Blood pressure response to central and/or peripheral inhibition of phenylethanolamine N-methyltransferase in normotensive and hypertensive rats

We studied the effects on blood pressure and heart rate of two different phenylethanolamine N-methyltransferase (PNMT) inhibitors in normotensive, in two-kidney renal hypertensive, and in deoxycorticosterone-salt (DOC-salt) hypertensive rats. One compound (SK&F 64139) blocks the conversion of norepinephrine to epinephrine in both the central and the peripheral nervous system, whereas the other (SK&F 29661) does not cross the blood-brain barrier and therefore is active mostly in the adrenal glands. In the rats given SK&F 29661, practically no acute blood pressure changes were in the adrenal glands. In the rats given SK&F 64139 induced only a minor blood pressure and heart rate response in normotensive and two-kidney renal hypertensive rats. However, in DOC-salt hypertensive rats, it reduced arterial pressure to approximately normal levels and concomitantly slowed pulse rate. There was a close correlation between the magnitude of the blood pressure response observed in all SK&F 64139-treated animals and the control plasma norepinephrine (4 = -0.795, P less than 0.001) and epinephrine (r = -0.789, P less than 0.001) levels. These results suggest an important role for central epinephrine in regulating the peripheral sympathoadrenomedullary and the baroreceptor reflex activity, particularly when the maintenance of the high blood pressure is not renin-dependent.

Evaluation de l'efficacite antihypertensive de l'isradipine SRO par enregistrement tensionnel en ambulatoire. [Evaluation of the antihypertensive efficacy of isradipine SRO as assessed by ambulatory blood pressure determination]

The calcium channel blocker isradipine has become recently available in a form with delayed release (isradipine SRO). The anti-hypertensive efficacy and tolerance of this preparation at a single daily dose of 5 mg was studied in 40 patients with uncomplicated essential hypertension over a period of 6 weeks. Blood pressure during office visits decreased under Isradipine SRO from 164/105 +/- 16/7 to 144/93 +/- 12/7 mmHg (mean +/- 1 standard deviation p < 0.001). Using ambulatory blood pressure recording we could show that antihypertensive efficacy of the new galenic form persisted over 24 hours. During the day the blood pressure dropped from 150/95 +/- 13/7 to 141/91 +/- 13/7 mmHg (p < 0.001), during the night from 131/85 +/- 13/3 to 121/81 +/- 15/9 mmHg (p < 0.001). Heart-rate was not changed by treatment and the drug was well tolerated. Isradipine SRO at a single dose is thus well suited for antihypertensive treatment.

Step count is associated with lower nighttime systolic blood pressure and increased dipping.

BACKGROUND: Higher nighttime blood pressure (BP) and the loss of nocturnal dipping of BP are associated with an increased risk for cardiovascular events. However, the determinants of the loss of nocturnal BP dipping are only beginning to be understood. We investigated whether different indicators of physical activity were associated with the loss of nocturnal dipping of BP. METHODS: We conducted a cross-sectional study of 103 patients referred for 24-hour ambulatory monitoring of BP. We measured these patients' step count (SC), active energy expenditure (AEE), and total energy expenditure simultaneously, using actigraphs. RESULTS: In our study population of 103 patients, most of whom were hypertensive, SC and AEE were associated with nighttime systolic BP in univariate (SC, r = -0.28, P < 0.01; AEE, r = -0.20, P = 0.046) and multivariate linear regression analyses (SC, coefficient beta = -5.37, P < 0.001; AEE, coefficient beta = -0.24, P < 0.01). Step count was associated with both systolic (r = 0.23, P = 0.018) and diastolic (r = 0.20, P = 0.045) BP dipping. Nighttime systolic BP decreased progressively across the categories of sedentary, moderately active, and active participants (125mm Hg, 116mm Hg, 112mm Hg, respectively; P = 0.002). The degree of BP dipping of BP increased progressively across the same three categories of activity (respectively 8.9%, 14.6%, and 18.6%, P = 0.002, for systolic BP and respectively 12.8%, 18.1%, and 22.2%, P = 0.006, for diastolic BP). CONCLUSIONS: Step count is continuously associated with nighttime systolic BP and with the degree of BP dipping independently of 24-hour mean BP. The combined use of an actigraph for measuring indicators of physical activity and a device for 24-hour measurement of ambulatory BP may help identify patients at increased risk for cardiovascular events in whom increased physical activity toward higher target levels may be recommended.

Blood pressure treatment in acute ischemic stroke: a review of studies and recommendations.

PURPOSE OF REVIEW: Elevated blood pressure (BP) is frequent in patients with acute ischemic stroke. Pathophysiological data support its usefulness to maintain adequate perfusion of the ischemic penumba. This review article aims to summarize the available evidence from clinical studies that examined the prognostic role of BP during the acute phase of ischemic stroke and intervention studies that assessed the efficacy of active BP alteration. RECENT FINDINGS: We found 34 observational studies (33,470 patients), with results being inconsistent among the studies; most studies reported a negative association between increased levels of BP and clinical outcome, whereas a few studies showed clinical improvement with higher BP levels, clinical deterioration with decreased BP, or no association at all. Similarly, the conclusions drawn by the 18 intervention studies included in this review (1637 patients) were also heterogeneous. Very recent clinical data suggest a possible beneficial effect of early treatment with some antihypertensives on late clinical outcome. SUMMARY: Observational and interventional studies of management of acute poststroke hypertension yield conflicting results. We discuss different explanations that may account for this and discuss the current guidelines and pathophysiological considerations for the management of acute poststroke hypertension.

Effect on blood pressure and the renin-angiotensin system of repeated doses of the converting enzyme inhibitor CGS 14824A.

A new, orally active angiotensin converting enzyme (ACE) inhibitor, CGS 14824A, was evaluated in 12 healthy male volunteers. Two groups each of 6 volunteers were given 5 or 10 mg once daily p.o. for 8 days. Four hours after the first and the last morning doses, plasma angiotensin II, aldosterone and plasma converting enzyme activity had fallen, while blood angiotensin I and plasma renin activity had risen. Throughout the study, more than 90% inhibition of ACE was found immediately before giving either the 5 or 10 mg dose and 50% blockade was still present 72 h following the last dose. Based on the determination of ACE, there was no evidence of drug accumulation. No significant change in blood pressure or heart rate was observed during the course of the study. CGS 14824A was an effective, orally active, long-lasting and well tolerated converting enzyme inhibitor.

Nitric ocide mediates the blood pressure response to mental stress in humans

Objectif : Le monoxyde d'azote (NO) régule la pression artérielle en modulant le tonus vasculaire périphérique et l'activité sympathique vasoconstrictrice. La synthèse du NO est altérée dans plusieurs maladies cardiovasculaires importantes. La perte de l'effet vasodilatateur du NO et de son effet freinateur sur la décharge sympathique pourrait entraîner une réponse vasopressive exagérée au stress mental. Méthodes : Nous avons donc comparé les réponses sympathique (activité nerveuse musculaire sympathique) et hémodynamique au stress mental pendant une perfusion isotonique de NaCI et lors de l'administration d'un inhibiteur systémique de la NO- synthase (NG-monomethyl-L-arginine, L-NMMA). Résultats : Le résultat principal est que le stress mental qui pendant la perfusion saline augmente l'activité nerveuse sympathique d'environ 50% et la pression artérielle moyenne d'environ 15%, n'a eu aucun effet sympathoexcitateur et vasopresseur détectable lors de la perfusion de L-NMMA. Ces observations ne sont pas liées à une atteinte généralisée de la réponse hémodynamique et/ou sympathique lors de la perfusion de L-NMMA, car ces réponses étaient conservées lors de l'immersion de la main dans de l'eau glacée. Conclusions : Le stress mental induit des effets vasopresseurs et sympathoexcitateurs chez l'homme qui sont médiés par le NO. Ces résultats laissent penser que, contrairement à ce qui a été généralement supposé, le NO peut dans certaines circonstances augmenter la pression artérielle in vivo.

Hypertension. L'enregistrement tensionnel en ambulatoire: indispensable pour diagnostiquer et traiter l'hypertension [Ambulatory blood pressure monitoring: essential for diagnosing and treating hypertension?].

According to recent international guidelines, 24-h ambulatory blood pressure monitoring plays an important role in the diagnostic and therapeutic approach of arterial hypertension. Indications of this technique are multiple, concerning both day- and night-time blood pressures. Blood pressures provided by ambulatory monitoring may be used to stratify cardiovascular risk.

Treating high blood pressure: is reaching the target more important than the means? No, the means are important.

All major antihypertensive drug classes i.e. diuretics, beta-blockers, calcium antagonists and blockers of the renin-angiotensin system have been shown to effectively lower blood pressure and hence to reduce cardiovascular outcomes in hypertensive patients. These drugs decrease cardiovascular complications in hypertension essentially because they reduce systemic blood pressure. Nevertheless, there is growing evidence that the extent of the benefits differed between drug classes suggesting that the various classes of antihypertensive agents are not equivalent in their ability to protect against target organ damages and cardiovascular and renal endpoints. More recently, evidence has also accumulated to demonstrate that even combination therapies are not equally effective in reducing the occurrence of cardiovascular complications in hypertension. These recent observations suggest that the means to lower blood pressure are as important as the achieved target blood pressure in the management of hypertensive patients.

Ambulatory blood pressure monitoring: a mean to stratify cardiovascular risk.

OBJECTIVE: Current hypertension guidelines stress the importance to assess total cardiovascular risk but do not describe precisely how to use ambulatory blood pressures in the cardiovascular risk stratification. METHOD: We calculated here global cardiovascular risk according to 2003 European Society of Hypertension/European Society of Cardiology guidelines in 127 patients in whom daytime ambulatory blood pressures were recorded and carotid/femoral ultrasonography performed. RESULTS: The presence of ambulatory blood pressures >or =135/85 mmHg shifted cardiovascular risk to higher categories, as did the presence of hypercholesterolemia and, even more so, the presence of atherosclerotic plaques. CONCLUSION: Further studies are, however, needed to define the position of ambulatory blood pressures in the assessment of cardiovascular risk.

How quickly should we titrate antihypertensive medication? Systematic review modelling blood pressure response from trial data.

Context There are no evidence syntheses available to guide clinicians on when to titrate antihypertensive medication after initiation. Objective To model the blood pressure (BP) response after initiating antihypertensive medication. Data sources electronic databases including Medline, Embase, Cochrane Register and reference lists up to December 2009. Study selection Trials that initiated antihypertensive medication as single therapy in hypertensive patients who were either drug naive or had a placebo washout from previous drugs. Data extraction Office BP measurements at a minimum of two weekly intervals for a minimum of 4 weeks. An asymptotic approach model of BP response was assumed and non-linear mixed effects modelling used to calculate model parameters. Results and conclusions Eighteen trials that recruited 4168 patients met inclusion criteria. The time to reach 50% of the maximum estimated BP lowering effect was 1 week (systolic 0.91 weeks, 95% CI 0.74 to 1.10; diastolic 0.95, 0.75 to 1.15). Models incorporating drug class as a source of variability did not improve fit of the data. Incorporating the presence of a titration schedule improved model fit for both systolic and diastolic pressure. Titration increased both the predicted maximum effect and the time taken to reach 50% of the maximum (systolic 1.2 vs 0.7 weeks; diastolic 1.4 vs 0.7 weeks). Conclusions Estimates of the maximum efficacy of antihypertensive agents can be made early after starting therapy. This knowledge will guide clinicians in deciding when a newly started antihypertensive agent is likely to be effective or not at controlling BP.

Ubiquitylation and control of renal na+ balance and blood pressure.

Ubiquitylation is crucial for regulating numerous cellular functions. In the kidney, ubiquitylation regulates the epithelial Na(+) channel ENaC. The importance of this process is highlighted in Liddle's syndrome, where mutations interfere with ENaC ubiquitylation, resulting in constitutive Na(+) reabsorption and hypertension. There is emerging evidence that NCC, involved in hypertensive diseases, is also regulated by ubiquitylation. Here, we discuss the current knowledge and recent findings in this field.

Mice carrying ubiquitin-specific protease 2 (Usp2) gene inactivation maintain normal sodium balance and blood pressure.

Ubiquitylation plays an important role in the control of Na⁺ homeostasis by the kidney. It is well established that the epithelial Na⁺ channel ENaC is regulated by the ubiquitin-protein ligase NEDD4-2, limiting ENaC cell surface expression and activity. Ubiquitylation can be reversed by the action of deubiquitylating enzymes (DUBs). One such DUB, USP2-45, was identified previously as an aldosterone-induced protein in the kidney and is also a circadian output gene. In heterologous expression systems, USP2-45 binds to ENaC, deubiquitylates it, and enhances channel density and activity at the cell surface. Because the role of USP2-45 in renal Na⁺ transport had not been studied in vivo, we investigated here the effect of Usp2 gene inactivation in this process. We demonstrate first that USP2-45 protein has a rhythmic expression with a peak at ZT12. Usp2-KO mice did not show any differences from wild-type littermates with respect to the diurnal control of Na⁺ or K⁺ urinary excretion and plasma levels either on a standard diet or after acute and chronic changes to low- and high-Na⁺ diets, respectively. Moreover, they had similar aldosterone levels on either a low- or high-Na⁺ diet. Blood pressure measurements using telemetry did not reveal variations compared with control mice. Usp2-KO mice did not display alterations in expression of genes involved in sodium homeostasis or the ubiquitin system, as evidenced by transcriptome analysis in the kidney. Our data suggest that USP2 does not play a primary role in the control of Na⁺ balance or blood pressure.

Blood pressure normalization in a large population of hypertensive patients treated with perindopril/indapamide combination: results of the OPTIMAX trial.

OBJECTIVE: To determine if the fixed-dose perindopril/indapamide combination (Per/Ind) normalizes blood pressure (BP) in the same fraction of hypertensive patients when treated in everyday practice or in controlled trials. METHODS: In this prospective trial, 17 938 hypertensive patients were treated with Per 2 mg/Ind 0.625 mg for 3-6 months. In Group 1 Per/Ind was initiated in newly diagnosed patients (n = 7032); in Group 2 Per/Ind replaced previous therapy in patients already treated but having either their BP still uncontrolled or experiencing side-effects (n = 7423); in Group 3 Per/Ind was added to previous treatment in patients with persistently high BP (n = 3483). BP was considered normalized when &lt; or = 140/90 mm Hg. A multivariate analysis for predictors of BP normalization was performed. RESULTS: Subjects were on average 62 years old and had a baseline BP of 162.3/93.6 mm Hg. After treatment with Per/Ind, BP normalization was reached in 69.6% of patients in the Initiation group, 67.5% in the Replacement Group, and 67.4% in the Add-on Group (where patients were more frequently at risk, diabetic, or with target organ damage). Mean decreases in systolic BP of 22.8 mm Hg and in diastolic BP of 12.4 mm Hg were recorded. CONCLUSIONS: This trial was established to reflect everyday clinical practice, and a treatment strategy based on the Per/Ind combination, administered as initial, replacement, or add-on therapy, led to normalization rates that were superior to those observed in Europe in routine practice. These results support recent hypertension guidelines which encourage the use of combination therapy in the management of arterial hypertension.