PPARalpha stimulation exerts a blood pressure lowering effect through different mechanisms in a time-dependent manner.

Peroxisome proliferator activated receptors (PPARs) are a family of nuclear receptors that, upon activation with selective ligands, work as transcription factors. Recently, these have been related with the cardiovascular system. Our aim was to study PPARalpha-stimulation and its effects on blood pressure in rats with aortic coarctation, and to explore the role of the antioxidant system. Male Wistar rats (250-280 g) were distributed into the following groups: 1) sham; 2) aortic coarctated-vehicle-treated (AoCo-V), and 3) AoCo-clofibrate (100mg/kg) treated (AoCo-C). Rats were treated for 1 or 21 days. Clofibrate lowered blood pressure in both 1- and 21-day treatments. Renal reactive oxygen species increased after 1 day in AoCo-V, while clofibrate prevented this effect. Superoxide dismutase (SOD)-1 expression increased 3.6-fold upon PPARalpha stimulation (1 day) and returned to normal values by day 21. SOD-1 activity increased slightly in response to clofibrate. Renal activity of catalase increased in AoCo-C (1 day) and returned to normal (21 days). eNOS expression was not modified acutely (1 day) but increased at 21 days of treatment with clofibrate. Angiotensin II AT(1)-receptor expression as well as angiotensin II decreased in clofibrate-treated rats, while angiotensin II AT(2)-receptor expression increased, in both treatment periods. Angiotensin-(1-7) increased at 21 days. Our results suggest that in the early development of AoCo-induced hypertension, stimulation of PPARalpha increases the antioxidant defenses, leading to improvement in endothelial factors while in the sub-chronic phase (21 days), eNOS and angiotensin II receptors appear to play major roles in controlling blood pressure.

Ibarra-Lara L ，Cervantes-Pérez LG ，Pérez-Severiano F ，Del Valle L ，Rubio-Ruíz E ，Soria-Castro E ，Pastelín-Hernández GS ，Sánchez-Aguilar M ，Martínez-Lazcano JC ，Sánchez-Mendoza A ... -  《-》

Endothelial nitric oxide synthase impairment is restored by clofibrate treatment in an animal model of hypertension.

Adequate production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) requires eNOS coupling promoted by tetrahydrobiopterin (BH(4)). Under pathological conditions such as hypertension, BH(4) is diminished, avoiding eNOS coupling. When eNOS is "uncoupled", it yields a superoxide anion instead of NO. Peroxisome proliferator activated receptors (NR1C) are a family of nuclear receptors activated by ligand. Clofibrate, a member of a hypolipidemic class of drugs, acts by activating the alpha isoform of NR1C. To determine the participation of NR1C1 activation in BH(4) and dihydrobiopterin (BH(2)) metabolism and its implications on eNOS coupling in hypertension, we performed aortic coarctation (AoCo) at inter-renal level on male Wistar rats in order to have a hypertensive model. Rats were divided into the following groups: Sham+vehicle (Sham-V); AoCo+vehicle (AoCo-V); Sham+clofibrate (Sham-C), and AoCo+clofibrate (AoCo-C). Clofibrate (7 days) increased eNOS coupling in the AoCo-C group compared with AoCo-V. Clofibrate also recovered the BH(4):BH(2) ratio in control values and prevented the rise in superoxide anion production, lipoperoxidation, and reactive oxygen species production. In addition, clofibrate increased GTP cyclohydrolase-1 (GTPCH-1) protein expression, which is related with BH(4) recovered production. NR1C1 stimulation re-establishes eNOS coupling, apparently through recovering the BH(4):BH(2) equilibrium and diminishing oxidative stress. Both can contribute to high blood pressure attenuation in hypertension secondary to AoCo.

Cervantes-Pérez LG ，Ibarra-Lara Mde L ，Escalante B ，Del Valle-Mondragón L ，Vargas-Robles H ，Pérez-Severiano F ，Pastelín G ，Sánchez-Mendoza MA ... -  《-》

Peroxisome proliferator-activated receptor-α stimulation by clofibrate favors an antioxidant and vasodilator environment in a stressed left ventricle.

Arterial high blood pressure is a risk factor for target organ damage; the most susceptible organs are the arteries, brain, kidneys, and heart. The damage mechanisms include oxidative stress and renin-angiotensin system (RAS) overactivity. Therefore, our aim was to study whether clofibrate-induced peroxisome proliferator-activated receptor-alpha (PPAR-α) stimulation is able to prevent alterations in cardiac functioning derived from RAS overstimulation in the left ventricle of rats with hypertension secondary to aortic coarctation and to improve antioxidant defenses. Male Wistar rats were assigned to Control (Sham)- or aortic coarctation-surgery and further divided to receive (1 or 21 days) vehicle, clofibrate (100mg/kg), captopril (20mg/kg), or clofibrate+captopril. The left ventricle was obtained to measure: angiotensin II and -(1-7), AT1 and AT2 receptors, angiotensin converting enzyme (ACE)-1 and -2, and MAS receptor; the activity and expression of superoxide dismutase, catalase, endothelial nitric oxide synthase, the production of reactive oxygen species (ROS) and peroxidated lipids; as well as ex vivo cardiac functioning. Clofibrate decreased angiotensin II, AT1 receptor and ACE expression, and raised angiotensin-(1-7), AT2 receptor, ACE-2 expression, superoxide dismutase and endothelial nitric oxide synthase participation. These effects promoted lower coronary vascular resistance and improved mechanical work compared to aortic coarctated vehicle-treated rats. Clofibrate-induced PPAR-α stimulation changes the angiotensin II receptor profile, favors the ACE2/angiotensin-(1-7)/AT2 receptor axis decreasing the vasoconstrictor environment, activates the antioxidant defense, and facilitates endothelial nitric oxide synthase activity favoring vasodilation. This may represent a protection for the stressed heart.

Ibarra-Lara L ，Del Valle-Mondragón L ，Soria-Castro E ，Torres-Narváez JC ，Pérez-Severiano F ，Sánchez-Aguilar M ，Ramírez-Ortega M ，Cervantes-Pérez LG ，Pastelín-Hernández GS ，Oidor-Chan VH ，Zarco-Olvera G ，Sánchez-Mendoza A ... -  《-》

Peroxisome proliferator-activated receptor alpha activation attenuated angiotensin type 1-mediated but enhanced angiotensin type 2-mediated hemodynamic effects to angiotensin II in the rat.

Banks T ，Oyekan A 《JOURNAL OF HYPERTENSION》

Effect of clofibrate on vascular reactivity in a model of high blood pressure secondary to aortic coarctation.

Cervantes-Pérez LG ，Ibarra-Lara ML ，Rubio ME ，Escalante B ，Pérez-Severiano F ，Soria-Castro E ，Ramírez-Ortega MC ，Sánchez-Mendoza MA ... -  《-》