Hypercholesterolemia modifies angiotensin II desensitisation and cross talk between α1-adrenoceptor and angiotensin AT1 receptor in rabbit aorta

This study characterised the effect of a hypercholesterolemic diet on the interactions of hormone receptors in the rabbit aorta, both in homologous desensitisation to angiotensin II and cross talk between α1-adrenoceptors and angiotensin AT1 receptors. Rabbits were fed either a normal chow or a diet containing 1% cholesterol for 6-7-weeks. Isometric contractions were measured in endothelium-intact or endothelium-removed aortic rings from control and hypercholesterolemic rabbits. Concentration response curves to angiotensin II or noradrenaline incubated with or without prazosin or losartan were performed. In another group, the resting potential was recorded at baseline and following angiotensin II or noradrenaline stimulation. Rabbits fed a hypercholesterolemic diet showed higher plasma levels of total cholesterol and LDL-cholesterol and impaired relaxation to acetylcholine. Homologous desensitisation to angiotensin II was found in endothelium-intact but not in endothelium-removed arteries. Cross talk between α1-adrenoceptors and angiotensin AT1 receptors was modified with respect to physiological conditions. In control rabbits, angiotensin II desensitised the noradrenaline response but noradrenaline did not modify the angiotensin II-response. However, in hypercholesterolemic rabbits, angiotensin II sensitised the noradrenaline-response and noradrenaline desensitised the angiotensin II-response. Furthermore, the resting potential remains hyperpolarised after noradrenaline stimulation in hypercholesterolemic rabbits. Modifications in homologous desensitisation to angiotensin II and cross talk between α1-adrenoceptors and angiotensin AT1 receptors suggest that hypercholesterolemia induces early tissue dysfunction by altering endothelial and smooth muscle cell regulatory properties. This may be one of the mechanisms by which hypercholesterolemia could be involved in the onset and progression of chronic vascular diseases such as hypertension and arteriosclerosis.Fil: Jerez, Susana Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; ArgentinaFil: Sierra, Liliana Beatríz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; ArgentinaFil: Scachi, Fabricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; ArgentinaFil: Peral, Maria de Los Angeles. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentin

Vascular hyporeactivity to angiotensin II and noradrenaline in a rabbit model of obesity

This study was conducted to explore the vascular reactivity of angiotensin II and noradrenaline and their relationship with endothelial function in rabbits fed a high-fat diet (HFD). The animals were fed either an HFD or regular chow [control diet (CD)]. After 12 weeks, the rabbits fed the HFD showed higher blood pressure, body weight, and insulin levels. Glucose tolerance was impaired and positively related to blood pressure. An endothelium-independent decrease of the sensitivity to angiotensin II [pD 2 endothelium-intact aortic rings (E+) in CD: 8.02 ± 0.07 vs. HFD: 7.60 ± 0.01; pD 2 endothelium-removed aortic rings (E-) in CD: 8.16 ± 0.11 vs. HFD: 7.83 ± 0.16] and noradrenaline (pD 2 E+ in CD: 6.36 ± 0.06 vs. HFD: 5.29 ± 0.06; pD 2 E- in CD: 6.11 ± 0.08 vs. HFD: 5.80 ± 0.08) was found. Noradrenaline desensitized the angiotensin II response (pD 2 with noradrenaline pretreatment in E+: 7.03 ± 0.16; in E-: 7.10 ± 0.02), but angiotensin II did not change the noradrenaline response. Acetylcholine maximal relaxation and basal nitric oxide (NO) release were comparable in both diet groups. The efficacy of angiotensin II (R max CD: 4604 ± 574 mg vs. HFD: 3251 ± 533 mg) and noradrenaline (R max CD: 11,675 ± 804 mg vs. HFD: 7975 ± 960 mg) was reduced in E+. L-N G-nitroarginine methyl ester (L-NAME) recovered the efficacy of noradrenaline (R max L-NAME: 12,015 ± 317 mg). In contrast, L-NAME had no effect on the angiotensin II response. Noradrenaline enhanced NO levels, but angiotensin II did not. Therefore, NO was associated with hyporeactivity to noradrenaline. The resting potential was more negative in E+, and the endothelium diminished the angiotensin II-induced depolarization. These findings demonstrated that the crosstalk and the endothelium may induce hyporeactivity to angiotensin II and noradrenaline as a mechanism to compensate the increase in the blood pressure in HFD-induced obesity.Fil: Jerez, Susana Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; ArgentinaFil: Scachi, Fabricio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; ArgentinaFil: Sierra, Liliana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; ArgentinaFil: Karbiner, María Sofía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; ArgentinaFil: Peral, Maria de Los Angeles. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Investigaciones Biológicas. Universidad Nacional de Tucumán. Instituto Superior de Investigaciones Biológicas; Argentin