betadex and Hypertension

Farnesol (FAR) is a sesquiterpene alcohol with a range of reported biological effects including cardioprotective, antioxidant and antiarrhythmic properties. However, due to its volatility, the use of drug incorporation systems, such as cyclodextrins, have been proposed to improve its pharmacological properties. Thus, the aim of this study was to evaluate and characterize the cardiovascular effects of FAR alone, and to investigate the antihypertensive effects of FAR complexed with β-cyclodextrin (βCD) in rats. Mean arterial pressure (MAP) and heart rate (HR) were measured before and after intravenous administration of FAR (0,5; 2,5; 5 and 7,5 mg/kg) in normotensive rats, and after oral acute administration (200 mg/kg) of FAR and FAR/βCD complex in NG-nitro-L-arginine-methyl-ester (L-NAME) hypertensive rats. In normotensive animals, FAR induced dose-dependent hypotension associated with bradycardia. These effects were not affected by pre-treatment with L-NAME or indomethacin (INDO), but were partially attenuated by atropine. Pre-treatment with hexamethonium (HEXA) only affected hypotension. In the hypertensive rats, FAR/βCD potentialized the antihypertensive effect when compared to FAR alone. Molecular docking experiments demonstrated for the first time that FAR has affinity to bind to the M

Topics: Animals; Arterial Pressure; beta-Cyclodextrins; Blood Pressure; Bradycardia; Cardiovascular Agents; Dose-Response Relationship, Drug; Enzyme Inhibitors; Farnesol; Heart Rate; Hypertension; Male; Molecular Docking Simulation; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Wistar

The blood-brain barrier (BBB) permeability primarily increases in cerebral venules during acute hypertension. Methyl-β-cyclodextrin (MβCD), a cholesterol-depleting agent, decreases the expression of caveolins disrupting caveolar structures. We aimed to determine the effects of MβCD on the BBB permeability of angiotensin (ANG) II-induced hypertensive rats. Three minutes after MβCD administration (5 mg/kg), acute hypertension was induced by ANG II (60 µg/kg). Evans blue (EB) and horseradish peroxidase (HRP) tracers were used to assess BBB permeability. Immunohistochemistry for caveolin (Cav)-1 and tight junction protein claudin-5 was performed. EB dye content significantly increased in both cerebral cortices and left hippocampus in MβCD (P < 0.05), right cerebral cortex and both hippocampi in ANG II (P < 0.05; P < 0.01), and both cerebral cortices and hippocampi in MβCD plus ANG II groups compared with controls (P < 0.05; P < 0.01). A significant decrease in claudin-5 immunostaining intensity was observed in animals treated with MβCD compared with controls (P < 0.05). Cav-1 immunostaining intensity increased in ANG II group (P < 0.05). Ultrastructurally, HRP reaction products were observed in endothelial cells of the microvessels in the hippocampus region in MβCD group while the tracer was mainly localized in astrocytes and neurons in ANG II, and MβCD plus ANG II groups. The endothelial cells of the venules in the cerebral cortex of the animals in the latter experimental groups also showed an abundance of caveolar vesicles devoid of HRP reaction products. Our results revealed that MβCD did not provide overall protective effects on BBB integrity in acute hypertension and even led to BBB disruption in normotensive animals.

Topics: Angiotensin II; Animals; Astrocytes; beta-Cyclodextrins; Blood Pressure; Blood-Brain Barrier; Caveolin 1; Cerebral Cortex; Claudin-5; Endothelial Cells; Hippocampus; Hypertension; Male; Permeability; Rats; Rats, Sprague-Dawley

Linalool (LIN) is a monoterpene alcohol present in some aromatic medicinal plants with biological activities that can impact cardiovascular diseases. This chemical class is highly volatile and β-cyclodextrin (β-CD) has been employed to improve the pharmacological properties of monoterpenes. Thus, the aim of this study was to evaluate the cardiovascular effects of LIN free focusing on the antihypertensive properties of this monoterpene and to study whether LIN, complexed in β-cyclodextrin (LIN-βCD) is able to improve the pharmacological activity of LIN. Spontaneously hypertensive rats (SHR) were randomly divided into 5 groups, each treated daily for 21 days, in the following manner: group 1 (vehicle solution); group 2 (captopril; 30 mg/kg/day); group 3 (LIN; 100 mg/kg/day); group 4 (LIN; 50 mg/kg/day) and group 5 (LIN/β-CD; 50 mg/kg/day). Daily body weight measurements were conducted and mean arterial pressure and heart rate were measured every 5 days. The mesenteric artery from treated animals was tested for phenylephrine and sodium nitroprusside (SNP) sensitivity. The SHR treated with vehicle demonstrated progressive increase in mean arterial pressure and captopril, a positive control, induced a significant decrease. After 21 days of treatment, the blood pressure of the SHR treated by (-)-LIN (100 mg/kg) was significantly reduced. In addition, various important cardiovascular parameters improved, including: the treatment with LIN prevented the development of cardiac hypertrophy, increased levels of the anti-inflammatory cytokine (IL-10), increased vasodilator responsiveness and reduced sensitivity to the sympathetic agonist. Furthermore, the inclusion complex containing LIN in β-CD produced a higher antihypertensive profile when compared with uncomplexed form. Taking together, our results suggested that LIN shown a potential antihypertensive effect and β-CD may be an important tool to improve the cardiovascular activity of LIN and other water-insoluble compounds.

Topics: Acyclic Monoterpenes; Animals; Antihypertensive Agents; beta-Cyclodextrins; Blood Pressure; Dose-Response Relationship, Drug; Drug Carriers; Hypertension; Monoterpenes; Rats, Inbred SHR; Vasodilation

Low angiotensin-(1-7) (Ang-(1-7)) concentration is observed in some cardiovascular diseases and exercise training seems to restore its concentration in the heart. Recently, a novel formulation of an orally active Ang-(1-7) included in hydroxy-propyl-beta-cyclodextrin (HPB-CD) was developed and chronically administered in experimental models of cardiovascular diseases. The present study examined whether chronic administration of HPB-CD/Ang-(1-7) produces beneficial cardiovascular effects in spontaneously hypertensive rats (SHR), as well as to compare the results obtained with those produced by exercise training. Male SHR (15-week old) were divided in control (tap water) or treated with HPB-CD/Ang-(1-7) (corresponding to 30μgkg(-1)day(-1) of Ang-(1-7)) by gavage, concomitantly or not to exercise training (treadmill, 10 weeks). After chronic treatment, hemodynamic, morphometric and molecular analysis in the heart were performed. Chronic HPB-CD/Ang-(1-7) decreased arterial blood pressure (BP) and heart rate in SHR. The inclusion compound significantly improved left ventricular (LV) end-diastolic pressure, restored the maximum and minimum derivatives (dP/dT) and decreased cardiac hypertrophy index in SHR. Chronic treatment improved autonomic control by attenuating sympathetic modulation on heart and vessels and the SAP variability, as well as increasing parasympathetic modulation and HR variability. Overall results were similar to those obtained with exercise training. These results show that chronic treatment with the HPB-CD/Ang-(1-7) inclusion compound produced beneficial effects in SHR resembling the ones produced by exercise training. This observation reinforces the potential cardiovascular therapeutic effect of this novel peptide formulation.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Administration, Oral; Angiotensin I; Animals; Antihypertensive Agents; beta-Cyclodextrins; Blood Pressure; Combined Modality Therapy; Drug Evaluation, Preclinical; Excipients; Exercise Therapy; Heart Rate; Hypertension; Male; Myocardium; Peptide Fragments; Physical Conditioning, Animal; Rats; Rats, Inbred SHR; Ventricular Pressure

The angiotensin II (AngII)-infused apolipoprotein E-deficient (ApoE(-/-)) mouse model is widely used to study atherosclerosis and abdominal aortic aneurysm. An increase in blood pressure has been reported in this model however the underlying mechanism has not been fully explored. In this study, we investigated whether vasomotor dysfunction develops in AngII-infused ApoE(-/-) mice and the underlying mechanism involved.. ApoE(-/-) mice were infused with vehicle (distilled water) or AngII subcutaneously for 14 days. Blood pressure and heart rate were measured using the non-invasive tail cuff method. Aortic vascular reactivity and expression of key proteins (endothelial nitric oxide synthase (eNOS), phospho-eNOS and caveolin-1) were assessed using tension myography and Western blotting respectively. Plasma nitric oxide (NO) level was estimated using a colorimetric assay.. AngII infusion caused a time-dependent increase in blood pressure (P<0.001). Aortas from AngII-infused mice were significantly less responsive to acetylcholine-induced endothelium-dependent relaxation when compared to aortas from mice infused with vehicle control (P<0.05). Contractile responses to phenylephrine (P<0.01) and potassium chloride (P<0.001) were significantly enhanced in aortas from AngII-infused mice. eNOS phosphorylation was significantly decreased in the aorta of AngII-infused mice (P<0.05). Aortic caveolin-1 protein expression was significantly increased in AngII-infused mice (P<0.05). Plasma nitrate/nitrite level was significantly reduced in AngII-infused mice (P<0.05). Pharmacological disruption of caveolae using methyl-β-cyclodextrin (MβCD) in isolated aortas from AngII-infused mice caused a significant leftward shift of the acetylcholine-induced relaxation concentration-response curve when compared to vehicle control (P<0.05).. Upregulation of caveolin-1 protein expression and reduced NO bioavailability contributes to aortic endothelial dysfunction in AngII-infused ApoE(-/-) mice.

Topics: Acetylcholine; Angiotensin II; Animals; Aorta; Apolipoproteins E; beta-Cyclodextrins; Blood Pressure; Caveolae; Caveolin 1; Endothelium, Vascular; Gene Expression Regulation; Heart Rate; Hypertension; Injections, Subcutaneous; Male; Mice; Mice, Knockout; Nitric Oxide; Nitric Oxide Synthase Type III; Vasodilation