Managing resistant hypertension: focus on mineralocorticoid-receptor antagonists

Juan Carlos Yugar-Toledo,1 Rodrigo Modolo,2 Ana Paula de Faria,2 Heitor Moreno2 1São José do Rio Preto Medicine School – FAMERP, São José do Rio Preto, 2School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil Abstract: Mineralocorticoid-receptor antagonists (MRAs) have proven to be effective in some types of hypertension, especially in resistant hypertension (RHTN). In this phenotype of hypertension, the renin–angiotensin–aldosterone pathway plays an important role, with MRAs being especially effective in reducing blood pressure. In this review, we show the relevance of aldosterone in RHTN, as well as some clinical characteristics of this condition and the main concepts involving its pathophysiology and cardiovascular damage. We analyzed the mechanisms of action and clinical effects of two current MRAs – spironolactone and eplerenone – both of which are useful in RHTN, with special attention to the former. RHTN represents a significant minority (10%–15%) of hypertension cases. However, primary-care physicians, cardiologists, nephrologists, neurologists, and geriatricians face this health problem on a daily basis. MRAs are likely one of the best pharmacological options in RHTN patients; however, they are still underused. Keywords: resistant hypertension, aldosterone, aldosteronism, mineralocorticoid-receptor antagonists, spironolactone, eplerenon

Effect of pharmaceutical care on blood pressure control and health-related quality of life in patients with resistant hypertension

Purpose. Verification of whether pharmacotherapeutic follow-up improves arterial blood pressure (BP) was conducted, and whether this improvement alters the quality of life of patients with resistant hypertension in a university teaching hospital in Brazil was determined. Methods. A prospective survey of 44 patients was carried out over a period of 20 months. Each patient was followed up for 12 months. Pharmaceutical care was assessed using the following methods: measurement of the office BP and ambulatory BP monitoring, adherence to therapy, drug-related problems, and the use of health care facilities (urgent care visits and hospital admissions). The health-related quality of life (HRQOL) of patients was also assessed using the 36-Item Short Form Health Survey (SF-36) questionnaire and a physical symptoms profile. Results. The majority (95.5%) of patients adhered to the treatment throughout the study, and there was a significant reduction in BP (p < 0.05). Nearly all of the domains of HRQOL assessed by SF-36 remained unchanged during the follow-up except for a significant improvement in social functioning (p = 0.041). There was a significant reduction in moderate and severe physical symptoms (p = 0.005). There were also significant reductions in the number of urgent care visits (p = 0.0001) and hospital admissions (p = 0.006). Conclusion. The pharmaceutical care provided by a pharmacist in an ambulatory care clinic in Brazil improved BP, adherence to anti hypertensive medications, and the social functioning of patients with resistant hypertension.64181955196

Cyclic guanosine monophosphate phosphodiesterase-5 inhibitor promotes an endothelium NO-dependent-like vasodilation in patients with refractory hypertension

The nitric oxide/cyclic-guanosine 3',5'-monophosphate signaling cascade plays an essential role in cardiovascular homeostasis but its involvement in the pathophysiology of refractory hypertension is unclear. The acute vasodilatory effect of a single oral dose of a phosphodiesterase-5 inhibitor (sildenafil citrate) on the brachial artery dilatation was evaluated in 25 normal healthy volunteers (NL) and in 25 refractory hypertensive patients (RH). Endothelial and vascular smooth muscle functions were assessed two times. First, the brachial artery response to endothelium-dependent (flow-mediated dilatation [FMD]) and independent (glyceryl trinitrate [GTN]) stimuli was examined. The FMD in NL was 14.2 +/- 3.2% compared to 10.3 +/- 3.5% in RH (P < 0.001) and the GTN-induced responses were 23.5 +/- 6.3 in NL compared to 18.4 +/- 5.7% in RH (P < 0.001). Two weeks later, the brachial artery responses to FMD were determined before and after the administration of sildenafil citrate. Sildenafil caused a significant, slow and progressive dilatation of the brachial artery until 45 min after administration (4.7 +/- 3.0%, 6.7 +/- 3.0% and 9.4 +/- 3.9 after 15', 30' and 45', respectively, in RH and 3.7 +/- 1.9%, 7.4 +/- 2.7% and 10.1 +/- 3.0%, respectively, in NL). A second FMD stimulus, applied 45 min after ingesting 50 mg of sildenafil resulted in an additional significant increase in the vasodilatory response (from 9.4 +/- 3.9% to 13.0 +/- 4.0% in RH; P < 0.001 and from 10.1 +/- 3.0 to 14.6 +/- 4.1 in NL; P < 0.001), but this was still significantly less than the response to GTN. Sildenafil citrate caused brachial artery vasodilatation similar to that caused by NO released during FMD in patients with refractory hypertension. (c) 2007 Elsevier Inc. All rights reserved.16331532

Endothelial nitric oxide synthase haplotypes are related to blood pressure elevation, but not to resistance to antihypertensive drug therapy

Objectives Most hypertensive patients require two or more drugs to control arterial blood pressure effectively. Although endothelial nitric oxide synthase (eNOS) haplotypes have been associated with hypertension, it is unknown whether eNOS genotypes/haplotypes are associated with resistance to antihypertensive therapy. Methods We studied the distribution of three eNOS genetic polymorphisms: single nucleotide polymorphisms in the promoter region (T(-786)C), and in exon 7 (Glu298Asp), and a variable number of tandem repeats in intron 4(b/a). Genotypes were determined for 111 normotensive controls (NT), 116 hypertensive individuals who were well controlled (HT), and 100 hypertensive individuals who were resistant to conventional antihypertensive therapy (RHT). We also compared the distribution of eNOS haplotypes in the three groups of subjects. Results No differences were found in genotype or allele distribution among the three groups (all P > 0.05). Conversely, the 'C Glu b' haplotype was more commonly found in the NT than in the HT or RHT groups (21 versus 8 and 7%, respectively; both P < 0.00625). In addition, the 'C Asp V haplotype was more commonly found in the HT or RHT groups than in the NT group (22 and 20%, respectively, versus 8%; both P < 0.00625). The distribution of eNOS haplotypes was not significantly different in the HT and RHT groups (P > 0.05). Conclusions Whereas our findings suggest a protective effect for the 'C Glu b' haplotype against hypertension and that the 'C Asp b' haplotype increases the susceptibility to hypertension, our results suggest that eNOS haplotypes are not associated with resistance to anti hypertensive therapy.24122393239

Intensive Monitoring of Adherence to Treatment Helps to Identify "True" Resistant Hypertension

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Intensive monitoring of adherence in patients with uncontrolled hypertension was evaluated over a 6-month period. After that period, only patients well characterized as having resistant hypertension were followed for 12 months. The goal of this study was to evaluate whether adherence to a drug regimen helps to identify patients with resistant hypertension. Forty-four hypertensive patients resistant to a 3-drug regimen (average blood pressure [BP] mm Hg, mean +/- standard deviation) were studied prospectively. Each patient was followed for a 12-month period. Adherence to treatment was evaluated through self-report, applying Morisky's questionnaire and the pill count method. Ambulatory BP monitoring and office BP measures were performed. By pill count, 63.6% of the patients were adherent to treatment at the start of the survey and 94% at the end, although 59% of the patients still did not reach normal BP levels. We found that non-adherence was not associated with resistance to antihypertensive treatment. Therefore, after investigation, we concluded that patients who presented with uncontrolled arterial BP may be truly resistant hypertensive to treatment.114183191Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Research and Teaching Fund Support ( FAEP) from the State University of Campinas ( Sao Paulo, Brazil)Federal University of Alfenas ( UNIFAL) ( Alfenas, Brazil)Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Low-renin (volume dependent) mild-hypertensive patients have impaired flow-mediated and glyceryl-trinitrate stimulated vascular reactivity

Background Low-renin (volume-dependent) hypertension represents 25-30% of all cases of primary hypertension. Endothelial dysfunction and vascular remodeling are associated with hypertension but their relevance to volume-dependent hypertension (VDH) is not yet known. To evaluate this, flow-mediated dilation (FMD) of the brachial artery and the carotid intima-media thickness in the distal common carotid artery were measured and compared between renin-dependent mild-hypertensive patients (RDH) and controls. Method and Results The study group comprised 40 mild-hypertensive patients and 25 controls. Plasma renin activity (PRA), plasma aldosterone concentration, angiotensin U and nitrite/nitrate plasma levels were measured. According to PRA, subjects were classified as VDH ( 0.6 ng(.)ml(-1.)h(-1)). Vascular function was evaluated by FMD before and after reactive hyperemia (RH) and glyceryl-trinitrate (GTN) administration. FMD in response to RH and GTN in the VDH group when compared with RDH group was 10.2 +/- 2.8% vs 13.3 +/- 3.6% (p=0.01); and 16.0 +/- 3.5% vs 19.9 +/- 4.5% (p=0.01), respectively. Conclusion This study showed impaired FMD and reduced GTN response in mildly hypertensive patients with low-renin plasma levels.69111380138