Journal of hypertension. Supplement : official journal of the International Society of Hypertension最新文献

Background: Although there is overwhelming evidence that hypertension promotes atherosclerosis, the relative contribution and/or interaction of vasoactive and hemodynamic factors remain undefined. Endothelial dysfunction complicates hypertension and is a precursor of atherosclerosis. It is characterized by a reduction in the bioavailability of vasodilators, particularly nitric oxide, and an increase in the activity of vasoconstrictors, including angiotensin (Ang) II and reactive oxygen species (ROS). Nitric oxide antagonizes the vasoconstrictive and pro-atherosclerotic effects of Ang II, whereas Ang II decreases nitric oxide bioavailability by promoting oxidative stress.

Objectives: The present review will focus on the interaction among nitric oxide, Ang II, and ROS in the endothelium and will examine their role in vascular tone and atherogenesis. In this context, studies from our laboratory will be reviewed demonstrating that salt-sensitive hypertension is a vascular diathesis characterized by a local activation of Ang II and NAD(P)H oxidase-derived ROS in the setting of insufficient nitric oxide. In hypertensive Dahl salt-sensitive rats, a paradigm of human salt-sensitive hypertension, inhibition of Ang II type 1 receptor or NAD(P)H oxidase-derived ROS prevented the development of endothelial dysfunction, upregulation of pro-atherogenic molecules, and vascular ROS generation, independently of blood pressure.

Conclusions: Salt sensitivity, an independent risk factor for increased cardiovascular morbidity and mortality, affects approximately 50% of hypertensives. Our studies suggest that, in salt-sensitive hypertension, atherogenesis is more closely linked to oxidative stress than to the hemodynamic stress of hypertension. To prevent or arrest atherosclerosis, antihypertensive therapy should aim at restoring the homeostatic balance between vasoactive factors in the vascular wall.

Background: Lower-body negative pressure (LBNP) induces a progressive activation of neurohormonal systems and a renal tubular and haemodynamic response that mimics the renal adaptation observed in congestive heart failure. Both angiotensin II receptor blockers and beta-blockers have been shown to reduce morbidity and mortality in patients with congestive heart failure.

Objective: To investigate whether part of the beneficial effects of angiotensin II receptor blockers and beta-blockers in congestive heart failure is mediated through an improvement in renal haemodynamics and sodium excretory capacity.

Methods and results: The study was performed in healthy normotensive individuals exposed to three levels of LBNP and treated with placebo, 200 mg metoprolol once daily, or 16 mg candesartan once daily, for 10 days. Our results show that candesartan increased renal blood flow, and thereby blunted the vasoconstriction induced by LBNP. This effect was not found with metoprolol. More importantly, both metoprolol and candesartan prevented the sodium retention induced by LBNP, but only candesartan promoted sodium excretion during the 2-h recovery period--that is, once LBNP was interrupted.

Conclusions: These results suggest that blockade of the renin-angiotensin and sympathetic nervous systems in heart failure may be beneficial in part as a result of improved sodium excretion.

Background: Reducing urinary protein excretion in patients with renal disease is an important therapeutic target to prevent the progression of renal and cardiovascular disease. Drugs such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARBs), which block the actions of the renin-angiotensin-aldosterone system, are recommended because they reduce blood pressure and proteinuria. Recently, the use of higher doses of ARBs, up to three times the maximal approved dose, resulted in further reductions in protein excretion. Despite the effectiveness of this therapeutic approach, no long-term safety analysis has been conducted in patients receiving high-dose ARB treatment.

Objective: To study the long-term safety of high-dose ARB treatment.

Methods: We observed 48 patients [44 men and 4 women; ages 64 +/- 15 years (mean +/- SD), weight 88 +/- 28 kg, estimated glomerular filtration rate 53 +/- 23 ml/min] receiving treatment with high doses (1.5-5 times greater than the maximum approved dose) of ARBs, for 40 +/- 24 months (range 6-98 months).

Results: The average ARB dose tended to increase over time and was 3.2 +/- 1.2 times greater at the end of the study than that at the start. Systolic blood pressure was similar at the beginning and end of the study period (132 +/- 20 and 125 +/- 20 mmHg, respectively), but diastolic blood pressure showed a decrease throughout the study and was significantly reduced (P < 0.05) in association with 1.5x and 2x the maximum ARB dose (73 +/- 11 and 72 +/- 10 mmHg, respectively) when compared with baseline (78 +/- 11 mm Hg). There was a trend (P > 0.05) for increases in concentrations of serum potassium (0.2 +/- 0.9 mmol/l) and creatinine (0.3 +/- 0.7 mg/dl) with increases in dose from baseline to the end of the study. Serum creatinine concentration was greater (P < 0.05) at the periods of 3x and 4x the maximum dose, but this represented increases of only 12 and 20% from baseline, respectively.

Conclusions: High-dose ARB treatment in patients with chronic renal disease is not associated with any clinically significant long-term negative effects on serum creatinine or potassium and is thus a important therapeutic modality with which to achieve further reductions in urinary protein excretion.

Background: The ability of biphenyl-tetrazole angiotensin type 1 (AT1) receptor antagonists (BTsartans) to block angiotensin II (Ang II)-mediated responses has been extensively investigated in vascular tissues and, more recently, in cell lines expressing the human AT1-receptor. When pre-incubated, BTsartans acted surmountably (shifting the Ang II concentration-response curve to the right) or insurmountably (also decreasing the maximal response). It was shown that their insurmountable behaviour is due to the formation of tight, long-lasting complexes with the receptor. Partial insurmountable antagonism is due to the co-existence of tight and loose complexes. The proportion of insurmountable antagonism, the potency and the dissociation rate of the BTsartans decreases in the order: candesartan > EXP3174 (losartan's active metabolite) > valsartan > irbesartan >> losartan.

Objective: It is of interest to explore how tight AT1-receptor binding of BTsartans such as candesartan might contribute to their long-lasting clinical effect.

Methods: Computer-assisted simulations (COPASI program) were performed to follow the receptor-occupation and protection by different antagonists as a function of time. Free antagonist concentrations were allowed to decrease exponentially with time.

Results: The simulations suggest that slow dissociation does not tangibly prolong receptor occupancy if the free antagonist is eliminated at a slower pace (as is the case for BTsartans). Yet when surmountable and insurmountable antagonists occupy the same amount of receptors, insurmountable antagonists offer appreciably better protection against fluctuations in natural messenger concentration.

Conclusion: Slow receptor dissociation and slow antagonist elimination are likely to act in synergy to produce long-lasting receptor protection.

Despite the renoprotective effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), many patients with chronic kidney disease develop end-stage kidney disease. Combination treatment with an ACEI and an ARB is a recently introduced approach to obtain more complete blockade of the renin-angiotensin system, based on the different mechanisms of action of the two classes of drug. To assess the shortcomings of single treatment with ACEIs and ARBs, and the potential benefits of combination treatment, we reviewed the experimental and clinical evidence suggesting that combination treatment offers more complete blockade of the renin-angiotensin system and identified areas in which further research is necessary to confirm the benefits of combination treatment. The available data suggest that combination treatment with an ACEI and an ARB has a greater renoprotective effect than either drug alone. In addition, more recent data have shown that combination treatment is more potent in suppressing renal fibrosis, and is well tolerated in patients with advanced chronic kidney disease. Clinical trials with rigorous endpoints are needed to further establish the benefits of combination treatment in renal protection.

Renal artery stenosis is a common problem, particularly for patients with other manifestations of atherosclerosis. Wide practice variations are apparent regarding how best to manage this disorder. Part of this variation is based on a broad range of clinical presentation, from incidentally identified disease of no clinical importance to rapidly progressive hypertension, renal failure, and refractory congestive heart failure. Advances in antihypertensive therapy, particularly as a result of angiotensin-converting enzyme inhibition and angiotensin receptor blockade, have led to improved blood pressure control and delayed recognition of renal artery disease. As a result, patients now sent for revascularization are older than before and have high comorbid disease risk, primarily related to cardiovascular events. Clinicians need to be vigilant for evidence of unsuspected renal artery stenosis as a cause of treatment-resistant hypertension and/or renal failure. Renal revascularization should be considered in viable individuals before the development of advanced renal insufficiency.

The treatment options for renal artery stenosis include bypass surgery, surgical endarterectomy, or balloon angioplasty with/without stenting. Each of these procedures is delivered today with differing frequency, morbidity/mortality, and outcomes. The procedure most applicable to patients with atherosclerotic disease is percutaneous transluminal renal angioplasty with stenting. Stents prevent plaque recoil, minimizing early restenosis, and the relatively large size of the renal artery (5-7 mm) minimizes late stent restenosis rates. The clinical features that help predict a favorable response to intervention are reviewed. In short, intervention provides a durable means to control renovascular hypertension, ischemic nephropathy, and congestive heart failure due to poor renal volume control.

Recent advances in endovascular technology have radically changed the options available for the clinical management of the patient with renovascular disease. These treatment options have fueled an ongoing debate concerning the appropriateness of interventional endovascular therapy for the stenotic renal artery versus conservative medical management. This review examines a typical clinical case scenario and analyzes relevant published literature and the recent guidelines from the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) highlighting the significant shortcomings of evidence-based data when it comes to the management of this complex patient population. Early diagnosis provides the best opportunity for appropriate utilization of therapeutic options and rational timing of deployment of interventional techniques. Recommendations for conservative medical management are made based on the review of the medical management arms of the published interventional series. In addition, suggestions are made for practical modifications to the JNC 7 hypertension management protocol to better address the challenging diagnostic and management issues raised by the renovascular patient.