than the effects of EPI.

Immunological modulation by lidocaine-epinephrine and prilocaine-felypressin on the functions related to natural immunity in neutrophils and macrophages.

There is accumulating evidence that local anesthetics have immunological properties in addition to their direct anesthetic activity. Because local anesthetics are often used together with blood vessel contraction drugs, such as epinephrine and felypressin in the clinical setting, we have examined possible abilities of both local anesthetic alone including lidocaine, mepivacaine, procaine, prilocaine and tetracaine, and local anesthetics with blood vessel contraction drugs including lidocaine with epinephrine and prilocaine with felypressin on the functions related to natural immunity in neutrophils and macrophages. In contrast, lidocaine, mepivacaine, procaine, prilocaine and tetracaine all inhibited adhesion, chemotaxis, phagocytosis, and the production of superoxide anion and hydrogen peroxide by neutrophils and macrophages. Lidocaine with epinephrine and prilocaine with felypressin were effective in significantly inhibiting adhesion, chemotaxis, phagocytosis, and the production of hydrogen peroxide by neutrophils and macrophages. Interestingly, lidocaine with epinephrine potentiated the production of superoxide anion, whereas prilocaine with felypressine inhibited the production, irrespective of cells. In addition, epinephrine potentiated the production of superoxide anion, whereas epinephrine inhibited the production of hydrogen peroxide as well as lidocaine with epinephrine. This potentiation by epinephrine was not prevented by adrenergic antagonists. Furthermore, superoxide dismutase potentiated the production of hydrogen peroxide, which was in part prevented by epinephrine. These results suggest that local anesthetics may inhibit the functions related to natural immunity in neutrophils and macrophages. In addition, lidocaine with epinephrine evidently differs from prilocaine with felypressine regarding the molecular mechanisms underlying the modulation of superoxide anion production by neutrophils and macrophages.

Effects of local injection of prilocaine-felypressin on the myocardial oxygen balance in dogs.

The authors investigated the effects of felypressin (Fely), a non-adrenergic vasoconstrictor, used together with prilocaine on myocardial oxygen balance. Six open-chest dogs were studied under urethane and alpha-chloralose anesthesia. Systolic arterial pressure, diastolic arterial pressure, mean pulmonary arterial pressure and pulmonary capillary wedge pressure, heart rate, coronary blood flow (CBF), internal and external myocardial oxygen tension (int- or ext-PmO2), and cardiac output were observed. Three doses of Citanest-Octapressin, which contains 3% prilocaine and 0.03 IU ml(-1) Fely (Pri-Fely) - 0.09, 0.18, and 0.3 ml kg(-1)- were injected into the tongue. Observations were performed up to 60 min after the injection. The CBF and int-PmO2 was reduced following the injection of each of the three doses of Pri-Fely. There were negative correlations between the Pri-Fely dose per body weight and the maximum reductions in CBF (r = -0.52, P < 0.05), in int-PmO2 (r = -0.78, P < 0.05), and in ext-PmO2 (r = -0.55, P < 0.05), respectively [corrected]. These results suggest that an administration of Fely at doses more than 2.7-5.4 mIU kg(-1) (3-6 cartridges of Pri-Fely) may induce an imbalance between the oxygen supply and demand in myocardial tissues of patients with cardiovascular diseases.

Verification of protector effect of the norepinephrine and felypressin upon the cardiovascular system under action of the lidocaine hydrochloride and prilocaine hydrochloride in anesthetized rats.

Vasoconstrictor substances, as norepinephrine and epinephrine, were mixtured to local anesthetics to decrease their toxic effects and to prolong the depth of the anesthesia. However, these catecholamines produce systolic and diastolic hypertension. The effects of felypressin, a synthetic vasoconstrictor, upon arterial blood pressure and heart are lesser than those of norepinephrine or epinephrine, but due to its effects like oxytocin these catecholamines are yet the most used vasoconstrictors in association with lidocaine or another anesthetic salt. These vasoconstrictors are contraindicated for some physician, mainly for cardiac patients. But, are the catecholamines or is the salt the most dangerous components of the local anesthetic? The effects of the salt and catecholamines are opposite, but which of these exercises their effects first when inside blood vessel? Singi et al. [Pharmacol. Res. 44 (2001)] demonstrated that the first effect is always of the salt and that norepinephrine promotes protector effects upon guinea-pig isolated heart against lidocaine action. But, is this true for in vivo animals? The present study was performed with the aiming to answer this question and to verify if felypressin can induce the same effect of the norepinephrine. Fourteen Rattus norvegicus albinus, weighing 350g on average, were used. After being anesthetized with sodic thiopental, they were tracheostomizeds and one jugular and one carotid were cannuled for application of substances and to record the blood arterial pressure, respectively. The ECG was gotten through electrodes located in the front and back paws of the animals. The animals were separated in two groups, each one with seven rats. The lidocaine hydrochloride 2% in the doses of 600 microg and 3% in the doses of 900 microg acted on the cardiovascular system reducing the arterial pressure and modifying the electrocardiogram, while the prilocaine hydrochloride, in the same doses, also reduced the arterial pressure, but did not modify the electrocardiogram. When norepinephrine was associated to lidocaine 3% hydrochloride, it was possible to observe that this salt always exercised its effect first and a protective effect against the fall of pressure produced for the lidocaine. The same protective effect did not occur when felypressin was associated with prilocaine hydrochloride 3%.

Effects of vasoconstrictors used in local anesthesia upon isolated rat heart.

Some reports have demonstrated that the vasoconstrictor effect of catecholamines may be amplified by felypressin. Thus, the association of felypressin and epinephrine with local anesthetics may be indicated to achieve more effective vasoconstrictor actions with fewer collateral effects from both the anesthetic and the vasoconstrictor. This study aimed to characterize the effects of felypressin and associations of felypressin and epinephrine upon the contraction force and the cardiac rate of the isolated rat heart (n=20) perfused by Langendorff's method. The following solutions were utilized: epinephrine, 4.5nmol; felypressin at doses of 0.5, 1.6 and 5.5IU and associations of felypressin at the same doses with 4.5nmol epinephrine. Contraction force and cardiac rate were recorded at 15, 30, 60 and 120s after the administration of each solution, and before the administration, a control measurement (time 0) was taken. Felypressin at a dose of 0.5IU did not have any effect upon the heart, but the doses of 1.6 and 5.5IU decreases the cardiac rate and the contraction force, respectively. Epinephrine and all of the felypressin and epinephrine associations produced increases in these parameters. The association of 0.5IU felypressin and 4.5nmol epinephrine promoted a similar effect to that of epinephrine (4.5nmol) alone up to 120s. The association of 1.6IU felypressin and 4.5nmol epinephrine increases the contraction force up to 60s. After the administration of the association of 5.5IU felypressin and 4.5nmol epinephrine this increase was observed up to just 30s. The cardiac rate values obtained after the administration of the associations of 1.6 and 5.5IU felypressin with 4.5nmol epinephrine were lower than those seen after the use of 4.5nmol epinephrine alone. In this study it was observed that the association of felypressin with epinephrine decreased the effects of epinephrine which increases the cardiac rate and the contraction force in the isolated rat heart.

Estudo comparativo do uso do cloridrato de prilocaína a 3 por cento com felipressina a 0, 03 UI e do cloridrato de lidocaína a 2 por cento com adrenalina a 1: 100000 em pacientes hipertensos / Comparative study of the use of the prilocaine chloridrate at 3 per cent with felipressin at 0, 03UI and the lidocaine chloridrate at 2 per cent with epinephrine at 1: 100000 in the blood pressure of hypertensive patients

Este trabalho tem como objetivo avaliar comparativamente os efeitos da soluçäo anestésica de cloridrato de prilocaína a 3 por cento, com felipressina a 0, 03 UI, com a soluçäo anestésica de cloridrato de lidocaína a 2 por cento, com adrenalina a 1: 100000, sobre a a pressäo arterial (PA) de pacientes hipertensos submetidos a exodontias convencionais

The influence of two different dental local anaesthetic solutions on the haemodynamic responses of children undergoing restorative dentistry: a randomised, single-blind, split-mouth study.

OBJECTIVES: This investigation was designed to study the haemodynamic effects of two different local anaesthetic solutions during restorative dental treatment in children. DESIGN: A randomised, single-blind, split-mouth cross-over design was employed using children undergoing bilaterally similar restorative treatments over two visits. SETTING: The study was performed in a dental hospital paediatric dentistry department. METHODS: Ten children participated. At one visit the local anaesthetic was 2% lidocaine (lignocaine) with 1:80,000 epinephrine (adrenaline); at the other the anaesthetic was 3% prilocaine with 0.03IU/ml felypressin. Local anaesthetic was administered at a dose of 0.5 ml/10 kg body weight. Blood pressure and heart rate were measured before and during treatment with an automatic blood pressure recorder. Data were analysed by ANOVA and Student's paired t test. RESULTS: Significant differences between treatments in diastolic blood pressure (F = 2.37; P = 0.05) and heart rate (F = 2.98; P< 0.02) were noted. The heart rate increased ten minutes following the injection of the epinephrine-containing solution. The diastolic blood pressure fell 20 minutes after injection of lidocaine with epinephrine. CONCLUSION: The choice of local anaesthetic solution influences the haemodynamic response during restorative treatment in children.

Differentiation by in vitro treatment of lidocaine-epinephrine and prilocaine-felypressine in neutrophils.

Neutrophils are often the first cells of the immune system to encounter an invader, such as bacteria and fungi. Lidocaine-epinephrine induced transient potentiation of the production of superoxide anion, while prilocaine-felypressine induced persistent inhibition of the production in neutrophils. Moreover, lidocaine-epinephrine inhibited the production of hydrogen peroxide in spite that it potentiated the production of superoxide anion, while prilocaine-felypressine inhibited the production of hydrogen peroxide as well as superoxide anion. By contrast, lidocaine-epinephrine and prilocaine-felypressine are both effective in significantly inhibiting adhesion and phagocytosis. Using flow cytometric analysis, both local anesthetics were found to be effective in inhibiting the expression of Mac-1 (CD11b/CD18) in neutrophils. These results suggest that lidocaine-epinephrine and prilocaine-felypressine differentially modulate the production of superoxide anion, and could similarly inhibit adhesion, phagocytosis, and the production of hydrogen peroxide by neutrophils.

Comparison of the effect of lidocaine-epinephrine and prilocaine-felypressine to alter macrophage functions.

In vitro treatment of macrophages with lidocaine-epinephrine or prilocaine-felypressine resulted in inhibition of their adhesion, chemotaxis and phagocytosis. However, prilocaine-felypressine was a much more potent inhibitor of adhesion and phagocytosis than lidocaine-epinephrine. On the other hand, lidocaine-epinephrine induced transient potentiation of superoxide anion production by macrophages, while prilocaine-felypressine consistently inhibited this. Moreover, lidocaine-epinephrine and prilocaine-felypressine both inhibited the production of hydrogen peroxide. In contrast, epinephrine strongly potentiated superoxide anion production, while markedly inhibiting hydrogen peroxide production. This potentiation by epinephrine was not prevented by adrenergic antagonists. In addition, superoxide dismutase potentiated the production of hydrogen peroxide, which was in part prevented by epinephrine. These results suggest that lidocaine-epinephrine and prilocaine-felypressine inhibit adhesion, chemotaxis, phagocytosis, and the production of hydrogen peroxide by macrophages. In addition, lidocaine-epinephrine evidently differs from prilocaine-felypressine regarding the molecular mechanisms underlying the modulation of superoxide anion production by macrophages.