Plasma Concentrations of Trace Elements Selenium and Cobalt During and After Coronary Artery Bypass Grafting Surgery.

Trace elements selenium (Se) and cobalt (Co) are essential in the human body, and a correlation between Se and cardiac surgery has been suggested. We investigated the plasma concentrations of Se and Co during and after coronary artery bypass grafting (CABG) surgery under cardiopulmonary bypass (CPB). From December 2019 to January 2020, preoperative plasma samples from isolated first-time CABG patients (n=20; 10 males, 10 females) were prospectively collected post-anesthesia and before CPB (T1), 45 min after CPB started (T2), 90 min after CPB started (T3), and postoperative days 1 (T4), and day 4 (T5). The plasma concentrations of Se and Co were measured. The Se concentration was significantly decreased at T2 (105.24±4.08 vs. 68.56±2.42 µg/L, p<0.001) and T3 (105.24±4.08 vs. 80.41±3.40 µg/L, p<0.001). The Co concentration was significantly decreased at T4 (0.35±0.19 vs. 0.26±0.13 µg/L, p<0.01) and T5 (0.35±0.19 vs. 0.23±0.11 µg/L, p<0.001). Five patients developed atrial fibrillation (AF); there was no other operative mortality or major morbidity. This is the first report of alterations of plasma Se and Co concentrations during and after CABG surgery. Our results may indicate that Se supplementation before or during CABG and Co supplementation after CABG may become necessary for patients undergoing CABG.

Alteration of plasma trace elements magnesium, copper, zinc, iron and calcium during and after coronary artery bypass grafting surgery.

BACKGROUND: Dietary factors including trace elements contribute to the development of disorders including coronary artery diseases. Whether there are differences in concentrations of trace elements between on-pump and off-pump coronary artery bypass grafting (CABG) surgery remains unclear. The aim of this study was to investigate the differences in the plasma level of four trace elements Cu, Fe, Zn, magnesium (Mg), and calcium (Ca) during and after CABG between on-pump and off-pump procedure and the correlation between these trace elements and the development of postoperative AF. METHODS: Fifty-three CABG patients using on-pump or off-pump methods were enrolled. The blood sample was taken before skin incision (T1), 4 h after skin incision (T2), postoperative day1 (T3), and day3 (T4) respectively. Plasma concentrations of Mg, Ca, Fe, Zn, and Cu were determined. RESULTS: The plasma Mg concentration reached the highest level at T3 (0.94 ± 0.03 vs. 1.20 ± 0.03 mmol/L,P < 0.001) and completely recovered at T4 whereas Zn (11.28 ± 0.23 vs. 6.80 ± 0.20 mmol/L, P < 0.001) and Fe (10.97 ± 0.51 vs. 2.22 ± 0.1 µmol/L, P < 0.001) was lowest at T3 and partially recovered at T4. Cu was lowest at T2 (12.10 ± 0.33 vs. 9.62 ± 0.25 µmol/L, P < 0.001) then increased until T4. There were significant differences in Mg and Fe (P < 0.05), as well as Cu (P < 0.01) between on-pump and off-pump groups. No significant differences were detected between postoperative atrial fibrillation and sinus rhythm groups. CONCLUSIONS: In CABG, Cu and Zn are significantly reduced and Cu is recovered at postoperative Day 1 but Zn takes longer to recover. Addition of Mg and Ca during CABG are sufficient to maintain the plasma concentration. However, supplementation of Cu and Zn during and after CABG may be necessary. Further, the correlation between these trace elements and postoperative AF is to be further determined.

Total Flavone of Rhododendron Improves Cerebral Ischemia Injury by Activating Vascular TRPV4 to Induce Endothelium-Derived Hyperpolarizing Factor-Mediated Responses.

BACKGROUND: Total flavonoids of Rhododendron (TFR) is extracted from Rhododendron, a herbal medicine widely used in China. The main components are flavone compounds such as warfarin, rutin, quercetin, and hyperoside. We investigated the role of TRPV4 channel in the TFR induced endothelium-dependent hyperpolarizing factor- (EDHF-) mediated responses against ischemia/reperfusion injury (IR) in cerebral IR (CIR) rats. METHODS: The morphological changes of cerebral cortex, the relaxation of cerebral basal artery (CBA), and cell membrane potential recording were studied in CIR rats. The outward potassium current in smooth muscle cell was recorded by whole-cell patch clamp recording. The protein expression of TRPV4, SKca, and IKca was determined. Confocal laser was used to measure the Ca2+ fluorescence intensity. RESULTS: After treatment with TFR, the number of pyramidal cells in brain tissue increased and the number of empty or lightly stained cells decreased and these effects were eliminated by using HC-067047, Apamin, or TRAM-34. TFR induced and EDHF-mediated dilatation and hyperpolarization in CBA were also attenuated by using these inhibitors. The increased outward current density elicited by TFR in acutely isolated CBA smooth muscle cells was abolished by using TRAM-34 and Apamin. TFR upregulated the protein expression of TRPV4, SKca, and IKca that was also eliminated by these inhibitors. Laser scanning showed that the increased mean fluorescence intensity of Ca2+ by CIR was decreased by using TFR and that this effect was again eliminated by the above inhibitors. CONCLUSIONS: We conclude that in the CBA of the CIR rats the protective effect of TFR on ischemic cerebrovascular injury may be related to the activation of the TRPV4 in both endothelium and smooth muscle by increasing its expression and activity. The activation of TRPV4 channel in the endothelium may be linked to the opening of endothelial IKca/SKca channels that induces EDHF-mediated relaxation and hyperpolarization in the smooth muscle cell. In addition, the activation of TRPV4 in the smooth muscle cell in CBA may be linked with the activation of BKCa channel through a TRPV4-dependent pathway, reduce Ca2+ concentration in the cell, and relaxes the vessel. These findings may form a new therapeutic target for protection of ischemic brain injury and facilitate the use of Chinese medicine in brain protection.

Effect of Benidipine in Human Internal Mammary Artery and Clinical Implications.

BACKGROUND: Graft spasm remains challenging in coronary artery bypass grafting (CABG). Calcium antagonists are commonly used in patients with coronary artery disease. This study investigated the inhibitory effect of third-generation dihydropyridine calcium channel antagonist benidipine on the vasoconstriction induced by various vasoconstrictors in the human internal mammary artery (IMA). METHODS: Isolated human IMA rings (N = 65, taken from 37 patients undergoing CABG) were studied in a myograph in 2 ways: the relaxing effect of benidipine on vasoconstrictor-induced precontraction by KCl and U46619 and the depressing effect of benidipine at plasma concentrations on the contraction. Enzyme-linked immunosorbent assay (ELISA) was used to measure the change of the protein related to the L-type calcium channel. RESULTS: Benidipine caused more relaxation in KCl-contracted (86.7% ± 3.3%; n = 12) than in U46619-contracted (63.8% ± 5.3%; n = 8; p < 0.001) IMA rings. Pretreatment of IMA with plasma concentrations of benidipine (-6.92 log M) significantly depressed subsequent contraction by KCl (from 17.3 ± 2.7 mN to 7.4 ± 1.2 mN; n = 6; p < 0.05) but did not significantly affect the contraction caused by U46619. Benidipine also caused a decrease of caveolin (CaV)1.2 protein content (0.55 ± 0.02 versus 0.63 ± 0.02 mg/mL; p < 0.05). CONCLUSIONS: We conclude that in human IMA, the third-generation dihydropyridine calcium channel antagonist benidipine has a potent inhibitory effect on the vasoconstriction mediated by a variety of vasoconstrictors. Use of benidipine in patients undergoing CABG may provide vasorelaxant or antispastic effects in the grafts.

L-citrulline for protection of endothelial function from ADMA-induced injury in porcine coronary artery.

Endogenous nitric oxide synthase (eNOS) inhibitor asymmetric dimethylarginine (ADMA) is a cardiovascular risk factor. We tested the hypothesis that L-citrulline may ameliorate the endothelial function altered by ADMA in porcine coronary artery (PCA). Myograph study for vasorelaxation, electrochemical measurement for NO, RT-PCR, and Western blot analysis for expression of eNOS, argininosuccinate synthetase (ASS), and p-eNOS(ser1177) were performed. cGMP was determined by enzyme immunoassay. Superoxide anion (O2.(-)) production was detected by the lucigenin-enhanced chemiluminescence method. Compare with controls (96.03% ± 6.2%), the maximal relaxation induced by bradykinin was significantly attenuated (61.55% ± 4.8%, p<0.01), and significantly restored by L-citrulline (82.67 ± 6.4%, p<0.05) after 24 hours of ADMA exposure. Expression of eNOS, p-eNOS(ser1177), and ASS in PCA significantly increased after L-citrulline incubation. L-citrulline also markedly restored the NO production, and cGMP level which was reduced by ADMA. The increased O2.(-) production by ADMA was also inhibited by L-citrulline. L-citrulline restores the endothelial function in preparations treated with ADMA by preservation of NO production and suppression of O2.(-) generation. Preservation of NO is attributed to the upregulation of eNOS expression along with activation of p-eNOS(ser1177). L-citrulline improves endothelium-dependent vasodilation through NO/ cGMP pathway.

Protective Effect and Mechanism of Total Flavones from Rhododendron simsii Planch on Endothelium-Dependent Dilatation and Hyperpolarization in Cerebral Ischemia-Reperfusion and Correlation to Hydrogen Sulphide Release in Rats.

We for the first time investigated the effect and mechanism of the total flavones of Rhododendron simsii Planch (TFR), a widely-used Chinese herb for a thousand years, on vasodilatation and hyperpolarization in middle cerebral artery (MCA) of rats subject to global cerebral ischemia-reperfusion (CIR). TFR (11~2700 mg/L) evoked dose-dependent vasodilation and hyperpolarization in MCA of both sham and CIR that were partially inhibited by 30 µM N-nitro-L-arginine-methyl-ester and 10 µM indomethacin and further attenuated by endogenous H2S synthese-CSE inhibitor PPG (100 µM) or Ca(2+)-activated potassium channel (Kca) inhibitor TEA (1 mM). In whole-cell patch clamp recording, TFR remarkably enhanced the outward current that was inhibited by TEA. CIR increased CSE mRNA expression and the contents of H2S that were further increased by TFR. We conclude that, in MCA of CIR rats, TFR induces non-NO and non-PGI2-mediated effects of vasodilatation and hyperpolarization involving Kca and increases CSE mRNA expression level in endothelial cells and H2S content in the cerebrum. These findings suggest that the response induced by TFR is potentially related to endothelium-derived hyperpolarizing factor mediated by the endogenous H2S and promote the use of TFR in protection of brain from ischemia-reperfusion injury.

Suxiao jiuxin pill induces potent relaxation and inhibition on contraction in human artery and the mechanism.

Suxiao Jiuxin Pill, a compound Chinese traditional medicine with main components of tetramethylpyrazine and borneol, is widely used for antiangina treatment in China but its pharmacological effect on human blood vessels is unknown. We investigated the effect and possible mechanism of SJP in the human internal mammary artery (IMA, n = 78) taken from patients undergoing coronary surgery. SJP caused full relaxation in KCl- (99.4 ± 10.5%, n = 6) and U46619- (99.9 ± 5.6%, n = 6) contracted IMA. Pretreatment of IMA with plasma concentrations of SJP (1 mg/mL), calculated from the plasma concentration of its major component borneol, significantly depressed the maximal contraction to KCl (from 35.8 ± 6.0 mN to 12.6 ± 5.6 mN, P = 0.03) and U46619 (from 19.4 ± 2.9 mN to 5.7 ± 2.4 mN, P = 0.007) while SJP at 10 mg/mL abolished the subsequent contraction. Endothelium denudation and inhibition of eNOS significantly altered the SJP-induced relaxation without changes of eNOS expression. We conclude that SJP has a potent inhibitory effect on the vasoconstriction mediated by a variety of vasoconstrictors in human arteries. The vasorelaxation involves both endothelium-dependent and -independent mechanisms. Thus, the effect of SJP on human arteries demonstrated in this study may prove to be particularly important in vasorelaxing therapy in cardiovascular disease.

Alteration of plasma trace elements in patients undergoing open heart surgery.

Trace elements may contribute to myocardial dysfunction and susceptibility of the phospholipid cell membrane to free-radical damage and oxidative changes. We studied the concentration of trace elements copper, zinc, and magnesium in cardiac surgery. Fifty-four consecutive patients for elective coronary artery bypass grafting (n = 30) and valve replacement (n = 24) were studied. Blood samples were collected every 30 min (T1-T5) during cardiopulmonary bypass and postoperatively (T6-T9). Plasma concentrations of copper, zinc, and magnesium were measured with flame atomic absorption spectrophotometry. The concentrations of copper, zinc, and magnesium were significantly different during and after cardiopulmonary bypass (p < 0.01). The zinc concentration at T7 and T8 (p < 0.01) and the copper concentration at T1, T9 (p < 0.05) were significantly different between two groups. However, the magnesium concentration had no significant differences between the two groups (p > 0.05). In patients undergoing valve replacement or coronary artery bypass grafting, the concentrations of copper and zinc decreased significantly during cardiopulmonary bypass. Our study suggests that the current cardiopulmonary bypass protocol is adequate in the maintenance of c magnesium. However, the low copper and zinc concentrations found in the present study may suggest that in the future, supplementation particularly of copper and zinc may become a necessary procedure in cardiac surgery with cardiopulmonary bypass.

Release of nitric oxide and endothelium-derived hyperpolarizing factor (EDHF) in porcine coronary arteries exposed to hyperkalemia: effect of nicorandil.

BACKGROUND: Although the detrimental effect of hyperkalemia on coronary endothelium has been reported, there is no direct evidence regarding the effect of hyperkalemic exposure on nitric oxide (NO) release from the coronary endothelium. In addition, it is unclear whether nicorandil, a KATP channel opener, used as hyperpolarizing cardioplegia or added in hyperkalemic cardioplegic solution may protect endothelial function during cardiac surgery. The present study was designed to clarify NO release and the function of endothelium-derived hyperpolarizing factor (EDHF) in coronary circulation with respect to the effect of hyperkalemia and nicorandil. METHODS: Nitric oxide was measured by using a NO-specific electrode, and EDHF-mediated relaxation was investigated in a myograph. Substance P- and calcium ionophore A23187-induced NO release was compared in porcine left circumflex coronary arteries before and after 1-hour exposure to 20 mM potassium (K+) at 37 degrees C. In coronary microarteries (diameter 200 to 450 microm), precontracted with U46619, in the presence of indomethacin (7 microM), NG-nitro-L-arginine (300 microM), and oxyhemoglobin (20 microM), EDHF-mediated relaxation was induced by bradykinin (-10 to -6.5 log M) after incubation with Krebs (control) or 20 mM K+ with or without 10 microM nicorandil at 37 degrees C for 1 hour. RESULTS: Neither substance P (58.8 +/- 5.0 versus 66.2 +/- 7.2 nmol/L) nor A23187 (86.6 +/- 9.0 versus 82.4 +/- 9.2 nmol/L in control) induced NO release was altered by hyperkalemic exposure (p > 0.05). In contrast, EDHF-mediated relaxation was decreased from 84.2% +/- 3.8% to 42.3% +/- 6.0% (p < 0.001) that was partially restored by nicorandil (50.7% +/- 5.5%, p < 0.05). CONCLUSIONS: Exposure to potassium at 20 mM does not affect NO release but impairs EDHF-mediated relaxation in coronary arteries. Supplementation of nicorandil in hyperkalemic cardioplegia may provide a protective effect on EDHF-related endothelial function.

Nitric oxide and endothelium-derived hyperpolarizing factor in human arteries and veins.

BACKGROUND: We have investigated and compared nitric oxide (NO) release and endothelium-derived hyperpolarizing factor (EDHF)-mediated hyperpolarization in the human internal mammary artery (IMA), radial artery (RA), saphenous vein (SV), and coronary artery. MATERIALS AND METHODS: Vessel segments taken from coronary artery bypass grafting or heart transplantation patients were placed in an organ chamber. NO-sensitive electrode or intracellular glass microelectrode was used to study NO or EDHF in response to acetylcholine (ACh) and bradykinin (BK). RESULTS: The resting membrane potential of the smooth muscle cells of IMA, RA, and SV was -58 +/- 0.84 (n = 61), -61 +/- 1.3 mV (n = 46, p = 0.03), and -62 +/- 0.9 mV (n = 23, p = 0.0001) respectively. BK- (10(-7) M) induced EDHF-mediated hyperpolarization (-10.9 +/- 1.5 mV, n = 7) in the IMA was significantly greater than that in RA (-5.8 +/- 0.9 mV, n = 6, p = 0.04) and SV (-5.1 +/- 0.5 mV, n = 8, p < 0.01). The basal release of NO in IMA (16.8 +/- 1.9 nM) was significantly higher than that in RA (11.1 +/- 1.0 nM, n = 12, p = 0.02) and in SV (9.9 +/- 2.8 nM, n = 13, p < 0.001). The stimulated release of NO to BK in IMA was significantly greater than that in RA (44.3 +/- 4.0 vs 25.8 +/- 3.6 nM, n = 8, p = 0.004). The duration of NO release was longer in IMA than in RA or in SV. CONCLUSIONS: The basal and stimulated release of NO and EDHF-mediated hyperpolarization in the IMA are significantly greater than that in the RA and SV. EDHF exists in all these human vessels. This study reveals the differences among human vessels regarding the endothelial function that have implications in vasospasm, coronary protection, or long-term graft patency.