Endothelium-Independent Relaxation of Vascular Smooth Muscle Induced by Persimmon-Derived Polyphenol Phytocomplex in Rats

The vasorelaxant effect of polyphenols is well known, and the mortality rate due to coronary artery disease is low in people who consume polyphenol-containing foods. We aimed to elucidate the mechanism by which polyphenols derived from persimmon juice (PJ) and persimmon leaves (PLs) induce vasorelaxation and suppress vasocontraction in the superior mesenteric arteries isolated from male Sprague Dawley rats. Vasocontraction was induced with 1 µM phenylephrine, and polyphenol-induced vasorelaxation was expressed as a percentage of the previous tone induced by phenylephrine. PJ powder (100 mg/L) induced higher levels of vasorelaxation (mean ± standard error of the mean, 88.6% ± 4.4%) than PLs powder (1 g/L; 72.0% ± 10.8%). Nitric oxide pathway inhibitors (NG-nitro-L-arginine methyl ester + carboxy-PTIO) did not affect persimmon-derived polyphenol-induced vasorelaxation, whereas potassium chloride, tetraethylammonium, and potassium-channel inhibitors did. Vasorelaxation was endothelium independent with both extracts. Phenylephrine-induced vasocontraction was suppressed by pretreatment with PJ and PLs powder, even when inositol triphosphate-mediated Ca2+ release and extracellular Ca2+ influx were inhibited. These results suggest that persimmon-derived polyphenol phytocomplex cause vasorelaxation and inhibit vasocontraction through hyperpolarization of smooth muscle cells. Persimmon-derived polyphenols may be able to prevent cardiovascular diseases caused by abnormal contraction of blood vessels.

Effect of Co-Administration of Curcumin with Amlodipine in Hypertension

Curcumin, a curcuminoid known as the main bioactive compound of turmeric, is used in foods, cosmetics, and pharmaceutical products. Amlodipine is a general antihypertensive drug used in combination with various other antihypertensive agents. To date, no studies have examined the effects of the co-administration of amlodipine with curcumin. In this study, the vasodilatory effects of curcumin, amlodipine, and the co-administration of curcumin with amlodipine on isolated rat aortic rings pre-contracted with phenylephrine were evaluated, and the hypotensive effects were evaluated using the tail cuff method. To measure blood pressure, male spontaneously hypertensive rats were divided into four groups, each containing six rats, as follows: amlodipine 1 mg/kg alone treated, amlodipine 1 mg/kg with curcumin 30 mg/kg treated, amlodipine 1 mg/kg with curcumin 100 mg/kg treated, and amlodipine 1 mg/kg with curcumin 300 mg/kg treated groups. Amlodipine and curcumin were intraperitoneally injected, and systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured at 1, 2, 4, and 8 h after administration. The combined administration of curcumin and amlodipine induced a stronger vasorelaxant effect than amlodipine alone. However, co-administration did not significantly lower SBP and DBP compared to the single administration of amlodipine. The results of this study suggest that hypertensive patients taking amlodipine can consume curcumin or turmeric for food or other medical purposes without inhibiting the blood pressure-lowering effect of amlodipine.

The Combined Inotropic and Vasorelaxant Effect of DHQ-11, A Conjugate of Flavonoid Dihydroquercetin with Isoquinoline Alkaloid 1-Aryl-6,7-Dimethoxy-1,2.3,4-Tetrahydroisoquinoline.

This study investigated the positive inotropic andvasorelaxant activity ofDHQ-11, aconjugate of flavonoid dihydroquercetin with isoquinoline alkaloid 1-aryl-6,7-dimethoxy-1,2.3,4-tetrahydroisoquinoline.A study was performed using anterior papillary muscle removed from the left ventricle and thoracic aorta dissected from rats. DHQ-11 produceda concentration-dependent positive inotropic effect which was more potent than their parent compounds alone. The positive inotropic effect of conjugate DHQ-11was significantly attenuated by the β-adrenoreceptor inhibitor propranolol and L-type Ca2+ channel blocker nifedipine. Also,conjugate DHQ-11 markedly potentiated first post-rest responses indicating that it can modulate Ca2+ loading/release processes in the sarcoplasmic reticulum.These results suggest that positive inotropic effect produced by conjugate DHQ-11may be mediated through activation oftheβ-AR/AC/cAMP/PKA pathway that leads to increased Ca2+ influx and rises in Ca2+ loading/release in the SR, resulting in increased [Ca2+]i and enhanced contraction force. DHQ-11 significantly relaxed both high KCl- and phenylephrine-induced contractions of rat aortic rings whichwere significantly inhibited by lowering extracellular Ca2+ concentration and in the presence of verapamil.DHQ-11 significantly inhibited phenylephrine-induced contractions in a Ca2+-free medium, in the presence of verapamil. The vasorelaxant effect of the DHQ-11 was significantly reduced by the removal of endothelium and in the presenceof L-NAME and methylene blue as well as glibenclamide and TEA.These results suggest that the vasorelaxation produced by conjugate DHQ-11may be mediatedbyan endothelium-independent mechanism involving activation of KATP and BKCa channels and inhibition of L-type VDCCs and Ca2+ release from the sarcoplasmic reticulum and endothelium-dependent mechanism through activation of the NO/sGC/cGMP/PKG signaling pathway resulting in a decrease of intracellular Ca2+levels. These observations reveal that the conjugate DHQ-11 due to its high positive inotropic and vasorelaxant activity could be a promising compound for the design and development of new drugs for the treatment of heart failure.

Gentiopicroside Produces Endothelium-Independent Vasodilation by Deactivating the PI3K/Akt/Rho-Kinase Pathway in Isolated Rat Thoracic Aorta

Gentiopicroside (GPS), a main active secoiridoid glucoside derived from the roots of perennial herbs in the Gentianaceae family, has antispasmodic and relaxant effects. However, the vasorelaxant effects of GPS on aortic rings and the molecular mechanisms involved in these effects are not yet clear. Therefore, we investigated whether GPS inhibits phenylephrine- (PE-) or KCl-induced contractions in isolated rat thoracic aortic rings. The present study found that GPS produced a dose-dependent relaxation in aortic rings precontracted with PE or KCl and significantly reduced CaCl2-, narciclasine- (Rho-kinase activator-), and phorbol-12,13-diacetate- (PKC activator-) induced vasocontractions. Pretreatment with NG-Nitroarginine methyl ester hydrochloride (L-NAME, NOS inhibitor), methylene blue (sGC inhibitor), indomethacin (COX inhibitor), 4-aminopyridine (KV channel inhibitor), and glibenclamide (KATP channel inhibitor) had no influence on the vasorelaxant effect of GPS, while BaCl2 (Kir channel inhibitor), tetraethylammonium chloride (KCa channel inhibitor), ruthenium red (RYR inhibitor), and heparin (IP3R inhibitor) significantly reduced GPS-induced vasorelaxation. Moreover, GPS pretreatment remarkably inhibited the influx of Ca2+ in vascular smooth muscle cells stimulated using KCl or PE-containing CaCl2 solution. Western blot analysis confirmed that GPS treatment inhibited PE-induced increases in the protein levels of p-Akt, p-myosin light chain (MLC), and p-myosin-binding subunit of myosin phosphatase 1 (MYPT1) in the aortic rings. Additionally, the vasorelaxation activity of GPS was attenuated upon pretreatment with LY294002 (PI3K/Akt inhibitor), Y27632 (Rho-kinase inhibitor), and verapamil (L-type Ca2+ channel inhibitor). These findings demonstrate that GPS exhibits endothelium-independent vasorelaxant effects through inhibition of voltage-dependent, receptor-operated, and inositol triphosphate receptor (IP3R)/ryanodine receptor- (RYR-) mediated Ca2+ channels as well as the PI3K/Akt/Rho-kinase signaling pathway.

Role of pregnancy on insulin-induced vasorelaxation: the influence of angiotensin II receptors

Pregnancy is characterized by insulin resistance that is associated with increased angiotensin II (AngII) and insulin levels. Therefore, pregnancy may change insulin-induced vasodilation through changes in AngII receptors. Insulin-induced vasorelaxation was evaluated in phenylephrine-precontracted aortic rings of pregnant and non-pregnant rats, using a conventional isolated organ preparation. Experiments were performed in thoracic or abdominal aorta rings with or without endothelium in the presence and absence of L-NAME (10-5 M), losartan (10-7 M) or PD123319 (10-7 M). AT1 and AT2 receptors expression were detected by immunohistochemistry. Insulin-induced vasodilation was endothelium and NO dependent and decreased in the thoracic aorta but increased in the abdominal segment of pregnant rats. Insulin’s vasorelaxant effect was increased by losartan mainly on the thoracic aorta. PD123319 decreased insulin-induced vasorelaxation mainly in the pregnant rat abdominal aorta. AT1 receptors’ expression was decreased while AT2 receptors’ expression was increased by pregnancy. In conclusion, pregnancy changes insulin-induced vasorelaxation. Moreover, insulin vasodilation is tonically inhibited by AT1 receptors, while AT2 receptors appear to have an insulin-sensitizing effect. The role of pregnancy and AngII receptors differ depending on the aorta segment. These results shed light on the role of pregnancy and AngII receptors on the regulation of insulin-mediated vasodilation.

Vasorelaxation in rat pulmonary artery induced by the monoterpene thymol: evaluation of the endothelium derived relaxant factors dependence

Thymol and carvacrol are the main compounds found in Lippia mycrophylla essential oil (LM-OE) and have presented some spasmolytic effects. This work was designed to explore a possible vasorelaxant effect of LM-OE and its major monoterpenes constituents on rat pulmonary artery. For that, the organ was in vitro stimulated with phenylephrine (Phe) 3 mM and over the tonic contraction the relaxant effect of LM-OE, carvacrol and thymol was observed in both intact and denuded-endothelium. Moreover, atropine, L-NAME, indomethacin, 2,3-O-isopropylidene adenosine, H-89 and Y-27632 were incubated before the relaxant curve of thymol over Phe-tonic contraction. Furthermore, the effects of thymol on KCl 30 or 80 mM and S-(−)-Bay K8644-induced tonic contractions were evaluated, as well as its inhibitory effect on CaCl2-induced cumulative contractions. LM-OE, carvacrol and thymol presented relaxant effect on pulmonary artery, thymol was the most potent and its relaxant potency in intact-endothelium preparations was reduced by atropine, L-NAME, indomethacin, 2,3-O-isopropylidene adenosine and H-89, despite there was not change on its maximum relaxat effect. Also, the monoterpene relaxed equipotently KCl 30 or 80 mM pre-contracted pulmonary artery, antagonized CaCl2-induced cumulative contractions and relaxed S-(−)-Bay K8644 pre-contracted organ. Ultimately, thymol relaxant potency was not modified by Y-27632. Therefore, thymol acts by endothelium-dependent and independent mechanisms, possibly positively modulating the endothelial cholinergic pathway, prostanoids release and further activation of AC/PKA and also inhibiting Ca2+ influx through CaV.