The Results of ACES (Antihypertensive Combinations’ Long Term Efficacy Comparing Study): Analysis of Metabolic Effects of Antihypertensive Combination Therapies

Nádházi, Zoltán; Dézsi, Csaba András

doi:10.1007/s40261-016-0431-x

Cited by 9 publications

(3 citation statements)

References 22 publications

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“…Studies have clearly shown that excess ANG II-mediated effects by AT 1 R have been detrimental to human physiology, although the drugs used to treat hypertension have demonstrated beneficial effects on cardiovascular diseases by reducing morbidity and mortality (45,72). However, the physiological enigma that arises from sex differences in blood pressure regulation remains unresolved.…”

Section: Discussionmentioning

confidence: 99%

2-Methoxyestradiol causes matrix metalloproteinase 9-mediated transactivation of epidermal growth factor receptor and angiotensin type 1 receptor downregulation in rat aortic smooth muscle cells

Ogola

Zhang

Iyer

et al. 2018

American Journal of Physiology-Cell Physiology

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Studies have demonstrated the therapeutic potential of estrogen metabolite 2-methoxyestradiol (2ME2) in several cardiovascular disorders, including hypertension. However, the exact mechanism(s) remains unknown. In this study, primary rat aortic smooth muscle cells (RASMCs) were exposed to 2ME2, and angiotensin type 1 receptor (ATR) expression, function, and associated signaling pathways were evaluated. In RASMCs, 2ME2 downregulated ATR expression in a concentration- and time-dependent manner, which was correlated with reduced mRNA expression. The 2ME2 effect was through G protein-coupled receptor 30 (GPR30) that inhibits second messenger cAMP. Moreover, 2ME2 exposure phosphorylated ERK1/2 that was sensitive to MEK inhibitor PD98059. Selective epidermal growth factor receptor (EGFR) inhibitor AG1478 blocked 2ME2-induced EGFR transactivation and attenuated subsequent phosphorylation of ERK1/2 preventing ATR downregulation. The transactivation was dependent on 2ME2-induced release of matrix metalloproteinase 9 (MMP9) and epidermal growth factor demonstrated by ELISA. Furthermore, transfection with small interfering (si) RNA targeting MMP9 impeded ERK1/2 activation and ATR downregulation in response to 2ME2 and G1 stimulation. Interestingly, under similar conditions, stimulation of GPR30 with the selective agonist G1 elicited similar signaling pathways and downregulated the ATR expression that was reversed by GPR30 antagonist G15. Furthermore, 2ME2 and G1 inhibited angiotensin II (ANG II) induced Ca release, a response consistent with ATR downregulation. Collectively, our study demonstrates for the first time that 2ME2 binding to GPR30 induces MMP9 specific transactivation of EGFR that mediates ERK1/2-dependent downregulation of ATR in RASMCs. The study provides critical insights into the newly discovered role and signaling pathways of 2ME2 in the regulation of ATR in vascular cells and its potential to be developed as a therapeutic agent that ameliorates hypertension.

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Section: Discussionmentioning

confidence: 99%

2-Methoxyestradiol causes matrix metalloproteinase 9-mediated transactivation of epidermal growth factor receptor and angiotensin type 1 receptor downregulation in rat aortic smooth muscle cells

Ogola

Zhang

Iyer

et al. 2018

American Journal of Physiology-Cell Physiology

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“…Some of them have neutral effects (e.g., nebivolol) [125], while others are associated with an increase in triglyceride levels (e.g., metoprolol and propranolol) [124]. A neutral or modest beneficial association is observed for the anti-hypertensive drug classes of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARB), calcium channel blockers, and alpha blockers [122,126]. Interestingly, the use of ACEIs when combined with diuretics seems to minimize or prevent the negative effects on lipid profiles induced by the latter drug category [127].…”

Section: Antilipidemic Effects Of Anti-diabetic and Anti-hypertensive...mentioning

confidence: 99%

Classical and Novel Lipid-Lowering Therapies for Diabetic Patients with Established Coronary Artery Disease or High Risk of Coronary Artery Disease—A Narrative Clinical Review

Velidakis,

Stachteas,

Gkougkoudi

et al. 2024

Pharmaceuticals

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Diabetic atherosclerosis is a complex process that is characterized by diffuse and unstable lesions increasing 2–4-fold the risk of adverse cardiovascular (CV) events. Diabetic dyslipidemia has a predominant role in coronary artery disease (CAD) and has been the target of classical and emerging pharmaceutical agents with established or promising CV benefits. The aim of the present narrative review was to summarize the effects of classical and novel lipid-lowering pharmaceutical agents on lipid profile and CV outcomes in diabetic patients with established CAD or high risk of CAD. Statins remain the first-line treatment for all diabetic patients since they considerably ameliorate lipid parameters and non-lipid CV risk factors, leading to reduced CV morbidity and mortality. Complementary to statins, ezetimibe exerts lipid-lowering properties with modest but significant reductions in major adverse cardiovascular events (MACEs) and CV mortality. PCSK9 inhibitors considerably reduce LDL-C levels and lower MACEs in diabetic patients. On the other hand, fibrates may confer a very modest decline in MACE incidence, while the CV impact of omega-3 fatty acids is promising but remains questionable. Bempedoic acid and inclisiran have a potential therapeutic role in the management of diabetic dyslipidemia, but this is still not adequately documented. Given the heightened CV risk among individuals with diabetes, more decisive results would be of great importance in the utility of all these drugs.

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“… 5 The beneficial impact of these agents on clinical events may be attributed largely to the synergistic, vascular protective, and metabolic effects common to perindopril, amlodipine, and atorvastatin. 6 , 7 …”

Section: Introductionmentioning

confidence: 99%

Treatment with triple combination of atorvastatin, perindopril, and amlodipine in patients with stable coronary artery disease: A subgroup analysis from the PAPA-CAD study

Dézsi

2018

J Int Med Res

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BackgroundIn patients with stable coronary artery disease, aspirin, a statin, and an angiotensin-converting enzyme inhibitor are recommended as first-line agents for secondary prevention. Subgroup analyses of the previously published Hungarian Perindopril plus Amlodipine in PAtients with Coronary Artery Disease (PAPA-CAD) non-interventional trial demonstrated that the addition of the metabolically beneficial, fixed combination of perindopril + amlodipine to atorvastatin further improves the patient’s lipid profile.MethodsThe PAPA-CAD study, a 6-month open-label, prospective, multicenter, observational/non-interventional survey evaluated data accumulated from patients with hypertensive patients with stable coronary artery disease. The herein-reported subgroup analysis was conducted using the findings from those 1130 patients, who were taking atorvastatin in addition to the fixed combination of perindopril + amlodipine at the time of all four study visits (i.e., at baseline and 1, 3, and 6 months later).ResultsIn the subgroup of patients taking atorvastatin as an add-on agent, 82.5% reached the target blood pressure of 140/90 mmHg compared with 78.8% of those not taking a statin. The addition of atorvastatin to the fixed combination of perindopril + amlodipine resulted in further significant improvements of key metabolic parameters.ConclusionThis subgroup analysis confirmed that favorable synergism exists among perindopril, amlodipine, and atorvastatin.

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The Results of ACES (Antihypertensive Combinations’ Long Term Efficacy Comparing Study): Analysis of Metabolic Effects of Antihypertensive Combination Therapies

Cited by 9 publications

References 22 publications

2-Methoxyestradiol causes matrix metalloproteinase 9-mediated transactivation of epidermal growth factor receptor and angiotensin type 1 receptor downregulation in rat aortic smooth muscle cells

2-Methoxyestradiol causes matrix metalloproteinase 9-mediated transactivation of epidermal growth factor receptor and angiotensin type 1 receptor downregulation in rat aortic smooth muscle cells

Classical and Novel Lipid-Lowering Therapies for Diabetic Patients with Established Coronary Artery Disease or High Risk of Coronary Artery Disease—A Narrative Clinical Review

Treatment with triple combination of atorvastatin, perindopril, and amlodipine in patients with stable coronary artery disease: A subgroup analysis from the PAPA-CAD study

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