Influence of Low Concentrations of Carbon Monoxide on Metabolism of Isolated Heart under Conditions of Ischemia-Reperfusion

The purpose of the study was to determine the effect of different concentrations of carbon monoxide on the metabolism of isolated mice hearts. Materials and methods. To elucidate the effect of low concentrations of carbon monoxide on the myocardium, we performed retrograde perfusion of isolated hearts of laboratory mice with Krebs-Henseleit solution, which was saturated with carbon monoxide for 5, 10, and 30 minutes. We then determined how different concentrations of carbon monoxide affected coronary volumetric flow rate, myocardial glucose and calcium uptake, creatinine release, and aspartate aminotransferase release. During perfusion, R-wave amplitude and R-R interval were measured using an electrocardiograph. To determine the effect of ischemia on the heart muscle during perfusion with solutions of different concentrations, we measured the area of the affected myocardium after staining with 2,3,5-triphenyltetrazolium chloride. Results and discussion. After these studies, it was found that different concentrations of carbon monoxide had a dose-dependent effect on the isolated mouse heart. However, the dependence of the effects does not follow the pattern «lowest concentration – lowest effect». At the same time, an increase in concentration did not mean an increase in adverse effects on the myocardium. Even on the contrary, the smallest concentration led to increased signs of ischemic myocardial damage. In particular, the use of the solution, through which carbon monoxide was passed for 5 minutes, caused vasoconstrictor effect during perfusion. At the end of reperfusion, vasoconstrictor effect was observed after using a solution through which carbon monoxide was passed for 10 minutes. Increased glucose uptake was observed in the group with 30-minute carbon monoxide permeation against the background of the minimal myocardial creatinine release. In this group there was also a decrease in Ca2+ loss at the beginning of reperfusion (immediately after ischemia). The above phenomenon explains the least degree of ischemic myocardial damage in the isolated mouse heart. The obtained data should be expanded. Since it is difficult to accurately determine the dose of carbon monoxide, then the use of donor compounds is promising. Such compounds include CORM-2 and CORM-3. Under physiological conditions, they decompose in a controlled manner, releasing a specific amount of carbon monoxide. Conclusion. The obtained results indicate that at different concentrations of carbon monoxide can differently influence different structures of cardiomyocyte: at one concentration it binds to calcium channels, other concentrations influence ion channels of plasma membrane, which can explain all these dependencies

Relationship between endothelin and nitric oxide pathways in the onset and maintenance of hypertension in children and adolescents

The mechanisms that regulate blood pressure are numerous and complex; one mechanism that plays an important role in this scenario is represented by the balance between the vasoconstrictor effect of endothelin-1 and the vasodilator effect of nitric oxide. While there is agreement on the fact that increased endothelin-1 activity and decreased nitric oxide bioavailability are present in hypertensive adults, the situation is less clear in children and adolescents. Not all studies agree on the finding of an increase in plasma endothelin-1 levels in hypertensive children and adolescents; in addition, the picture is often confused by the concomitant presence of obesity, a condition that stimulates the production of endothelin-1. Furthermore, there is recent evidence that, in younger obese and hypertensive subjects, there is an overproduction of nitric oxide, rather than a reduction. This condition may change over time, causing endothelial dysfunction due to a reduced availability of nitric oxide in hypertensive adolescents. The purpose of this review is to address the main biochemical and pathophysiological aspects of endothelin and nitric oxide involvement in hypertension and to summarize the available scientific evidence on their role in the onset and maintenance of high blood pressure in children and adolescents.

Sphingosine-1-Phosphate Enhances α1-Adrenergic Vasoconstriction via S1P2–G12/13–ROCK Mediated Signaling

Sphingosine-1-phosphate (S1P) has been implicated recently in the physiology and pathology of the cardiovascular system including regulation of vascular tone. Pilot experiments showed that the vasoconstrictor effect of S1P was enhanced markedly in the presence of phenylephrine (PE). Based on this observation, we hypothesized that S1P might modulate α1-adrenergic vasoactivity. In murine aortas, a 20-minute exposure to S1P but not to its vehicle increased the Emax and decreased the EC50 of PE-induced contractions indicating a hyperreactivity to α1-adrenergic stimulation. The potentiating effect of S1P disappeared in S1P2 but not in S1P3 receptor-deficient vessels. In addition, smooth muscle specific conditional deletion of G12/13 proteins or pharmacological inhibition of the Rho-associated protein kinase (ROCK) by Y-27632 or fasudil abolished the effect of S1P on α1-adrenergic vasoconstriction. Unexpectedly, PE-induced contractions remained enhanced markedly as late as three hours after S1P-exposure in wild-type (WT) and S1P3 KO but not in S1P2 KO vessels. In conclusion, the S1P–S1P2–G12/13–ROCK signaling pathway appears to have a major influence on α1-adrenergic vasoactivity. This cooperativity might lead to sustained vasoconstriction when increased sympathetic tone is accompanied by increased S1P production as it occurs during acute coronary syndrome and stroke.

ECMO usefulness in refractory shock secondary to Phenylephrine poisoning: About a case in a Pediatric subject

Introduction: Phenylephrine is an alpha-agonist with vasoconstrictor effect. Systemic absorption or adverse reaction can cause complications that can be lethal. In those cases of adverse drug reactions with failure to conventional management, the use of ECMO has been reported as a treatment modality. Clinical case: We report the case of a 13 years old teenager, who presented acute pulmonary edema and acute heart failure subsequent to the application of topical phenylephrine during the a rhino-septoplasty procedure, and that warranted placement of ECMO due to failure of conventional treatment. Discussion: Venoarterial ECMO was placed by central cannulation, with ventilatory and hemodynamic improvement, performing the explant successful 4th postoperative day. Conclusions: ECMO as a "bridge to recovery" may be an alternative in those cases of pulmonary or cardiac failure and refractory with a poor response to conventional treatment, as well as an option to save the life of these patients.

The Role of Endothelial Dysfunction in the Development of Cardiotoxic Action of Cytostatics in Patients with Lymphoproliferative Diseases

Understanding mechanisms of chemotherapy cardiotoxicity is an important problem due to the lack of clear understanding of its occurrence. Development of endothelial dysfunction is considered to be one of possible ways in implementation of these side effects. The analysis of endothelin-1 and e-selectin levels in 26 patients with lymphoproliferative diseases before and after the completion of the treatment program was been performed. The results of the study showed normal values of E-selectin level and increased level of endothelin-1 in the whole group of patients before treatment. After completion of chemotherapy program, in the whole group, there was a decrease of these two markers. However, values of level of endothelin-1 with vasoconstrictor effect remained high even after the end of therapy. It is imp ortant that at detailed analysis the dynamics of investigated markers in patients of older age group (median age 64 years) was associated with worsening of endothelial dysfunction.

Adding low concentrations of clonidine to ropivacaine for transversus abdominis plane blocks does not reduce plasma ropivacaine levels, suggesting a lack of vasoconstrictor effect

Clonidine has been used successfully to prolong the duration of action of local anaesthetics in peripheral nerve blocks, but its mechanism of action in this setting remains unclear. Some studies suggest that clonidine exerts a vasoconstrictor effect, limiting the washout of local anaesthetic from its site of deposition. We investigated this potential vasoconstrictor effect, using plasma ropivacaine concentrations as a surrogate measure of vasoconstriction, in patients who received transversus abdominis plane (TAP) blocks with and without clonidine. Eighty women undergoing laparoscopic gynaecological surgery were randomly assigned to receive one of four TAP block solutions: 0.2% ropivacaine (control), ropivacaine with clonidine 2 μg/kg (clonidine), ropivacaine with 1:400,000 adrenaline (adrenaline) or ropivacaine and a subcutaneous injection of clonidine 2 μg/kg (SC clonidine). The primary outcome was total venous plasma ropivacaine concentrations up to 6 h after the block. There were no significant differences in plasma ropivacaine concentrations between the control group and the clonidine group at any timepoint in the study, nor were there differences in either the mean maximum ropivacaine concentration ( Cmax) (1.99 μg/mL versus 2.05 μg/mL, P = 0.712) or the time to maximum concentration ( Tmax) (51.0 min versus 56.0 min, P = 0.537). The SC clonidine group also did not differ significantly from the controls ( Cmax 2.13 μg/mL versus 1.99 μg/mL, P = 0.424; Tmax 43.5 min versus 51.0 min, P = 0.201). Plasma ropivacaine concentrations in the adrenaline group were significantly lower than the controls from 10 to 90 min ( P < 0.003 for each comparison), and the Cmax was less than that of the control group (1.36 μg/mL versus 1.99 μg/mL, P < 0.001) with a longer Tmax (103.5 min versus 51.0 min, P = 0.001). These findings indicate that clonidine at a concentration of 1.35 μg/mL added to ropivacaine for TAP blocks did not produce a reduction in plasma ropivacaine concentrations. This suggests a lack of vasoconstrictor effect during TAP blocks. Further studies should evaluate whether vasoconstriction occurs when clonidine is used at higher concentrations or for other blocks.

Abstract 079: Dipeptidyl Peptidase IV (DPP4) Inhibition Enhances the Vasoconstrictor Response to Neuropeptide Y During Angiotensin-converting Enzyme Inhibition

Background: Dipeptidyl peptidase IV (DPP4) inhibitors are antidiabetic medications that may increase risk of heart failure. Neuropeptide Y (NPY), a substrate of DPP4, is co-released with norepinephrine (NE) and causes vasoconstriction via the Y1 receptor. We tested the hypothesis that DPP4 inhibition would potentiate the effect of exogenous NPY on forearm blood flow (FBF). Methods: Seven healthy non-smokers participated in a randomized, double-blinded, placebo-controlled crossover study. Subjects underwent two study days and received sitagliptin 100 mg daily or placebo for seven days before each study day. On each study day, NPY was infused at 0.1, 0.3, 1.0, and 3.0 nmol/min through the brachial artery and FBF was measured using plethysmography. Following 90-minute washout, subjects received intra-arterial enalaprilat and NPY infusion was repeated. Venous and arterial samples were obtained for NE and NPY. Results: FBF decreased to a similar extent with increasing doses of NPY during sitagliptin and placebo (Figure 1). During enalaprilat, sitagliptin potentiated the vasoconstrictor effect of NPY compared to placebo (FBF 1.32 vs 1.94 mL/min/100mL at 0.3 nmol/min NPY during sitagliptin and placebo, respectively, P=0.039, Figure 1). NE decreased with ACE inhibition during NPY infusion, but this effect was not altered by DPP4 inhibition (Change in NE -47 vs -66 pg/mL with sitagliptin and placebo, respectively, P=0.92). Conclusion: DPP4 inhibition potentiates the vasoconstrictor effect of NPY in the forearm vasculature in the setting of ACE inhibition. These findings have implications for the cardiovascular effects of DPP4 inhibitors in patients receiving ACE inhibitors.

Terlipressin Induced Severe Hyponatremia

Terlipressin is a vasopressin analogue used for its vasoconstrictor effect in the treatment of variceal bleeding. Despite its good safety profile compared to vasopressin, some adverse reactions may occur during its use – e.g. hyponatremia. We describe a case of a cirrhotic patient with active variceal bleeding treated during two separate hospitalizations with terlipressin. In both drug treatment periods, severe laboratory hyponatremia developed. After terlipressin discontinuation, mineral disbalance corrected rapidly. Positive dechallenge and rechallenge corresponding to the drug administration schedule confirms the causality between terlipressin administration and hyponatremia. Hyponatremia was preceded with substantial fluid retention in both episodes. In this case report we want to highlight the need for fluid balance monitoring immediately after first terlipressin dose, which may individually predict the patient risk for the development of hyponatremia as other risk factors have rather limited predictive value in real clinical settings.

Hydrogen sulfide modulates sinusoidal constriction and contributes to hepatic micorcirculatory dysfunction during endotoxemia

Hydrogen sulfide (H2S) affects vascular resistance; however, its effect on the hepatic microcirculation has not been investigated. Hepatic sinusoidal perfusion is dysregulated during sepsis, contributing to liver injury. Therefore, the present study determined the effect of H2S on the hepatic microcirculation and the contribution of endogenous H2S to hepatic microcirculatory dysfunction in an endotoxin model of sepsis. Portal infusion of H2S increased portal pressure in vivo (6.8 ± 0.2 mmHg before H2S vs. 8.6 ± 0.8 mmHg peak during H2S infusion, P < 0.05). Using intravital microscopy, we observed decreased sinusoidal diameter (6.2 ± 0.27 μm before H2S vs. 5.7 ± 0.3 μm after H2S, P < 0.05) and increased sinusoidal heterogeneity during H2S infusion ( P < 0.05) and net constriction. Since hepatic H2S levels are elevated during sepsis, we used the cystathionine γ lyase inhibitor dl-propargylglycine (PAG) to determine the contribution of H2S to the hypersensitization of the sinusoid to the vasoconstrictor effect of endothelin-1 (ET-1). PAG treatment significantly attenuated the sinusoidal sensitization to ET-1 in endotoxin-treated animals. ET-1 infusion increased portal pressure to 175% of baseline in endotoxemic animals, which was reduced to 143% following PAG treatment ( P < 0.05). PAG abrogated the increase in sinusoidal constriction after ET-1 infusion in LPS-treated rats (30.9% reduction in LPS rats vs. 11.6% in PAG/LPS rats, P < 0.05). Moreover, PAG treatment significantly attenuated the increase in NADH fluorescence following ET-1 exposure during endotoxemia (61 grayscale units LPS vs. 21 units in PAG/LPS, P < 0.05), suggesting an improvement in hepatic oxygen availability. This study is the first to demonstrate a vasoconstrictor action of H2S on the hepatic sinusoid and provides a possible mechanism for the protective effect of PAG treatment during sepsis.