Meta-analysis of randomized trials of angioedema as an adverse event of renin-angiotensin system inhibitors

Angioedema is a rare, potentially life-threatening adverse event of renin-angiotensin system inhibitors. The objective of the present study was to determine the risk of angioedema from randomized clinical trials. A PubMed/CENTRAL/EMBASE search was made for randomized clinical trials from 1980 to October 2011 in patients on angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or direct renin inhibitor (DRI). Trials with a total number of patients ≥100 and a duration of ≥8 weeks were included for analysis. Incidence of angioedema was pooled by weighing the incident rate of each trial by the inverse of the variance. Twenty-six trials with 74,857 patients in the ACE inhibitor arm with 232,523 person-years of follow-up, 19 trials with 35,479 patients on ARB with 122,293 person-years of follow-up, and 2 trials with 5,141 patients on DRI with 1,735 person-years of follow-up met the inclusion criteria and were included in the analysis. In head-to-head comparison in 7 trials, risk of angioedema with ACE inhibitors was 2.2 times higher than with ARBs (95% confidence interval [CI] 1.5 to 3.3). With ACE inhibitors and ARBs, incidence of angioedema was higher in heart failure trials compared to hypertension or coronary artery disease trials without heart failure (p <0.0001). Weighted incidence of angioedema with ACE inhibitors was 0.30% (95% CI 0.28 to 0.32) compared to 0.11% (95% CI 0.09 to 0.13) with ARBs, 0.13% (95% CI 0.08 to 0.19) with DRIs, and 0.07% with placebo (95% CI 0.05 to 0.09). In conclusion, incidence of angioedema with ARBs and DRI was <1/2 than that with ACE inhibitors and not significantly different from placebo. Incidence of angioedema was higher in patients with heart failure compared to those without heart failure with ACE inhibitors and ARBs.     

Salt and Hypertension: Is Salt Dietary Reduction Worth the Effort?

In numerous epidemiologic, clinical, and experimental studies, dietary sodium intake has been linked to blood pressure, and a reduction in dietary salt intake has been documented to lower blood pressure. In young subjects, salt intake has a programming effect in that blood pressure remains elevated even after a high salt intake has been reduced. Elderly subjects, African Americans, and obese patients are more sensitive to the blood pressure-lowering effects of a decreased salt intake. Depending on the baseline blood pressure and degree of salt intake reduction, systolic blood pressure can be lowered by 4 to 8 mm Hg. A greater decrease in blood pressure is achieved when a reduced salt intake is combined with other lifestyle interventions, such as adherence to Dietary Approaches to Stop Hypertension. A high salt intake has been shown to increase not only blood pressure but also the risk of stroke, left ventricular hypertrophy, and proteinuria. Adverse effects associated with salt intake reduction, unless excessive, seem to be minimal. However, data linking a decreased salt intake to a decrease in morbidity and mortality in hypertensive patients are not unanimous. Dietary salt intake reduction can delay or prevent the incidence of antihypertensive therapy, can facilitate blood pressure reduction in hypertensive patients receiving medical therapy, and may represent a simple cost-saving mediator to reduce cardiovascular morbidity and mortality.     

Drug-induced hypertension: an unappreciated cause of secondary hypertension

A myriad variety of therapeutic agents or chemical substances can induce either a transient or persistent increase in blood pressure, or interfere with the blood pressure-lowering effects of antihypertensive drugs. Some agents cause either sodium retention or extracellular volume expansion, or activate directly or indirectly the sympathetic nervous system. Other substances act directly on arteriolar smooth muscle or do not have a defined mechanism of action. Some medications that usually lower blood pressure may paradoxically increase blood pressure, or an increase in pressure may be encountered after their discontinuation. In general, drug-induced pressure increases are small and transient: however, severe hypertension involving encephalopathy, stroke, and irreversible renal failure have been reported. The deleterious effect of therapeutic agents is more pronounced in patients with preexisting hypertension, in those with renal failure, and in the elderly. Careful evaluation of a patient's drug regimen may identify chemically induced hypertension and obviate unnecessary evaluation and facilitate antihypertensive therapy. Once chemical-induced hypertension has been identified, discontinuation of the causative agent is recommended, although hypertension can often be managed by specific therapy and dose adjustment if continued use of the offending agent is mandatory. The present review summarizes the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action.     

Diurnal variations of cardiac rhythm,arterial pressure,and urinary catecholamines in borderline and established essential hypertension

Ambulatory continuous ECG and arterial pressure (BP) were recorded simultaneously (Delmar Avionics Pressurometer II) for 24 hours in 13 age-matched normotensive subjects, 11 patients with borderline hypertension (HBP), and in 10 patients with uncomplicated established essential HBP. Urinary concentrations of epinephrine, norepinephrine, and dopamine were simultaneously collected over four successive 4-hour periods and one 8-hour period. Prevalence and total number of ventricular and supraventricular ectopic beats was low and not affected by arterial BP. Twenty-four-hour heart rate (HR) and 4-hourly excretion of epinephrine, norepinephrine, and dopamine were comparable between normotensive and HBP persons and no correlation between urinary catecholamines and arterial BP (systolic, diastolic, or mean), HR, or prevalence of ectopic beats was found in any of the three groups or in the total study population. We conclude that HBP patients without ECG evidence of left ventricular hypertrophy do not have a higher prevalence of supraventricular or ventricular ectopic beats. Urinary catecholamines are not related to circadian fluctuations or variability in arterial BP, HR, or prevalence of ectopic beats.     

Disparate hemodynamic responses to mental challenge after antihypertensive therapy with beta blockers and calcium entry blockers

The hemodynamic response to mental challenge was studied in 40 male outpatients with mild essential hypertension. The patients were treated randomly either with a beta adrenoreceptor blocker (oxprenolol) or with a calcium entry blocker (nitrendipine). Cardiovascular reactivity was evaluated with two different mental arithmetic tasks before and six months after treatment by continuously measuring systolic and diastolic pressure (ultrasonic Doppler device), heart rate (electrocardiography), and stoke volume (impedance cardiography). Patients in both treatment groups had equal decreases in arterial pressure and the same pressures at rest. In patients receiving calcium entry blockers, mental challenge provoked an increase in stroke volume and a decrease in total peripheral resistance similar to results in the pretreatment phase. In contrast, beta adrenoreceptor blockade reversed the hemodynamic response pattern to a distinct decrease in stroke volume (p less than or equal to 0.05) and an increase in total peripheral resistance (p less than or equal to 0.05). In addition, an attenuated heart rate response (p less than or equal to 0.01) and a larger increase in diastolic pressure (p less than or equal to 0.01) were found in the beta blocker group compared with the calcium entry blocker group. Although beta blockers and calcium blockers produce equal decreases in arterial pressure, beta blockers evoke an abnormal hemodynamic response to mental challenge, whereas calcium entry blockers preserve the physiologic reactivity pattern of the untreated state.     

Neurulation and neurite extension require the zinc transporter ZIP12 (slc39a12)

Zn²⁺ is required for many aspects of neuronal structure and function. However, the regulation of Zn²⁺ in the nervous system remains poorly understood. Systematic analysis of tissue-profiling microarray data showed that the zinc transporter ZIP12 (slc39a12) is highly expressed in the human brain. In the work reported here, we confirmed that ZIP12 is a Zn²⁺ uptake transporter with a conserved pattern of high expression in the mouse and Xenopus nervous system. Mouse neurons and Neuro-2a cells produce fewer and shorter neurites after ZIP12 knockdown without affecting cell viability. Zn²⁺ chelation or loading in cells to alter Zn²⁺ availability respectively mimicked or reduced the effects of ZIP12 knockdown on neurite outgrowth. ZIP12 knockdown reduces cAMP response element-binding protein activation and phosphorylation at serine 133, which is a critical pathway for neuronal differentiation. Constitutive cAMP response element-binding protein activation restores impairments in neurite outgrowth caused by Zn²⁺ chelation or ZIP12 knockdown. ZIP12 knockdown also reduces tubulin polymerization and increases sensitivity to nocodazole following neurite outgrowth. We find that ZIP12 is expressed during neurulation and early nervous system development in Xenopus tropicalis, where ZIP12 antisense morpholino knockdown impairs neural tube closure and arrests development during neurulation with concomitant reduction in tubulin polymerization in the neural plate. This study identifies a Zn²⁺ transporter that is specifically required for nervous system development and provides tangible links between Zn²⁺, neurulation, and neuronal differentiation.