Basis For Antihypertensive Therapy Research Articles

MTOR INHIBITOR IMPROVES TESTOSTERONE-INDUCED MYOCARDIAL HYPERTROPHY IN HYPERTENSIVE RATS

Objective: Compelling evidence have described the incidence of hypertension and left ventricular hypertrophy (LVH) in postmenopausal women is significantly increased worldwide. Our team’s previous research identified that androgen was an underlying factor contributing to increased blood pressure and LVH in postmenopausal women. However, little is known about how androgens affect LVH in postmenopausal hypertensive women. The purpose of this study was to evaluate the role of mTOR signaling pathway in myocardial hypertrophy in androgen-induced postmenopausal hypertension and whether mTOR inhibitors can protect the myocardium from androgen-induced interference to prevent and treat cardiac hypertrophy. Design and method: For that, ovariectomized (OVX) spontaneously hypertensive rats (SHR) aged 12 weeks were used to study the effects of testosterone (T 2.85 mg/kg/weekly im) on blood pressure and myocardial tissue. On the basis of antihypertensive therapy (chlorthalidone 8 mg/kg/day ig), the improvement of blood pressure and myocardial hypertrophy in rats treated with different dose gradients of rapamycin (0.8 mg/kg/day Vs 1.5 mg/kg/day Vs 2 mg/kg/day ip) in OVX+ estrogens (E 9.6 mg/Kg/day, ig)+T group was further evaluated. Results: After T intervention, the OVX female rats exhibited significant increments in the heart weight / tibial length (TL), cross-sectional area of cardiomyocytes and the mRNA expressions of atrial natriuretic peptide, B- myosin heavy chain and matrix metalloproteinase 9 accompanied by a significant reduction in the uterine weight/TL and issue inhibitor of metalloproteinase 1. Mammalian rapamycin receptor (mTOR), ribosomal protein S6 kinase (S6K1), 4E-bindiong protein 1(4EBP1) and eukaryotic translation initiation factor 4E in myocardial tissue of OVX+E+T group were expressed at higher levels than those of the other four groups. On the other hand, rapamycin abolished the effects of T-induced cardiac hypertrophy, decreased the systolic and diastolic blood pressure of SHR, and inhibited the activation of mTOR/ S6K1/4EBP1 signaling pathway in a concentration-dependent manner. Conclusions: Collectively, these data suggest that the mTOR/S6K1/4EBP1 pathway is an important therapeutic target for the prevention of LVH in postmenopausal hypertensive women with high T levels. Our findings also support the standpoint that the mTOR inhibitor, rapamycin, can eliminate T-induced cardiomyocyte hypertrophy.

MTOR inhibitor improves testosterone-induced myocardial hypertrophy in hypertensive rats.

Compelling evidence has described that the incidence of hypertension and left ventricular hypertrophy (LVH) in postmenopausal women is significantly increased worldwide. Our team’s previous research identified that androgen was an underlying factor contributing to increased blood pressure and LVH in postmenopausal women. However, little is known about how androgens affect LVH in postmenopausal hypertensive women. The purpose of this study was to evaluate the role of mammalian rapamycin receptor (mTOR) signaling pathway in myocardial hypertrophy in androgen-induced postmenopausal hypertension and whether mTOR inhibitors can protect the myocardium from androgen-induced interference to prevent and treat cardiac hypertrophy. For that, ovariectomized (OVX) spontaneously hypertensive rats (SHR) aged 12 weeks were used to study the effects of testosterone (T 2.85 mg/kg/weekly i.m.) on blood pressure and myocardial tissue. On the basis of antihypertensive therapy (chlorthalidone 8 mg/kg/day ig), the improvement of blood pressure and myocardial hypertrophy in rats treated with different dose gradients of rapamycin (0.8 mg/kg/day vs 1.5 mg/kg/day vs 2 mg/kg/day i.p.) in OVX + estrogen (E 9.6 mg/kg/day, ig) + testosterone group was further evaluated. After testosterone intervention, the OVX female rats exhibited significant increments in the heart weight/tibial length (TL), area of cardiomyocytes and the mRNA expressions of ANP, β-myosin heavy chain and matrix metalloproteinase 9 accompanied by a significant reduction in the uterine weight/TL and tissue inhibitor of metalloproteinase 1. mTOR, ribosomal protein S6 kinase (S6K1), 4E-binding protein 1 (4EBP1) and eukaryotic translation initiation factor 4E in myocardial tissue of OVX + estrogen + testosterone group were expressed at higher levels than those of the other four groups. On the other hand, rapamycin abolished the effects of testosterone-induced cardiac hypertrophy, decreased the systolic and diastolic blood pressure of SHR, and inhibited the activation of mTOR/S6K1/4EBP1 signaling pathway in a concentration-dependent manner. Collectively, these data suggest that the mTOR/S6K1/4EBP1 pathway is an important therapeutic target for the prevention of LVH in postmenopausal hypertensive female rats with high testosterone levels. Our findings also support the standpoint that the mTOR inhibitor, rapamycin, can eliminate testosterone-induced cardiomyocyte hypertrophy.

Результаты международного симпозиума, посвященного артериальной гипертензии и блокаторам кальциевых каналов: фокус на лерканидипине

В обзоре представлены материалы симпозиума с участием основных мировых экспертов в области артериальной гипертензии на тему «Современные перспективы использования блокаторов кальциевых каналов для лечения пациентов с артериальной гипертензией». Было отмечено, что все 5 применяемых в настоящее время классов антигипертензивных средств, включая блокаторы кальциевых каналов (БКК), способны снижать артериальное давление и составляют основу антигипертензивной терапии. А вот способность снижать риск развития других сердечно-сосудистых осложнений может различаться между классами. Например, было продемонстрировано, что БКК снижают риск развития инсультов и основных сердечно-сосудистых осложнений. В обсуждении рассматривалось положение о том, что БКК входят в категорию «лучшие средства» при борьбе с повреждением ряда органов-мишеней. Так, для гипертрофии левого желудочка лучшими были названы ингибиторы ангиотензинпревращающего фермента (иАПФ) и БКК, для снижения ремоделирования малых артерий — иАПФ, блокаторы рецепторов ангиотензина (БРА) и БКК. Ожидается, что некоторые новые БКК войдут и в число лучших средств для лечения хронической болезни почек. При рассмотрении конкретных представителей БКК основное внимание было уделено лерканидипину — относительно новому липофильному дигидропиридину 3-го поколения с высокой сосудистой селективностью. В дополнение ко всем свойствам, перечисленным выше, для препарата характерен ряд дополнительных преимуществ: медленное начало действия, приводящее к плавному снижению артериального давления и предотвращению рефлекторной тахикардии; меньшее число побочных эффектов, особенно отеков голеней и стоп. Например, в одном из исследований частота отеков в группе лерканидипина составила 9,3 % по сравнению с 19 % в группе амлодипина. В отличие от многих других БКК, лерканидипин расширяет и афферентную, и эфферентную артериолы клубочков почек, что потенциально снижает гломерулярную гипертензию и может вносить вклад в нефропротекцию. Комбинация «лерканидипин + эналаприл» устойчиво снижает альбуминурию в большей степени, чем монотерапия данными препаратами. В целом эффективность лерканидипина подтверждена у пациентов с различной степенью гипертензии; у пациентов всех возрастов (молодых, средних лет и пожилых); при изолированной систолической гипертензии; у пациентов с диабетом и почечными нарушениями. Препарат хорошо переносится.

Current Guidelines for the Treatment of Arterial Hypertension in Patients with Diabetes Mellitus and Chronic Kidney Disease

The current understanding of the management of patients with diabetes mellitus (DM) based on the concept of the cardiovascular continuum involves not only the prevention and treatment of cardiovascular diseases (CVD), but also the prevention and treatment of chronic kidney disease (CKD). The fact is that patients with DM and CKD represent a special group of patients with a very high risk of CVD and cardiovascular mortality. Such patients require early diagnosis and timely identification of risk factors for the development and progression of CKD for their adequate correction. Arterial hypertension, along with hyperglycemia, is the main risk factor for the development and progression of CKD in patients with diabetes. In this regard, the choice of antihypertensive therapy (AHT) in patients with diabetes is of particular importance. The basis of AHT in diabetes and CKD is the combination of a blocker of the renin-angiotensin-aldosterone system (an angiotensin-converting enzyme inhibitor [ACE inhibitor] or an angiotensin II receptor blocker [ARB]) and a calcium channel blocker (CCB) or a thiazide / thiazide-like diuretic. The task of the performed AHT is to achieve the target level of blood pressure (BP). At the same time, the optimal blood pressure values in patients with diabetes and CKD are blood pressure values in the range of 130-139/70-79 mm Hg. If the target blood pressure is not achieved, it is necessary to intensify antihypertensive therapy by adding a third antihypertensive drug to the therapy: CCB or a diuretic (thiazide / thiazide-like or loop). In case of resistant hypertension, it is necessary to consider the possibility of adding antagonists of mineralocorticoid receptors, other diuretics or alpha-blockers to the conducted AHT. Beta-blockers can be added at any stage of therapy if the patient has exertional angina, a history of myocardial infarction, atrial fibrillation, and chronic heart failure. The need to normalize blood pressure parameters by prescribing combined antihypertensive therapy in patients with diabetes and CKD is explained by a decrease in renal and cardiovascular risks, and, therefore, a decrease in the risk of mortality in this cohort of patients.

Diuretics as a basis of antihypertensive therapy. An overview.

Diuretics have been, except for during a few recent years, the most commonly used therapy for hypertension. Although use of these agents fell significantly in the early 1990s, since then it has begun to increase again. Their recent return to popularity reflects 3 major factors: (i) recognition of the effectiveness of much lower dosages than previously used, thereby providing good antihypertensive activity with fewer adverse effects; (ii) the excellent reductions in morbidity and mortality achieved by low dosage diuretic-based therapy in multiple randomised controlled trials in elderly patients with hypertension; and (iii) the increasing recognition that some diuretic-induced shrinkage of effective blood volume is essential for the adequate treatment of many, if not most, patients with hypertension. Therefore, diuretics will probably continue to be the basis for antihypertensive therapy, and the indapamide sustained release 1.5 mg formulation provides all the essential characteristics of diuretic therapy.

Potency of vascular risk factors as the basis for antihypertensive therapy.

Hypertension is a powerful predisposing risk factor for cardiovascular disease at all ages and in both sexes. Epidemiological assessment indicates the largest risk ratios for stroke and congestive heart failure (CHF), but coronary heart disease (CHD) is the most common and most lethal sequela of hypertension. Examination of the risk of cardiovascular sequelae in the hypertensive population indicates that this is not uniform and varies over a 10-fold range, depending on the associated risk factors. Systolic pressure merits greater consideration than the diastole pressure because isolated systolic hypertension is a powerful cardiovascular risk at all ages. Furthermore, recent trials have indicated the benefit of therapy for systolic-based hypertension in the elderly, even using a diuretic, for coronary disease as well as stroke. Persons with hypertension have a high prevalence of associated cardiovascular risk factors, including elevated cholesterol, reduced HDL-C, diabetes, left ventricular hypertrophy (LVH), and obesity. About 9% under the age of 65 years have an associated overt cardiovascular disease; above age 65 about 30% are so afflicted. Each of these risk factors can double the risk associated with hypertension. Because they are so common, a large fraction of the disease sequelae of hypertension is attributable to these associated risk factors. The high risk of coronary disease in hypertensive patients is concentrated in those with a high total/HDL-cholesterol ratio, impaired glucose tolerance, high fibrinogen, ECG abnormalities, and cigarette smokers. Stroke risk in hypertensive persons is concentrated in those with cardiovascular disease, diabetes, atrial fibrillation, LVH and cigarette smoking.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological basis for antihypertensive therapy with a novel dopamine agonist.

In the past, nearly all major mechanisms involved in the regulation of blood pressure have become targets of antihypertensive drugs. They include the brain stem with its neuronal circuits of central cardiovascular regulation, the sympathetic neuro-effector system, the kidney, the renin angiotensin aldosterone system and the vascular smooth muscle cell. There are various ways of influencing the function of the sympathetic nervous system, but the clinical potential of one mechanism of action has not yet been explored in detail. Drugs that inhibit noradrenaline release through stimulation of inhibitory receptors located at adrenergic nerve terminals in the cardiovascular system (inhibitory presynaptic receptors) are not available for the treatment of hypertension. Among the multiple presynaptic receptors, dopamine receptors which belong to the dopamine2 subtype, are of particular interest. Carmoxirole is a novel indole derivative with a potent agonist action selective for dopamine2-receptors of the periphery. Experimental evidence shows that carmoxirole lowers blood pressure in various models of hypertension mainly or exclusively through inhibition of noradrenaline release from sympathetic nerve endings. This effect of carmoxirole is mediated by presynaptic dopamine receptors with the characteristic that release inhibition is restricted to low rates of sympathetic nerve discharge.