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      Calcium channels and effects of aliskiren on vascular smooth muscle

      , , ,
      Trace Elements and Electrolytes
      Dustri-Verlag Dr. Karl Feistle
      ICP-OES, thyroid cancer, trace elements

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          Abstract

          Abstract. The renin-angiotensin-aldosterone system (RAAS) has always earned a key position in the regulation of blood pressure either under physiological conditions or in the pathogenesis and maintenance of arterial hypertension. With the approval of aliskiren – a renin antagonist that is meant to directly bind to the protease renin – the possibilities of interfering with the RAA system have been enhanced. However, a comprehensive in vitro characterization of the effects of aliskiren is limited. This seems particularly important since the results regarding systemic effects and side effects in a clinical setting are not that explicit. To this end, we aim to characterize the effects of aliskiren on vascular function in an in vitro model of vascular tissues. To this purpose, we investigated the effects of aliskiren in ascending concentrations (1 – 50 µM) on a range of vascular smooth muscle preparations, i.e., iliac artery, aorta, and portal vein, in a conventional organ bath. While we found vasodilatatory effects of aliskiren for the preparations of the iliac artery and aorta, the portal vein showed a concentration-dependent biphasic response with an inhibitory component at lower concentrations and excitatory effects with an increase of mechanical activity and frequency of spontaneous activity in higher concentrations. Our findings extend the literature regarding aliskiren and suggest an effect that is independent of renal inhibition of renin.


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          Most cited references65

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          International union of pharmacology. XXIII. The angiotensin II receptors.

          The cardiovascular and other actions of angiotensin II (Ang II) are mediated by AT(1) and AT(2) receptors, which are seven transmembrane glycoproteins with 30% sequence similarity. Most species express a single autosomal AT(1) gene, but two related AT(1A) and AT(1B) receptor genes are expressed in rodents. AT(1) receptors are predominantly coupled to G(q/11), and signal through phospholipases A, C, D, inositol phosphates, calcium channels, and a variety of serine/threonine and tyrosine kinases. Many AT(1)-induced growth responses are mediated by transactivation of growth factor receptors. The receptor binding sites for agonist and nonpeptide antagonist ligands have been defined. The latter compounds are as effective as angiotensin converting enzyme inhibitors in cardiovascular diseases but are better tolerated. The AT(2) receptor is expressed at high density during fetal development. It is much less abundant in adult tissues and is up-regulated in pathological conditions. Its signaling pathways include serine and tyrosine phosphatases, phospholipase A(2), nitric oxide, and cyclic guanosine monophosphate. The AT(2) receptor counteracts several of the growth responses initiated by the AT(1) and growth factor receptors. The AT(4) receptor specifically binds Ang IV (Ang 3-8), and is located in brain and kidney. Its signaling mechanisms are unknown, but it influences local blood flow and is associated with cognitive processes and sensory and motor functions. Although AT(1) receptors mediate most of the known actions of Ang II, the AT(2) receptor contributes to the regulation of blood pressure and renal function. The development of specific nonpeptide receptor antagonists has led to major advances in the physiology, pharmacology, and therapy of the renin-angiotensin system.
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            Is Open Access

            The Renin-Angiotensin Aldosterone System: Pathophysiological Role and Pharmacologic Inhibition

            BACKGROUND: The renin-angiotensin aldosterone system (RAAS) is a hormonal cascade that functions in the homeostatic control of arterial pressure, tissue perfusion, and extracellular volume. Dysregulation of the RAAS plays an important role in the pathogenesis of cardiovascular and renal disorders. OBJECTIVES: To review the role of the RAAS in the development of hypertensive cardiovascular disease and related conditions and provide an overview of the classes of pharmacologic agents that inhibit this system. RESULTS: The RAAS is initiated by the regulated secretion of renin, the rate-limiting enzyme that catalyzes the hydrolysis of angiotensin (Ang) I from the N-terminus of angiotensinogen. Ang I is in turn hydrolyzed by angiotensin-converting enzyme (ACE ) to form Ang II, a potent vasoconstrictor and the primary active product of the RAAS. Recent evidence has suggested that other metabolites of Ang I and II may have biological activity, particularly in tissues. Development of agents that block the RAAS (e.g., beta blockers, ACE inhibitors [ACE Is], and angiotensin receptor blockers [ARBs]) began as a therapeutic strategy to treat hypertension. Preclinical and clinical studies have indicated important additional cardiovascular and renal therapeutic benefits of ACE Is and ARBs. However, blockade of the RAAS with these agents is incomplete. CONCLUSIONS: Therapeutic approaches that target more complete inhibition of the RAAS may offer additional clinical benefits for patients with cardiovascular and renal disorders. These approaches may include dual blockade using ACE Is and ARBs in combination, or new therapeutic modalities such as direct renin inhibition with aliskiren, recently approved for the treatment of hypertension. 
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              Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.

              Patients with chronic heart failure (CHF) are at high risk of cardiovascular death and recurrent hospital admissions. We aimed to find out whether the use of an angiotensin-receptor blocker could reduce mortality and morbidity. In parallel, randomised, double-blind, controlled, clinical trials we compared candesartan with placebo in three distinct populations. We studied patients with left-ventricular ejection fraction (LVEF) 40% or less who were not receiving angiotensin-converting-enzyme inhibitors because of previous intolerance or who were currently receiving angiotensin-converting-enzyme inhibitors, and patients with LVEF higher than 40%. Overall, 7601 patients (7599 with data) were randomly assigned candesartan (n=3803, titrated to 32 mg once daily) or matching placebo (n=3796), and followed up for at least 2 years. The primary outcome of the overall programme was all-cause mortality, and for all the component trials was cardiovascular death or hospital admission for CHF. Analysis was by intention to treat. Median follow-up was 37.7 months. 886 (23%) patients in the candesartan and 945 (25%) in the placebo group died (unadjusted hazard ratio 0.91 [95% CI 0.83-1.00], p=0.055; covariate adjusted 0.90 [0.82-0.99], p=0.032), with fewer cardiovascular deaths (691 [18%] vs 769 [20%], unadjusted 0.88 [0.79-0.97], p=0.012; covariate adjusted 0.87 [0.78-0.96], p=0.006) and hospital admissions for CHF (757 [20%] vs 918 [24%], p<0.0001) in the candesartan group. There was no significant heterogeneity for candesartan results across the component trials. More patients discontinued candesartan than placebo because of concerns about renal function, hypotension, and hyperkalaemia. Candesartan was generally well tolerated and significantly reduced cardiovascular deaths and hospital admissions for heart failure. Ejection fraction or treatment at baseline did not alter these effects.
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                Author and article information

                Journal
                Trace Elements and Electrolytes
                TE
                Dustri-Verlag Dr. Karl Feistle
                0946-2104
                2019
                October 01 2019
                : 36
                : 10
                : 180-189
                Article
                10.5414/TEX01590
                5c3c5d11-c744-4390-8b32-4d2f360027a0
                © 2019
                History

                Endocrinology & Diabetes,General medicine,Medicine,Gastroenterology & Hepatology,Nutrition & Dietetics
                ICP-OES,trace elements,thyroid cancer

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