Functional Effects of Alagebrium (ALT-711)–Isolated Rat Carotid Artery

Abstract

Objective: In our study, the effects of glycosylated protein cross-link breaker, alagebrium was investigated on isolated rat carotid artery using myography. Alagebrium showed vasodilator effect on carotid artery rings; particularly, this effect was significantly increased in endothelium-intact rings. Materials and Methods:To clarify the vasodilator mechanism of alagebrium, different antagonists such as N(G)-Nitro-L-arginine methyl ester (L-NAME), glibenclamide, indomethacin, metoprolol, propranolol, tetraethylammonium, and calcium channel activator BAYK-8644 were used to reverse this effect.Results: Relaxation% responses to alagebrium were more significantly increased in intact endothelium than in denuded arteries. Blocking vasodilation related to channels (K-ATP, PGI2, BKca) and receptors (ß1, ß2) did not reverse the relaxation response to alagebrium. Vasodilator response to alagebrium was only slightly decreased after L-NAME incubation and significantly decreased after BAYK-8644 incubation. Conclusion:Results of present study suggest that the mechanism of alagebrium-induced vasodilator effect may include the blockage of L-type calcium channels and partially of the nitric oxide synthase enzyme.Keywords: Alagebrium, calcium channel blockage, carotid artery, nitric oxide, vasodilatation ÖZ Amaç: Çalışmamızda, glikozile protein çapraz bağ kırıcısı olan alagebriumun sıçanlardan elde edilen karotis arter preparatları üzerindeki etkisi myograf yöntemi ile araştırılmıştır. Alagebrium karotis arter preparatlarında vazodilatör etki göstermiş ve bu etkinin özellikle endoteli sağlam damarlarda arttığı gözlenmiştir.Gereç ve Yöntem: Alagebriumun vazodilatör mekanizmasını aydınlatmak amacıyla N(G)-Nitro-L-arginine methyl ester (L-NAME), glibenklamid, indometazin, metoprolol, propranolol, tetraetilamonyum gibi antagonistler ve kalsiyum kanal aktivatörü olan BAYK 8644 bu etkiyi geri çevirmek amacıyla kullanılmıştır. Bulgular: Alagebrium % gevşeme yanıtları, endoteli sağlam damarlarda endoteli bozulmuş damarlara göre anlamlı derecede artmıştır.. Vazodilatasyon ile ilgili kanalların (KATP, PGI2, BKca) ve reseptörlerin (ß1,ß2) bloke edilmesi de alagebrium un gevşeme yanıtını geri çevirememiştir. Alagebriuma vazodilatör cevap L-NAME uygulanması ile hafif derecede azalırken BAYK-8644 uygulanması ile anlamlı derecede azalmıştır.Sonuç: Çalışmamızın sonuçları; alagebriuma bağlı vazodilatör etki mekanizmasının L-tipi kalsiyum kanal blokajı ve kısmen de nitrik oksit sentaz enzim blokajına bağlı olduğunu göstermektedir.Anahtar Kelimeler: Alagebrium, nitrik oksit, kalsiyum kanal blokajı, karotis arter, vazodilatasyon Eurasian J Med 2017; 49: 188-92

Gut Microbiome-Derived Metabolite Trimethylamine N-Oxide Induces Aortic Stiffening and Increases Systolic Blood Pressure With Aging in Mice and Humans

“…Aortic segments were incubated under standard conditions (37 °C, 5% CO 2 , 20% O 2 , humidified) for 72 hours in culture medium alone (vehicle; DMEM supplemented with 10% fetal calf serum and 1% penicillin-streptomycin) or with the addition of 30 µmol/L TMAO (Sigma-Aldrich Corp), the average concentration measured in plasma from the dietary supplementation intervention. Vehicle- and TMAO-treated segments from a subset of mice were also treated with the AGEs inhibitor alagebrium 35–37 (N=5; 2 mmol/L; AstaTech, Inc, Bristol, PA) or the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL; N=5 mice; 100 μmol/L; Sigma-Aldrich, Corp) to suppress reactive oxygen species (ROS) production. Following the incubation, stress-strain testing was performed to assess intrinsic mechanical stiffness.…”

“…Trimethylamine N-Oxide and Aortic Stiffness measured in plasma from the dietary supplementation intervention. Vehicle-and TMAO-treated segments from a subset of mice were also treated with the AGEs inhibitor alagebrium [35][36][37] (N=5; 2 mmol/L; AstaTech, Inc, Bristol, PA) or the superoxide dismutase mimetic 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL; N=5 mice; 100 μmol/L; Sigma-Aldrich, Corp) to suppress reactive oxygen species (ROS) production. Following the incubation, stress-strain testing was performed to assess intrinsic mechanical stiffness.…”

Research Advances in Targeted Therapy for Heart Failure

“…), so changes in cooking habits and methods can help to reduce the accumulation of AGEs in the body [79]. Toprak et al [80] observed that the mechanism of the diastolic effect of alagebrium (ALT-711) on carotid arteries in healthy animals is not only to reduce the cross-linking of AGEs with collagen but that ALT-711 has the ability to improve the uptake and release of Ca 2+ from the sarcoplasmic reticulum of cardiac myocytes. Some studies have shown that the angiotensin II receptor blockers telmisartan and losartan inhibit endogenous AGE production in cultured cells in vitro [81].…”

Alagebrium Mitigates Metabolic Insults in High Carbohydrate and High Fat Diet Fed Wistar Rats

“…15 Alagebrium (ALA) was the primary drug originally introduced to break the covalent bonds formed in crosslinked proteins, in order to maintain the normal function of these proteins after being detached, and even if rebonding occur, ALA can also break up these bonds again, so reducing the tissue levels of AGEs and ameliorating their hazardous effects. 16,17 Metformin (MF) the most commonly prescribed drug for diabetes mellitus type 2 (DM-2), works by decreasing absorption of glucose from the intestine, enhancing peripheral glucose uptake, lowering fasting plasma insulin and enhancing insulin sensitivity, 18 leading to the reduction in blood glucose without causing hypoglycemia, MF can also inhibit gluconeogenesis through the activation of AMP-activated protein kinase (AMPK), which is an important energy metabolism regulator. 19 Besides, the glucose-lowering action of MF, it improves other features of MS, not only by improving the insulin sensitivity in liver and muscle 18 but also by its beneficial hypolipidemic, antioxidant, cardio-protective and anti-inflammatory actions.…”