Metabolic model for laboratory control of anti-ischaemic therapy effectiveness: a case study of nicorandil

Scientific relevance. A key anti-ischaemic mechanism of some medicinal products involves their effects on the metabolism of endothelial vasodilators, particularly the synthesis of nitric oxide from arginine and its precursor citrulline.Aim. The study was aimed to determine whether the plasma time course of guanidine derivatives (arginine precursors) is applicable to laboratory control of anti-ischaemic therapy effectiveness using a single oral dose of nicorandil in patients with coronary heart disease as a case study.Materials and methods. The authors used high-performance liquid chromatography to determine metabolites. Blood samples for analysis were obtained from 30 patients with angina pectoris (Grade II–III, Canadian Cardiovascular Society) and 30 healthy donors. All the study participants received a single oral dose of 20 mg nicorandil after 10 h of fasting.Results. At baseline, patients showed significantly higher plasma citrulline levels than donors. However, the elevated levels decreased to the healthy range after nicorandil administration. Plasma arginine levels in patients showed a statistically significant increase following nicorandil administration. Plasma homoarginine levels in patients remained reduced both before and after dosing. Nicorandil did not influence elevated levels of the endogenous nitric oxide synthase inhibitor (asymmetrical dimethylarginine).Conclusions. In addition to the established mechanisms responsible for altering cell metabolism, nicorandil enhances the contribution of citrulline to arginine resynthesis. It is reasonable to include citrulline and arginine, which are involved in the vasodilator response, in model schemes for laboratory control of the effectiveness of anti-ischaemic therapy

Метаболическая модель для лабораторного контроля эффективности антиишемической терапии на примере использования никорандила

A key anti-ischaemic mechanism of some medicinal products involves their effects on the metabolism of endothelial vasodilators, particularly the synthesis of nitric oxide from arginine and its precursor citrulline.The aim of the study was to determine whether the plasma time course of guanidine derivatives (arginine precursors) is applicable to laboratory control of anti-ischaemic therapy effectiveness using a single oral dose of nicorandil in patients with coronary heart disease as a case study.Materials and methods. The authors used high-performance liquid chromatography to determine metabolites. Blood samples for analysis were obtained from 30 patients with angina pectoris (Grade II–III, Canadian Cardiovascular Society) and 30 healthy donors. All the study participants received a single oral dose of 20 mg nicorandil after 10 h of fasting.Results. At baseline, patients showed significantly higher plasma citrulline levels than donors. However, the elevated levels decreased to the healthy range after nicorandil administration. Plasma arginine levels in patients showed a statistically significant increase following nicorandil administration. Plasma homoarginine levels in patients remained reduced both before and after dosing. Nicorandil did not influence elevated levels of the endogenous nitric oxide synthase inhibitor (asymmetrical dimethylarginine).Conclusions. In addition to the established mechanisms responsible for altering cell metabolism, nicorandil enhances the contribution of citrulline to arginine resynthesis. It is reasonable to include citrulline and arginine, which are involved in the vasodilator response, in model schemes for laboratory control of the effectiveness of anti-ischaemic therapy.Важным механизмом антиишемического действия некоторых препаратов является их влияние на метаболизм эндотелиальных факторов вазодилатации, в частности на образование оксида азота из аминокислоты аргинина и его предшественника цитруллина.Цель работы: изучение возможности использования показателей динамики гуанидиновых производных — предшественников аргинина — в плазме крови для лабораторного контроля эффективности антиишемической терапии на примере однократного перорального приема никорандила у пациентов с ишемической болезнью сердца.Материалы и методы: метаболиты определяли методом высокоэффективной жидкостной хроматографии в образцах крови, взятых у 30 пациентов со стенокардией напряжения II–III функционального класса. Референтной группой являлись 30 здоровых доноров. Никорандил использовали перорально в разовой дозе 20 мг после 10-часового голодания.Результаты: у пациентов исходный уровень цитруллина был достоверно выше, чем у здоровых доноров. После приема никорандила содержание цитруллина снижалось до уровня, не отличающегося от уровня в плазме крови здоровых доноров группы сравнения. Содержание аргинина в плазме крови пациентов после приема препарата достоверно возрастало. При этом у них сохранялся пониженный уровень гомоаргинина как до, так и после приема никорандила. Обнаружено также отсутствие влияния приема никорандила на уровень эндогенного ингибитора синтазы оксида азота — асимметричного диметиларгинина.Вывод: в дополнение к известным механизмам воздействия никорандила на клеточный метаболизм показано усиление участия цитруллина в ресинтезе аргинина. При оценке эффективности антиишемической терапии в модельную схему для лабораторного контроля целесообразно включать цитруллин и аргинин, которые являются участниками вазодилатационного ответа

TRANSFORMING GROWTH FACTOR-BETA-1 BY DIFFERENT CLINICAL COURSE OF ISCHEMIC HEART DISEASE AFTER CORONARY ARTERY BYPASS GRAFTING SURGERY

The article presents data on the levels of transforming growth factor-beta-1 (TGF-β1) in blood serum and their correlation with clinical features of coronary artery disease in 130 patients with non-ST elevation acute coronary syndrome (non-ST ACS), who underwent coronary artery bypass grafting surgery (CABG), at different terms (6, 12, 24, 48 mo) following surgical intervention. It was revealed that a recurrent myocardial ischemia is associated with increased levels of TGF-β1. Following CABG, the TGF-β1 levels are significantly increasing, and reach their preoperative values by the end of observation period

A1166C POLYMORPHISM OF THE GENE FOR ANGIOTENSIN II RECEPTOR 1ST TYPE AND ENDOTHELIAL DYSFUNCTION IN MEN WITH A HISTORY OF MYOCARDIAL INFARCTION IN YOUNG AGE

The renin-angiotensin-aldosterone system (RAAS) is involved in the pathogenesis of Coronary Heart Disease and myocardial infarction. The crucial component of the RAAS is angiotensin II and its effects are carried out by angiotensin II receptors 1st type (AT1R).Aim of the study: determine the incidence of the mutant allele of the AT1R gene, estimate possible correlations between AT1R gene polymorphism and the extension of endothelial dysfunction in patients who have suffered MI in the age under 45.Materials and methods: 122 men suffering myocardial infarction under the age of 45 have been examined. In all patients we measured a relative increase of brachial artery diameter during the test with reactive hyperemia, the number of circulating endotheliocytes. Identification of A1166C polymorphism of the AT1R gene was carried out by means of polymerase chain reaction (PCR).Results: in patients with a history of myocardial infarction in the age under 45 we have found evidence of endothelial dysfunction: increased circulating endotheliocytes, decreased endothelium-mediated vasodilation. Among patients with a vasoconstrictive reaction the incidence of the C allele of the AT1R gene was higher than in patients exhibitng a vasodilative response during a test with reactive hyperemia (P<0.007). The incidence of the mutant allele of the AT1R gene was reliably lower in coronary patients with arterial hypertension than in those without hypertension

ACUTE ATORVASTATIN RECAPTURE THERAPY IN CORONARY ARTERY BYPASS GRAFTING

Aim. To assess the safety of the application of high-dose atorvastatin and its effect on metabolic parameters, such as the total level of nitric oxide and homocysteine in the blood plasma in patients with ischemic heart disease during a coronary artery bypass surgery (CABG).Material and methods. The study included 42 patients with stable effort angina II-IV functional class. A special criterion for selection was the taking atorvastatin at a dose of 20 mg/day for at least 30 days before patient was directed to surgical revascularization of the myocardium. Immediately before the intervention, the dose of atorvastatin was increased to the maximum allowed with subsequent taking of 40 mg/day. Complications after CABG, indicators of lipid metabolism and biochemical safety of statin use were analyzed. The duration of observation of results of the acute atorvastatin recapture therapy was 3 weeks during hospital period. We used modern enzymatic method for nitrogen oxides determination with the application of nitrate reductase. Determination of total homocysteine was performed by high performance liquid chromatography.Results. It was found that atorvastatin 80 mg for 12 hours and 2 hours before CABG in patients previously treated with atorvastatin 20 mg/day is well tolerated and leads to decrease in total levels of nitric oxide by 1.6 (0.18-10.8 ) μmol/l and homocysteine by 0.9 (0.17-2.69) μmol/l (p< 0.05 for both)Conclusion. It is assumed that the metabolic effects of high-dose therapy with atorvastatin may have a positive influence on the immediate postoperative period