Yves Lacourcière

The Effect of an Endothelin-Receptor Antagonist, Bosentan, on Blood Pressure in Patients with Essential Hypertension

BACKGROUND Endothelin is a powerful vasoconstrictor peptide derived from the endothelium. We evaluated the contribution of endothelin to blood-pressure regulation in patients with essential hypertension by studying the effect of an endothelin-receptor antagonist, bosentan. METHODS We studied 293 patients with mild-to-moderate essential hypertension. After a placebo run-in period of four to six weeks, patients were randomly assigned to receive one of four oral doses of bosentan (100, 500, or 1000 mg once daily or 1000 mg twice daily), placebo, or the angiotensin-converting-enzyme inhibitor enalapril (20 mg once daily) for four weeks. Blood pressure was measured before and after treatment. RESULTS As compared with placebo, bosentan resulted in a significant reduction in diastolic pressure with a daily dose of 500 or 2000 mg (an absolute reduction of 5.7 mm Hg at each dose), which was similar to the reduction with enalapril (5.8 mm Hg). There were no significant changes in heart rate. Bosentan did not result in activation of the sympathetic nervous system (as determined by measurement of the plasma norepinephrine level) or the renin-angiotensin system (as determined by measurements of plasma renin activity and angiotensin II levels). CONCLUSIONS An endothelin-receptor antagonist, bosentan, significantly lowered blood pressure in patients with essential hypertension, suggesting that endothelin may contribute to elevated blood pressure in such patients. The favorable effect of treatment with bosentan on blood pressure occurred without reflexive neurohormonal activation.

Effect of angiotensin receptor blockade and antihypertensive drugs on diastolic function in patients with hypertension and diastolic dysfunction: a randomised trial

BACKGROUND Diastolic dysfunction might represent an important pathophysiological intermediate between hypertension and heart failure. Our aim was to determine whether inhibitors of the renin-angiotensin-aldosterone system, which can reduce ventricular hypertrophy and myocardial fibrosis, can improve diastolic function to a greater extent than can other antihypertensive agents. METHODS Patients with hypertension and evidence of diastolic dysfunction were randomly assigned to receive either the angiotensin receptor blocker valsartan (titrated to 320 mg once daily) or matched placebo. Patients in both groups also received concomitant antihypertensive agents that did not inhibit the renin-angiotensin system to reach targets of under 135 mm Hg systolic blood pressure and under 80 mm Hg diastolic blood pressure. The primary endpoint was change in diastolic relaxation velocity between baseline and 38 weeks as determined by tissue doppler imaging. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00170924. FINDINGS 186 patients were randomly assigned to receive valsartan; 198 were randomly assigned to receive placebo. 43 patients were lost to follow-up or discontinued the assigned intervention. Over 38 weeks, there was a 12.8 (SD 17.2)/7.1 (9.9) mm Hg reduction in blood pressure in the valsartan group and a 9.7 (17.0)/5.5 (10.2) mm Hg reduction in the placebo group. The difference in blood pressure reduction between the two groups was not significant. Diastolic relaxation velocity increased by 0.60 (SD 1.4) cm/s from baseline in the valsartan group (p<0.0001) and 0.44 (1.4) cm/s from baseline in the placebo group (p<0.0001) by week 38. However, there was no significant difference in the change in diastolic relaxation velocity between the groups (p=0.29). INTERPRETATION Lowering blood pressure improves diastolic function irrespective of the type of antihypertensive agent used.

Determinants of Elevated Pulse Pressure in Middle-Aged and Older Subjects With Uncomplicated Systolic Hypertension The Role of Proximal Aortic Diameter and the Aortic Pressure-Flow Relationship

Background—Elevated pulse pressure (PP) is associated with increased cardiovascular risk and is thought to be secondary to elastin fragmentation with secondary collagen deposition and stiffening of the aortic wall, leading to a dilated, noncompliant vasculature. Methods and Results—By use of calibrated tonometry and pulsed Doppler, arterial stiffness and pulsatile hemodynamics were assessed in 128 subjects with uncomplicated systolic hypertension (supine systolic pressure ≥140 mm Hg off medication) and 30 normotensive control subjects of comparable age and gender. Pulse-wave velocity was assessed from tonometry and body surface measurements. Characteristic impedance (Zc) was calculated from the ratio of change in carotid pressure and aortic flow in early systole. Effective aortic diameter was assessed by use of the water hammer equation. Hypertensives were heavier (P <0.001) and had higher PP (P <0.001), which was attributable primarily to higher Zc (P <0.001), especially in women. Pulse-wave velocity was higher in hypertensives (P =0.001); however, this difference was not significant after adjustment for differences in mean arterial pressure (MAP) (P >0.153), whereas increased Zc remained highly significant (P <0.001). Increased Zc in women and in hypertensive men was attributable to decreased effective aortic diameter, with no difference in wall stiffness at comparable MAP and body weight. Conclusions—Elevated PP in systolic hypertension was independent of MAP and was attributable primarily to elevated Zc and reduced effective diameter of the proximal aorta. These findings are not consistent with the hypothesis of secondary aortic degeneration, dilation, and wall stiffening but rather suggest that aortic function may play an active role in the pathophysiology of systolic hypertension.

Effects of modulators of the renin-angiotensin-aldosterone system on cough

Objective To compare the incidence of cough in patients with a history of angiotensin converting enzyme (ACE) inhibitor-related cough who received losartan [a type 1 angiotensin II (Ang II) receptor antagonist], lisinopril (an ACE inhibitor) or hydrochlorothiazide (a diuretic). Design An international, multicentre, randomized, double-blind, parallel-group controlled trial. Setting Outpatient clinics at 20 tertiary care medical centres in 11 countries. Patients One hundred and thirty-five patients with uncomplicated primary hypertension with a history of ACE inhibitor-related cough were randomly assigned to the double-blind treatment phase and completed the study. Intervention After confirming that the cough was ACE inhibitor-related by a single-blind rechallenge, followed by a placebo washout period, patients were randomly assigned to receive 50 mg losartan, 20mg lisinopril or 25 mg hydrochlorothiazide once a day for 8 weeks. Main outcome measures Cough incidence, severity and frequency were assessed by a self-administered questionnaire and a visual analogue scale. Results The percentage of patients who complained of cough was significantly higher with lisinopril than with losartan or hydrochlorothiazide. The mean visual analogue scale scores for patients treated with lisinopril demonstrated that these patients coughed more frequently than those who received losartan or hydrochlorothiazide. Conclusion The incidence of cough related to the type 1 Ang II receptor antagonist losartan is significantly lower than that observed with lisinopril, and similar to that observed with hydrochlorothiazide in patients with a rechallenged ACE inhibitor cough. Type 1 Ang II receptor antagonists represent a potential new treatment for hypertensive patients in whom ACE inhibitors are indicated, but who develop a cough with these agents.

A comparison of the efficacy and duration of action of candesartan cilexetil and losartan as assessed by clinic and ambulatory blood pressure after a missed dose, in truly hypertensive patients ☆: A placebo-controlled, forced titration study

The purpose of this double-blind, forced titration study was to compare the antihypertensive effect duration of candesartan cilexetil, which has a longlasting binding to the human AT1-receptor, to that of losartan on ambulatory BP (ABP) not only during the 24-h dosing interval but also during the day of a missed dose intake. After a 4-week placebo lead-in period, 268 patients with sitting diastolic BP 95 to 110 mm Hg and mean awake ambulatory DBP > or =85 mm Hg were randomized to receive either 8 mg of candesartan, 50 mg of losartan, or placebo for a 4-week period. Thereafter, the doses were doubled in all patients for an additional 4-week period. Ambulatory BP monitoring was performed for 36 h after dosing and clinic BP measured 48 h after dosing. Candesartan cilexetil (16 mg) reduced ABP to a significantly greater extent than 100 mg of losartan, particularly for systolic ABP during daytime (P<.05), nighttime (P<.05), and 24-h (P<.01) periods, systolic (P<.01) and diastolic (P<.05) ABP between 0 and 36 h, and both systolic (P<.001) and diastolic (P<0.001) ABP during the day of a missed dose. Clinic BP at 48 h after dosing was significantly reduced exclusively with 16 mg of candesartan. The differences in BP reduction between 8 mg of candesartan and 50 mg of losartan were statistically significant for systolic ABP during daytime (P<.01), nighttime (P<.05), 24-h (P<.01), 0 to 36 h (P<.05) and during the day of missed dose (P<.05). Moreover, although losartan did not significantly reduce ambulatory BP in a dose-related manner, ambulatory systolic and diastolic BP reductions with 16 mg of candesartan were significantly greater (P<.01 and <.001) than those seen with 8 mg of candesartan during every period at the ABP supporting a dose-response relationship. In conclusion, this forced titration study in ambulatory hypertensive patients demonstrates that candesartan cilexetil provides significant dose-dependent reduction in both clinic and ambulatory BP in doses ranging from 8 to 16 mg once daily. Furthermore, candesartan cilexetil is superior to losartan in reducing systolic ABP and in controlling both systolic and diastolic ABP on the day of a missed dose. The differences observed between both agents are most likely attributable to a tighter binding to, and a slower dissociation from, the receptor binding site with candesartan cilexetil.

Triple Antihypertensive Therapy With Amlodipine, Valsartan, and Hydrochlorothiazide. A Randomized Clinical Trial

Many patients with hypertension require ≥3 agents to achieve target blood pressure (BP). The efficacy/safety of the dual combinations of valsartan (Val)/hydrochlorothiazide (HCTZ) and amlodipine (Aml)/Val in hypertension are well established. This randomized, double-blind study evaluated the efficacy/safety of triple therapy with Aml/Val/HCTZ for moderate or severe hypertension (mean sitting systolic BP: ≥145 mm Hg; mean sitting diastolic BP: ≥100 mm Hg). The study included a single-blind, placebo run-in period, followed by double-blind treatment for 8 weeks; patients were randomly assigned to 1 of 4 groups titrated to Aml/Val/HCTZ 10/320/25 mg, Val/HCTZ 320/25 mg, Aml/Val 10/320 mg, or Aml/HCTZ 10/25 mg once daily. Dual-therapy recipients received half of the target doses of both agents for the first 2 weeks, titrating to target doses during week 3. Those on triple therapy received Val/HCTZ 160.0/12.5 mg during week 1, Aml/Val/HCTZ 5.0/160.0/12.5 mg during week 2, and target doses of all 3 of the agents during week 3. Of the 4285 patients enrolled, 2271 were randomly assigned to treatment, and 2060 completed the study. Triple therapy was significantly superior to all of the dual therapies in reducing mean sitting systolic BP and mean sitting diastolic BP from baseline to end point (all P<0.0001). Significantly more patients on triple therapy achieved overall BP control (<140/90 mm Hg; P<0.0001) and systolic and diastolic control (P≤0.0002) compared with each dual therapy. Aml/Val/HCTZ was well tolerated. The benefits of triple therapy over dual therapy were observed regardless of age, sex, race, ethnicity, or baseline mean sitting systolic BP. In conclusion, this study demonstrates the efficacy/safety of treating moderate and severe hypertension with Aml/Val/HCTZ 10/320/25 mg.

Aortic Diameter, Wall Stiffness, and Wave Reflection in Systolic Hypertension

Systolic hypertension is associated with increased pulse pressure (PP) and increased risk for adverse cardiovascular outcomes. However the pathogenesis of increased PP remains controversial. One hypothesis suggests that aortic dilatation, wall stiffening and increased pulse wave velocity result from elastin fragmentation, leading to a premature reflected pressure wave that contributes to elevated PP. An alternative hypothesis suggests that increased proximal aortic stiffness and reduced aortic diameter leads to mismatch between pressure and flow, giving rise to an increased forward pressure wave and increased PP. To evaluate these two hypotheses, we measured pulsatile hemodynamics and proximal aortic diameter directly using tonometry, ultrasound imaging, and Doppler in 167 individuals with systolic hypertension. Antihypertensive medications were withdrawn for at least 1 week before study. Patients with PP above the median (75 mm Hg) had lower aortic diameter (2.94±0.36 versus 3.13±0.28 cm, P<0.001) and higher aortic wall stiffness (elastance-wall stiffness product: 16.1±0.7 versus 15.7±0.7 ln[dyne/cm], P<0.001) with no difference in augmentation index (19.9±10.4 versus 17.5±10.0%, P=0.12). Aortic diameter and wall stiffness both increased with advancing age (P<0.001). However, an inverse relation between PP and aortic diameter remained significant (P<0.001) in models that adjusted for age, sex, height, and weight and then further adjusted for aortic wall stiffness, augmentation index, and mean arterial pressure. Among individuals with systolic hypertension, increased PP is primarily attributable to increased wall stiffness and reduced aortic diameter rather than premature wave reflection.

Aftereffects of exercise on regional and systemic hemodynamics in hypertension.

Several studies have indicated that a single bout of physical exercise induced a significant antihypertensive effect during the hours after the activity. However, little information is presently available on the underlying hemodynamic changes. We examined 13 essential hypertensive patients and nine normotensive subjects in a randomized, crossover study design during 3 hours after a 30-minute period of upright leg cycling at 50% of peak aerobic capacity and during 3 hours after a 30-minute control period of rest. Blood pressure, heart rate, cardiac output, total peripheral resistance, and regional vascular resistance in the forearm as well as venous plasma catecholamine concentrations were measured repeatedly. After exercise, systolic (-11 +/- 2 mm Hg) and diastolic (-4 +/- 1 mm Hg) blood pressures, total peripheral resistance (-27 +/- 5%), forearm vascular resistance (-25 +/- 6%), and plasma norepinephrine levels (-21 +/- 7%) were significantly (p less than or equal to 0.05) decreased, and cardiac output was increased (+31 +1- 8%) compared with control in hypertensive subjects. In contrast, in normotensive subjects blood pressure, forearm vascular resistance, and plasma norepinephrine were unchanged, and systemic hemodynamics changed to a lesser extent than in hypertensive subjects after exercise. It is concluded that a decrease in regional vascular resistance in skeletal muscles and possibly in the skin in hypertensive patients may contribute importantly to the antihypertensive effect of prior exercise. A decreased sympathetic nervous activity, as seen from lower plasma norepinephrine levels, may be involved in this effect.

Captopril or conventional therapy in hypertensive type II diabetics. Three-year analysis.

The effects of long-term treatment with captopril and conventional therapy on albuminuria and metabolic parameters were compared in 74 hypertensive type II diabetics with normal serum creatinine. Patients were treated double-blind with either captopril monotherapy or combined with hydrochlorothiazide or therapy with metoprolol, hydrochlorothiazide, or both for 36 months. The treatment was titrated to achieve goal diastolic blood pressure of < or = 85 mm Hg. The reductions in blood pressures during treatment were similar in patients with (n = 21) and without (n = 53) microalbuminuria treated with either captopril or conventional therapy. No significant changes in albuminuria occurred in normoalbuminuric patients with either therapy. Although albuminuria fell in nearly all patients with microalbuminuria treated with captopril, it rose in eight of 12 patients on conventional therapy, with macroalbuminuria developing in two of them. Renal function was preserved by both types of treatment in both patient groups. Long-term treatment with either conventional therapy or captopril did not alter metabolic variables. We conclude that captopril alone or in combination decreases albuminuria and prevents the development of macroalbuminuria in hypertensive type II diabetics with persistent microalbuminuria. The renoprotective effect of this agent, however, remains to be demonstrated with longer term data on renal function. Aggressive antihypertensive treatment with either captopril or conventional therapy appears to be effective in preventing the onset of microalbuminuria in most normoalbuminuric patients. In contrast, with previous short-term studies, the use of converting enzyme inhibitors or conventional therapy did not cause adverse metabolic effects.

Effects of different training intensities on 24-hour blood pressure in hypertensive subjects.

BackgroundIt is generally accepted that physical training decreases blood pressure in hypertensive subjects, but the importance of training intensity has not been established. This study compared the effects of endurance training at different intensities on ambulatory blood pressure and on blood pressure load (percentage of readings above 140/90 and 120/80 mm Hg during the waking and sleeping periods, respectively). Methods and ResultsPreviously sedentary subjects with mild to moderate hypertension were evaluated in a crossover fashion according to a Latin square after a sedentary control period and after training at low and at moderate intensity corresponding to 50%o and 70%o of maximal oxygen uptake, respectively. Each period lasted 10 weeks. After training at moderate intensity, a higher maximal oxygen uptake was found compared with sedentary values but not after training at low intensity. Both training intensities exerted a similar antihypertensive effect of about 5 mm Hg for systolic and diastolic 24-hour blood pressures. However, training at low intensity reduced blood pressure exclusively during the waking hours, whereas training at a moderate intensity reduced blood pressure only during the evening and sleeping hours. Waking blood pressure load decreased from 66% to 49%v after training at low intensity, whereas sleeping blood pressure load decreased from 61% to 34% after training at moderate intensity (both P<.05). ConclusionLow- and moderate-intensity training produce similar 24-hour blood pressure reductions, but each training intensity may interfere with different pathogenic effects associated with different blood pressure profiles.