RESUMEN
The aim of this study was to examine the function of perivascular adiposa tissue (PVAT) on vascular relaxation response in spontaneously hypertensive rats (SHR) and the modulatory effects of the atorvastatin therapy on the PVAT functions. We investigated the mechanisms of the perivascular adipocyte-derived relaxation factor (PVRF) by using isolated rat's aortic rings and isometric contraction measurements. We found that contraction of the thoracic aorta induced by phenylephrine was significantly attenuated in the presence of PVAT from normotensive Wistar-Kyoto rats (WKY group) or the spontaneously hypertensive rats treated with atorvastatin (SHR-A group, atorvastatin 50mg/kg/day), whereas this effect was not observed in the thoracic aortic rings from the control SHR (SHR group). Transferring the solution incubated with PVAT-intact thoracic aorta to PVAT-free thoracic aorta, it induced a remarkable relaxation response in the WKY but not in the control SHR. Tetraethylammoniumchloride (TEA) could block the above relaxation. It was also shown that the PVRF function was likely, depending on the extracellular [Ca(2+)]; the anti-contractile effect of PVAT could be reduced by the inhibitor of the adenosine triphosphate (ATP)-dependent potassium channels, glibenclamide, and could be reduced by the inhibitor of cyclooxygenase by indomethacin. We thus infer that the PVAT function was distorted in hypertension rats, and the lipid-lowering treatment with atorvastatin could restore the PVAT function. The function of the PVRF may involve the Ca(2+)-activated potassium channels, the ATP-dependent potassium channels in vascular smooth muscle cell (SMC), and the release of PVRF from PVAT may involve prostaglandins (PGs) and the calcium metabolism. These results provide an insight into the pathological mechanisms of hypertension development, and indicate that the PVAT may be a potential new target for the hypertensive therapy.
Asunto(s)
Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/fisiopatología , Ácidos Heptanoicos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hipertensión/fisiopatología , Pirroles/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/fisiopatología , Atorvastatina , Tejido Conectivo/metabolismo , Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Factores Relajantes Endotelio-Dependientes/metabolismo , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiología , Vasodilatación/efectos de los fármacos , Vasodilatación/fisiologíaRESUMEN
OBJECTIVE: To investigate the effect and mechanism of valsartan and felodipine extended release tablets (Plendil) on a novel salt-sensitive hypertensive rat induced by sensory denervation. METHODS: Newborn Wistar rats were given 50 mg/kg capsaicin subcutaneously on the 1st and 2nd day of life. Control rats were treated with vehicle solution (10%ethanol, 10%Tween 80 in saline). After weanling period (3 weeks), male rats were divided into 5 groups and subject to the following treatment for 4 weeks: control + high salt diet (4%, CON-HS), capsaicin + normal salt diet (0.5%, CAP-NS), capsaicin + high salt diet (CAP-HS), capsaicin + high salt diet + Valsartan (30 mg/kg per day, by orally) (CAP-HS-VAL), capsaicin + high salt diet + Plendil (30 mg/kg per day, by orally) (CAP-HS-PLE). Tail-cuff systolic blood pressure, body weight, intralymphocytic [Ca(2+)](i), plasma calcitonin gene-related peptide concentration ([CGRP]), angiotensin II concentration ([AngII]) and 24 hour water intake, urinary volume, urinary Na(+) and K(+) concentrations were examined. RESULTS: Tail-cuff systolic blood pressure and intralymphocytic [Ca(2+)](i) were lower in CAP-HS-VAL or CAP-HS-PLE group than those in CAP-HS group. Plasma [AngII] were higher in CAP-HS-VAL group than that in other groups. Tail-cuff systolic blood pressure were lower in CAP-HS-VAL group than that in CAP-HS-PLE group. Intralymphocytic [Ca(2+)](i) were lower in CAP-HS-PLE group than that in CAP-HS-VAL group. The 24 hour urine sodium excretion was higher in CAP-HS-PLE group than that in CAP-HS or CAP-HS-VAL group. CONCLUSION: Valsartan or Plendil could prevent the development of salt-sensitive hypertension induced by sensory denervation and the overloading of intracellular [Ca(2+)](i), which indicated that salt-sensitive hypertension induced by sensory nerve degeneration might be related to renin-angiotensin-aldosterone system (RAAS) and the over loading intracellular [Ca(2+)](i), and might be more closely to RAAS.
Asunto(s)
Antihipertensivos/uso terapéutico , Felodipino/uso terapéutico , Hipertensión/tratamiento farmacológico , Tetrazoles/uso terapéutico , Valina/análogos & derivados , Animales , Presión Sanguínea , Hipertensión/inducido químicamente , Hipertensión/fisiopatología , Masculino , Ratas , Ratas Wistar , Cloruro de Sodio Dietético , Valina/uso terapéutico , ValsartánRESUMEN
OBJECTIVE: To investigate the importance of the specific structure of L-4F, an apolipoprotein A-1 mimetic, in inhibiting atherosclerosis. The study was designed to compare the effect of L-4F and scramble-4F (SC-4F) in preventing low density lipoprotein (LDL) induced endothelial cell dysfunction. L-4F and SC-4F has the same amino acids but different nucleotide sequence. METHODS: Bovine aortic endothelial cells (BAEC) were incubated with single L-4F 10 microg/ml or SC-4F 10 microg/ml, or LDL 6.2 mmol/L in the absence or presence of L-4F 10 microg/ml or SC-4F 10 microg/ml for 24 h and assayed for (1) changes of superoxide anion (O2-*) generation in BAEC by superoxide dismutase (SOD)-inhibitable ferricytochrome C reduction, and (2) the production of nitric oxide (NO) in BAEC by ozone chemiluminescence with VCL3. RESULTS: (1) L-4F and SC-4F themselves had no affect on BAEC O2-* generation. (2) LDL significantly increased O2-* generation in BAEC and LDL-induced O2-* generation was inhibited by pretreatment of LDL with L-4F. However, pretreatment of LDL with SC-4F had no effect on inhibition of LDL-induced O2-* generation. (3) LDL significantly inhibited NO generation in BAEC and pretreatment of LDL with L-4F could inhibit LDL-induced decrease of NO generation, but pretreatment of LDL with SC-4F still inhibited NO generation in BAEC. CONCLUSION: L-4F can prevent LDL induced endothelial cell dysfunction by maintaining the balance of NO and O2-*, but SC-4F doesn't. It suggests that the specific structure of L-4F may play a crucial role in preventing atherosclerosis and it may provide a new clue for searching a novel approach on prevention and therapeutics of atherosclerosis in the future.
Asunto(s)
Aterosclerosis/prevención & control , Células Endoteliales/efectos de los fármacos , Lipoproteínas LDL/antagonistas & inhibidores , Péptidos/farmacología , Animales , Bovinos , Células Cultivadas , Células Endoteliales/fisiología , Óxido Nítrico/biosíntesis , Superóxidos/metabolismoRESUMEN
The purpose of this study was to investigate the role of the renin-angiotensin-aldosterone system in hypertension development and cardiovascular structural changes in a salt-sensitive hypertensive model induced by capsaicin (CAP). Newborn male Wistar rats were injected with either capsaicin or vehicle. After weaning at 3 weeks, these rats were divided into the following six treatment groups: capsaicin plus high-salt diet (CAP+HS), control plus high-salt diet (CON+HS), control plus normal salt diet (CON+NS), capsaicin plus high-salt diet and telmisartan (CAP+HS+T, 10 mg/kg/day), capsaicin plus high-salt diet and perindopril (CAP+HS+P, 2 mg/kg/day), and capsaicin plus high-salt diet and spironolactone (CAP+HS+S, 80 mg/kg/day). Treatment with different salt diets and drugs was initiated at 3 weeks of age and lasted 18 weeks. We found that beginning at the second week after the initiation of the treatment, blood pressure became significantly higher in CAP+HS than in other groups, accompanied by the development of cardiac hypertrophy. Treatment with telmisartan, perindopril or spironolactone prevented the development of hypertension in the CAP+HS group. Cardiac hypertrophy was prevented in the perindopril treatment group. The medial thickness, media-to-lumen ratio and cross-sectional area of the thoracic, renal and mesenteric arteries were significantly increased in CAP+HS than in other groups. Lumen diameter was similar in all the vessels among all the groups. Treatment with telmisartan, perindopril or spironolactone prevented the development of vascular remodeling, as found in the CAP+HS group. Beginning at 8 weeks after the initiation of the salt diet treatment (11 weeks of age), blood pressure also became higher in CON+HS than in CON+NS, but lower than CAP+HS. Structural changes of vessels were also present in CON+HS, but the degree of change was less when compared with CAP+HS. We conclude that neonatal treatment with capsaicin plus a high-salt diet, and a high-salt diet alone both induced hypertension development in normal Wistar rats, which are associated with cardiovascular remodeling. The renin-angiotensin-aldosterone system is involved in this salt-sensitive model because treatment that interfered with this system also prevented the development of hypertension and vascular remodeling.
Asunto(s)
Vasos Sanguíneos/fisiopatología , Hipertensión/fisiopatología , Sistema Renina-Angiotensina/efectos de los fármacos , Sodio en la Dieta/efectos adversos , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Animales Recién Nacidos , Antihipertensivos/farmacología , Arterias/patología , Arterias/fisiopatología , Bencimidazoles/farmacología , Benzoatos/farmacología , Presión Sanguínea/efectos de los fármacos , Vasos Sanguíneos/patología , Peso Corporal/efectos de los fármacos , Capsaicina , Hipertensión/inducido químicamente , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacología , Perindopril/farmacología , Ratas , Ratas Wistar , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Espironolactona/farmacología , TelmisartánRESUMEN
1. The objective of the present study was to investigate the arterial structural changes in a salt-sensitive hypertensive rat model induced by treatment with capsaicin. 2. Newborn male Wistar rats were treated with 50 mg/kg capsaicin subcutaneously for 2 days. Control rats were treated with vehicle solution (5% ethanol and 5% Tween 80 in saline). After weaning at 3 weeks, rats were divided into four groups: (i) control with a normal salt diet (0.5% NaCl; CON + NS); (ii) control with a high-salt diet (4% NaCl; CON + HS); (iii) capsaicin plus normal salt diet (CAP + NS); and (iv) capsaicin plus a high-salt diet (CAP + HS). Treatment with different salt diets was initiated at 3 weeks of age and lasted for 18 weeks. Tail-cuff systolic blood pressure (BP) and bodyweight were examined. At the end of the treatment period, blood vessels were prepared by perfusion fixation. Heart weight and vascular dimensions were measured in the thoracic (artery) aorta, renal artery and mesenteric artery. 3. Two weeks after the initiation of the salt diet treatment, BP became significantly higher in the CAP + HS group than in any of the other groups and this difference was maintained until the end of the treatment period. 4. Beginning at 8 weeks after the initiation of the salt diet treatment (11 weeks of age), BP became higher in the CON + HS group than in the CON + NS and CAP + NS groups. Blood pressure was not significantly different between the CON + NS and CAP + NS groups. 5. Media thickness, media thickness to lumen ratio and cross-sectional area of the aorta, renal artery and mesenteric artery were significantly increased in the CAP + HS group compared with the other groups. Heart weight was also increased in the CAP + HS and CON + HS groups compared with the other groups. 6. Similar structural changes in the blood vessels and heart were also found in the CON + HS group compared with the CON + NS group. Lumen diameter was not altered by the treatments in any of the arteries studied. 7. We conclude that treatment with capsaicin increased the sensitivity of the BP of these rats to salt and this increase in BP is correlated with hypertrophy of the arteries (vascular remodelling) with no change in lumen size. A long-term high-sodium load induced hypertension in normal Wistar rats, which was accompanied by cardiovascular hypertrophy.