Carmen Mingorance

Endothelial dysfunction and aging: An update

Aging is an important risk factor for the development of many cardiovascular diseases as atherosclerosis and hypertension with a common underlying circumstance: the progressive decline of endothelial function. Vascular endothelial dysfunction occurs during the human aging process and is accompanied by deterioration in the balance between vasodilator and vasoconstriction substances produced by the endothelium. This imbalance is mainly characterized by a progressive reduction of the bioavailability of nitric oxide (NO) and an increase in the production of cyclooxygenase (COX)-derived vasoconstrictor factors. Both circumstances are in turn related to an increased production of reactive oxygen and nitrogen species. The aim of this review is to describe the pathophysiological mechanisms involved in the endothelial function declination that accompanies the multifactorial aging process, including alterations related to oxidative stress and pro-inflammatory cytokines, senescence of endothelial cells and genetic factors.

Pharmacological effects and clinical applications of propionyl-L-carnitine

Propionyl-L-carnitine (PLC) is a naturally occurring derivative of carnitine that plays an important role in the metabolism of both carbohydrates and lipids, leading to an increase of ATP generation. PLC, however, is not only a metabolic drug; it is also a potent antiradical agent and thus may protect tissues from oxidative damage. PLC has been demonstrated to exert a protective effect in different models of both cardiac and endothelial dysfunction, to prevent the progression of atherosclerosis, and, more recently, to improve some of the cardiometabolic alterations that frequently accompany insulin resistance. As a result, most of the clinical trials conducted in humans highlight PLC as a potential treatment option in cardiovascular diseases such as peripheral arterial disease, chronic heart failure, or stable angina, especially when type 2 diabetes mellitus or hyperglycemia (i.e., patients on hemodialysis) are also present. The aim of this review is to summarize the pharmacological effects and possible therapeutic applications of PLC, including the most recent findings to date.

l-carnitine and its propionate: Improvement of endothelial function in SHR through superoxide dismutase-dependent mechanisms

To clarify the mechanism underlying the antioxidant properties of l-carnitine (LC) and propionyl-l-carnitine (PLC) on spontaneously hypertensive (SHR) and normotensive WKY, animals were treated with either PLC or LC (200 mg kg− 1). Aorta was dissected and contraction to (R)-( − )-phenylephrine (Phe) and relaxation to carbachol (CCh) were assessed in the presence or not of the NO synthase (NOS) inhibitor, l-NAME. production was evaluated by lucigenin-enhanced chemiluminescence and its participation on relaxation was observed after incubation with superoxide dismutase (SOD) plus catalase. Protein expressions of eNOS, Cu/Zn-SOD and Mn-SOD were studied by western blot. Both LC and PLC treatments improved endothelial function of SHR through increasing NO participation and decreasing probably involving higher Cu/Zn-SOD expression. PLC treatment augmented eNOS expression in SHR. Surprisingly, LC increased produced by aorta from WKY and thus diminished NO and damaged endothelial function. Conversely, PLC did not affect CCh-induced relaxation in WKY. These results demonstrate that LC and PLC prevent endothelial dysfunction in SHR through an antioxidant effect.

Propionyl-L-carnitine Corrects Metabolic and Cardiovascular Alterations in Diet-Induced Obese Mice and Improves Liver Respiratory Chain Activity

Aims Obesity is a primary contributor to acquired insulin resistance leading to the development of type 2 diabetes and cardiovascular alterations. The carnitine derivate, propionyl-L-carnitine (PLC), plays a key role in energy control. Our aim was to evaluate metabolic and cardiovascular effects of PLC in diet-induced obese mice. Methods C57BL/6 mice were fed a high-fat diet for 9 weeks and then divided into two groups, receiving either free- (vehicle-HF) or PLC-supplemented water (200 mg/kg/day) during 4 additional weeks. Standard diet-fed animals were used as lean controls (vehicle-ST). Body weight and food intake were monitored. Glucose and insulin tolerance tests were assessed, as well as the HOMAIR, the serum lipid profile, the hepatic and muscular mitochondrial activity and the tissue nitric oxide (NO) liberation. Systolic blood pressure, cardiac and endothelial functions were also evaluated. Results Vehicle-HF displayed a greater increase of body weight compared to vehicle-ST that was completely reversed by PLC treatment without affecting food intake. PLC improved the insulin-resistant state and reversed the increased total cholesterol but not the increase in free fatty acid, triglyceride and HDL/LDL ratio induced by high-fat diet. Vehicle-HF exhibited a reduced cardiac output/body weight ratio, endothelial dysfunction and tissue decrease of NO production, all of them being improved by PLC treatment. Finally, the decrease of hepatic mitochondrial activity by high-fat diet was reversed by PLC. Conclusions Oral administration of PLC improves the insulin-resistant state developed by obese animals and decreases the cardiovascular risk associated to this metabolic alteration probably via correction of mitochondrial function.

Critical update for the clinical use of L-carnitine analogs in cardiometabolic disorders

Acetyl-L-carnitine (ALC) and propionyl-L-carnitine (PLC) are two naturally occurring carnitine derivates formed by carnitine acetyltransferase. The beneficial cardiovascular effects of ALC and PLC have been extensively evaluated in animals and humans during the last 20 years. For instance, many clinical trials have suggested ALC and PLC as potential strategies in the management of peripheral arterial disease, heart and cerebral ischemia, and congestive heart failure. As a result, several experts have already aimed to revise the clinical evidence supporting the therapeutic use of ALC and PLC. On the basis of their conclusions, our aim was a critical review of the effectiveness of ALC and PLC in the treatment of cardiovascular diseases. Type 2 diabetes mellitus is an independent risk factor for the development of cardiovascular disease. Therefore we also describe recent studies that have addressed the emerging use of ALC and PLC amelioration of the insulin resistant state and its related morbidities.

Effects of HMG-CoA Reductase Inhibition by Simvastatin on Vascular Dysfunction Induced by Lipopolysaccharide in Rats

Aims: Statins have been identified as a potentially interesting treatment against sepsis. Here, we study the vascular reactivity of aortae from rats treated with lipopolysaccharide (LPS), 4 mg · kg–1, following chronic administration of simvastatin (SV) 10 mg · kg–1. Methods: The rats were treated with either vehicle or SV for 4 weeks before administration of LPS. After 18 h, the systolic blood pressure (SBP) was measured using a tail cuff and vascular and endothelial responses of aortic rings to several agonists were studied in an organ bath. Results: LPS injection decreased the SBP by 38 mm Hg and vascular response to phenylephrine (Phe) by 60%. Plasma nitrates and nitrites (NOx) were 3-fold higher after LPS. This attenuated response to Phe was prevented by incubation with either the inducible-nitric-oxide-synthase (iNOS)-selective inhibitor 1400W or the endothelial nitric oxide synthase (eNOS)/iNOS nonselective blocker L-NAME. The presence of endothelium did not alter these findings. Administering LPS to SV-treated rats also decreased the SBP and increased the NOx concentration. The impaired response to Phe was restored by blocking NO synthesis in endothelium-denuded but not in intact aortic rings. The response to acetylcholine demonstrated an enhanced reduction in arteries from the SV + LPS group compared with the LPS group. The inhibition of iNOS prevented acetylcholine-induced relaxation in rings from LPS-treated rats but not in those from the SV + LPS group. Conclusion: These results suggest that statins may reduce iNOS-mediated NO production in endothelial but not in vascular smooth-muscle cells.

Effects of Chronic Treatment With the CB1 Antagonist, Rimonabant on the Blood Pressure, and Vascular Reactivity of Obese Zucker Rats

Rimonabant (RM) is a cannabinoid CB1 receptor antagonist useful in the treatment of obesity associated cardiovascular risk factors. Since cannabinoids are vasoactive compounds, the aim of this study is to evaluate the effect of chronic treatment with RM on systolic blood pressure (SBP), and endothelial and vascular reactivity. Obese Zucker rats (OZRs) and their lean counterparts were orally treated during 20 weeks with either RM (10 mg/kg/day). Endothelial and vascular function was assessed in aorta and small mesenteric arteries (SMAs) by concentration response curves to acetylcholine (ACh) and phenylephrine (Phe), respectively. Participation of nitric oxide (NO) was evaluated by incubation with the NO synthase (NOS) inhibitor NG‐nitro‐l‐arginine methyl ester (L‐NAME) and cyclooxygenase (COX)‐derived products involvement was analyzed by incubation with indomethacin (INDO). Plasma lipid profile, insulin and adiponectin were also analyzed. Sympathetic activity was evaluated by urinary excretion of noradrenaline. As expected, RM decreased body weight gain and enhanced adiponectin concentration. Insulin resistance and sympathetic activity were also decreased. The increase in SBP observed in OZRs was reduced by treatment with RM. Aortae and SMAs from OZRs exhibited lower contractile response to Phe, being this effect prevented by RM administration. Although ACh‐induced response and NO participation remained unaltered with obesity, enhanced COX‐derived constrictor products were found in OZRs. RM treatment neither altered endothelium‐dependent relaxation nor L‐NAME‐sensitive component of the response. Nevertheless, it was able to regulate COX‐derived vasoactive products participation. Those effects may contribute to explain some of the cardiovascular protective actions elicited by this drug.

Oral supplementation of propionyl-l-carnitine reduces body weight and hyperinsulinaemia in obese Zucker rats.

Propionyl-L-carnitine (PLC) is an SCFA esterified to carnitine that plays an important role in fatty acid oxidation and energy expenditure, in addition to having a protective effect on the endothelium. In order to evaluate the effect of PLC on an animal model of obesity, insulin resistance and, consequently, endothelial dysfunction, lean and obese Zucker rats (OZR) received either vehicle- or PLC-supplemented drinking water (200 mg/kg per d) for 20 weeks. Body weight, food intake, systolic blood pressure and heart rate were controlled weekly and an oral glucose tolerance test was performed. Fasting glucose, TAG, cholesterol, HDL, NEFA, adiponectin and insulin were analysed in serum. Visceral adipose tissue and liver were weighed and liver TAG liver composition was evaluated. Endothelial and vascular functions were assessed in the aorta and small mesenteric arteries by response to acetylcholine, sodium nitroprusside and phenylephrine (Phe); NO participation was evaluated after incubation with the NO synthase (NOS) inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and endothelial NOS protein expression by Western blotting. PLC decreased body-weight gain, food intake, adiposity, insulin serum concentration and TAG liver content and improved insulin resistance. Aortae from OZR receiving either vehicle or PLC exhibited a lower contractile response to Phe. PLC-treated OZR showed an enhanced release of endothelial NO upon the adrenergic stimulation. The protection of vascular function found after treatment with PLC in an animal model of insulin resistance supports the necessity of clinical trials showing the effect of L-carnitine supplements on metabolic disorders.

Cedrelopsis grevei improves endothelial vasodilatation in aged rats through an increase of NO participation

Cedrelopsis grevei Baill. (Ptaeroxylaceae) trunk bark extract is empirically used in Madagascar against several pathologies, from persistent catarrh to hypertension. The effect C. grevei extract on age-related changes in systolic blood pressure (SBP) and endothelial function was investigated. Rats (90-100 week-old) received treatment either with C. grevei extract (80 mg kg(-1)) or vehicle for 8 weeks. SBP was evaluated by tail-cuff and vascular reactivity and endothelial vasodilatation of both aortae and small mesenteric arteries (SMA) were assessed by acetylcholine (ACh) in the presence or in the absence of either reactive oxygen species (ROS) scavengers superoxide dismutase (SOD) plus catalase or the nitric oxide synthase inhibitor, NG-L-arginine methyl ester (L-NAME). Plasma nitric oxide (NO) was evaluated by nitrite assay and expressions of eNOS, Cu/Zn-, Mn- and EC-SOD were determined by Western Blot. C. grevei administration prevented the increase of SBP and improved endothelium-dependent relaxations in aortae and SMA from aged rat via increased NO and decreased participation of ROS. Furthermore, C. grevei treatment enhanced plasma nitrite content but did not modify eNOS, Cu/Zn-, Mn- or EC-SOD expressions in the two arteries studied. These results suggest that C. grevei prevents both increased blood pressure and age-related endothelial dysfunction supporting the empirical use of C. grevei trunk bark extract against mild hypertension often associated with aging.

Chronic treatment with the cannabinoid 1 antagonist rimonabant altered vasoactive cyclo-oxygenase-derived products on arteries from obese Zucker rats.

To investigate the effect of chronic cannabinoid 1 antagonism on vascular prostanoid production, obese Zucker rats were treated with rimonabant (10 mg/kg per day) during 20 weeks and then vascular and endothelial reactivity were assessed in aortic rings by analyzing response to phenylephrine and acetylcholine. The presence of cyclo-oxygenase-1 and cyclo-oxygenase-2 selective inhibitors (SC-560 and NS-398, respectively) and the enzyme immunoassay revealed lower PGI2 production by aortic rings from obese rats with rimonabant able to restore such response toward levels found in the lean animals. The treatment also reduced TXB2 but did not alter its participation on acetylcholine-induced relaxation as the TP receptor antagonist ICI-192,605 revealed. Those effects were associated with an enhancement of cyclo-oxygenase-2 expression without affecting p38MAPK phosphorylation. Obese rats also exhibited higher nitric oxide plasma concentrations and greater inducible nitric oxide synthase participation on vascular phenylephrine-induced response without changes in inducible nitric oxide synthase protein expression. Although rimonabant reduced such alteration, the values were still higher than those found in lean rats. Finally, rimonabant was also able to reduce tumor necrosis factor-α produced by adipose tissue of obese Zucker rats. These results highlight a crosstalk among cannabinoids and cyclo-oxygenase-derived products in the vasculature of obese animals.