Efeito do Diterpeno Manool sobre a Pressão Arterial e Reatividade Vascular em Ratos Normotensos e Hipertensos / Effect of Diterpene Manool on the Arterial Blood Pressure and Vascular Reactivity in Normotensive and Hypertensive Rats

Resumo Fundamento: Diversos estudos têm mostrado que as classes de diterpenos exercem efeito significativo no sistema cardiovascular. Os diterpenos, em particular, estão entre os principais compostos associados às propriedades cardiovasculares, como a propriedade vasorrelaxante, inotrópica, diurética e a atividade hipotensora. Embora o mecanismo de vasorrelaxamento do manool seja visível, seu efeito sobre a pressão arterial (PA) ainda é desconhecido. Objetivo: Avaliar o efeito hipotensor in vivo do manool e verificar o efeito de vasorrelaxamento ex vivo em anéis aórticos de ratos. Métodos: Os animais foram divididos aleatoriamente em dois grupos: normotensos e hipertensos. O grupo normotenso foi submetido à cirurgia sham e adotou-se o modelo 2R1C para o grupo hipertenso. Realizou-se monitoramento invasivo da PA para testes com manool em diferentes doses (10, 20 e 40 mg/kg). Foram obtidas curvas de concentração-resposta para o manool nos anéis aórticos, com endotélio pré-contraído com fenilefrina (Phe) após incubação com Nω-nitro-L-arginina metil éster (L-NAME) ou oxadiazolo[4,3-a]quinoxalina-1-ona (ODQ). Os níveis plasmáticos de óxido nítrico (NOx) foram medidos por ensaio de quimioluminescência. Resultados: Após a administração de manool, a PA se reduziu nos grupos normotenso e hipertenso, e esse efeito foi inibido pelo L-NAME em animais hipertensos apenas na dose de 10 mg/kg. O manool ex vivo promoveu vasorrelaxamento, inibido pela incubação de L-NAME e ODQ ou remoção do endotélio. Os níveis plasmáticos de NOx aumentaram no grupo hipertenso após a administração de manool. O manool induz o relaxamento vascular dependente do endotélio na aorta de ratos, mediado pela via de sinalização NO/cGMP e redução da PA, e também pelo aumento plasmático de NOx. Esses efeitos combinados podem estar envolvidos na modulação da resistência periférica, contribuindo para o efeito anti-hipertensivo do diterpeno. Conclusão: Esses efeitos em conjunto podem estar envolvidos na modulação da resistência periférica, contribuindo para o efeito anti-hipertensivo do diterpeno.

Abstract Background: Many studies have shown that the diterpenoid classes exert a significant effect on the cardiovascular system. Diterpenes, in particular, are among the main compound links to cardiovascular properties such as vasorelaxant, inotropic, diuretic and hypotensive activity. While the manool vasorelaxation mechanism is visible, its effect on blood pressure (BP) is still unknown. Objective: To evaluate the in vivo hypotensive effect of manool and check the ex vivo vasorelaxation effect in rat aortic rings. Methods: The animals were divided randomly into two groups: normotensive and hypertensive. The normotensive group was sham-operated, and the 2K1C model was adopted for the hypertensive group. Invasive BP monitoring was performed for manool tests at different doses (10, 20 and 40 mg/kg). Concentration-response curves for manool were obtained in the aorta rings, with endothelium, pre-contracted with phenylephrine (Phe) after incubation with Nω-nitro-L-arginine methyl ester(L-NAME) or oxadiazole [4,3-a]quinoxalin-1-one (ODQ). Nitric oxide (NOx) plasma levels were measured by chemiluminescence assay. Results: After manool administration, BP was reduced in normotensive and hypertensive groups, and this effect was inhibited by L-NAME in hypertensive animals only in 10 mg/kg dose. Ex vivo manool promoted vasorelaxation, which was inhibited by L-NAME and ODQ incubation or endothelium removal. NOx plasma levels increased in the hypertensive group after manool administration. Manool elicits endothelium-dependent vascular relaxation in rat aorta mediated by the NO/cGMP signaling pathway and BP reduction, also by NOx plasma increase. These combined effects could be involved in modulating peripheral resistance, contributing to the antihypertensive effect of diterpene. Conclusion: These effects together could be involved in modulating peripheral resistance, contributing to the antihypertensive effect of diterpene.

Effect of rosmarinic acid on the arterial blood pressure in normotensive and hypertensive rats: Role of ACE.

BACKGROUND: In recent years, it has been demonstrated the inhibitory effect of some plant species on the angiotensin-converting enzyme and rosmarinic acid is a prominent constituent of these species. HYPOTHESIS/PURPOSE: This study was carried out to verify the effect of rosmarinic acid on blood pressure through inhibitory activity on angiotensin-converting enzyme in rats. STUDY DESIGN: The arterial hypertension was promoted using 2-kidneys 1-clip model in rats. The potential inhibitory rosmarinic acid effect on angiotensin-converting enzyme activity was compared with captopril actions by analyzing in vivo blood pressure dose-response curves to angiotensin I and bradykinin. The in vitro plasma angiotensin-converting enzyme activity was measured by fluorimetry using the substrate Abz-FRK(Dnp)P-OH substrate. In addition, dosages of nitrite/nítrate analysis were carried out. RESULTS: (1) rosmarinic acid caused systolic blood pressure dose-dependent decrease in hypertensive rats; (2) The angiotensin I dose-response curves demonstrated that rosmarinic acid promotes minor changes in systolic blood pressure only in the hypertensive group; (3) The bradykinin dose-response curves showed that both rosmarinic acid and captopril promoted a systolic blood pressure reduction, but only the captopril effect was significant; (4) The angiotensin-converting enzyme activity in rat lung tissue was inhibited by the rosmarinic acid in a dose dependent manner; (5) The analysis of nitrite/nítrate plasma concentrations showed no significant difference among the experimental groups. CONCLUSION: The rosmarinic acid is effective in reducing blood pressure, selectively, only in hypertensive animals. The rosmarinic acid (173µM) promoted almost a 98.96% reduction on angiotensin-converting enzyme activity.

Is rosmarinic acid underestimated as an experimental cardiovascular drug?

PURPOSE: The rationale of the present review is to analize the activity of Rosmarinus officinalis in the the cardiovascular system METHODS: A MEDLINE database search (from January 1970 to December 2011) using only rosmarinic acid as searched term. RESULTS: The references search revealed 509 references about rosmarinic acid in 40 years (the first reference is from 1970). There is a powerful prevalence of antioxidant and cancer studies. Other diseases are few cited, as inflammation, brain (Alzheimer and Parkinson disease) and, memory; allergy; diabetes; atherosclerosis, and; hypertension. It is necessary to consider the complete absence of studies on coronary artery disease, myocardial ischemia, heart failure or ischemia/reperfusion injury. CONCLUSION: Rosmarinic acid is underestimated as an experimental cardiovascular drug and deserves more attention.

Does rosmarinic acid underestimate as an experimental cardiovascular drug? / Seria o ácido rosmarínico subestimado como droga cardiovascular experimental?

PURPOSE: The rationale of the present review is to analize the activity of Rosmarinus officinalis in the the cardiovascular system METHODS: A MEDLINE database search (from January 1970 to December 2011) using only rosmarinic acid as searched term. RESULTS: The references search revealed 509 references about rosmarinic acid in 40 years (the first reference is from 1970). There is a powerful prevalence of antioxidant and cancer studies. Other diseases are few cited, as inflammation, brain (Alzheimer and Parkinson disease) and, memory; allergy; diabetes; atherosclerosis, and; hypertension. It is necessary to consider the complete absence of studies on coronary artery disease, myocardial ischemia, heart failure or ischemia/reperfusion injury. CONCLUSION: Rosmarinic acid is underestimated as an experimental cardiovascular drug and deserves more attention.

OBJETIVO: A justificativa da revisão é analisar a atividade de Rosmarinus officinalis no sistema cardiovascular MÉTODOS: Uma busca de banco de dados MEDLINE (de janeiro de 1970 a dezembro de 2011), utilizando apenas o ácido rosmarínico como termo pesquisado. RESULTADOS: A busca referências revelou 509 referências sobre o ácido rosmarínico em 40 anos (a primeira referência é de 1970). Há uma prevalência poderoso antioxidante e estudos do câncer. Outras doenças são citados alguns, como o cérebro, inflamação (de Alzheimer e doença de Parkinson) e, a memória, hipertensão, alergia, diabetes, aterosclerose, e. É necessário ter em conta a ausência completa de estudos sobre a doença de artéria coronária, isquemia do miocárdio, insuficiência cardíaca ou isquemia / lesão de reperfusão. CONCLUSÃO: O ácido rosmarínico é subestimado como uma droga experimental cardiovascular e merece mais atenção.