Attenuation of endothelin-1 induced vasoconstriction by 17beta estradiol is not sustained during long-term therapy in postmenopausal women with coronary heart disease.

OBJECTIVES: The goal of this study was to determine the long-term effects of estrogen replacement therapy on the response to endothelin-1 (ET-1) in postmenopausal women with coronary heart disease. BACKGROUND: It is thought that the vasoconstrictor ET-1 is involved in the development and progression of atherosclerosis. Estrogen replacement may slow the development of atherosclerosis in postmenopausal women. METHODS: Nineteen of 20 postmenopausal women randomized to either three months of 2 mg oral estradiol or placebo completed the double-blind placebo-controlled protocol. Change in forearm blood flow (FBF) in response to a 60 min brachial arterial infusion of ET-1 (5 pmol/min) was measured before randomization, after one month of randomized therapy and after three months of therapy using venous occlusion plethysmography. RESULTS: Estrogen treatment had no effect on baseline FBF. Systolic and diastolic blood pressure and heart rate did not change in response to estrogen therapy or ET-1. Before randomization, in response to ET-1, FBF was reduced by -21.9% (mean response over 60 min) in the placebo group and -19.0% in the estradiol group (p = 0.67). After one month of therapy, the response was attenuated in the estrogen group, -10.0%, compared with the placebo group, -23.6 (difference in means 13.6%, 95% confidence interval [0.7%, 26.6%], p = 0.041). After three months of therapy, there was no difference in response between the placebo group, -27.0%, and estrogen group, -30.2% (p = 0.65). CONCLUSIONS: In postmenopausal women with coronary heart disease, estrogen therapy inhibits the vasoconstrictor response to ET-1 after one month of therapy. This effect is lost after three months of therapy, suggesting that tachyphylaxis to one potentially beneficial action of estradiol develops during chronic treatment.

Bradykinin B(2) receptor antagonism attenuates blood pressure response to acute angiotensin-converting enzyme inhibition in normal men.

The physiological effects of angiotensin-converting enzyme (ACE) inhibition may be in part mediated by bradykinin. We investigated the effect of coadministration of the specific bradykinin B(2) receptor antagonist icatibant on hemodynamic and neurohormonal responses to acute intravenous ACE inhibition in normal men on a normal sodium diet. We performed a 4-phase, double-blind, double-dummy, placebo-controlled study in 12 male volunteers. The bradykinin antagonist icatibant (10 mg IV) was coadministered over the first 15 minutes of a 2-hour infusion of the ACE inhibitor perindoprilat (1.5 mg IV). Perindoprilat inhibited ACE activity and elicited the expected changes in active renin concentration and angiotensin peptides. Over the 3 hours after the start of drug infusion, perindoprilat lowered and icatibant increased mean arterial blood pressure (each P<0.0005 versus placebo). Coadministration of icatibant attenuated the mean arterial blood pressure response to perindoprilat (P<0.0005) but had no effect on neurohormonal responses to perindoprilat. Our study indicates that the bradykinin B(2) receptor antagonist icatibant attenuates the short-term blood pressure-lowering effect of acute ACE inhibition in normal men on a normal sodium diet. Bradykinin B(2) receptor antagonism alone increases resting blood pressure. Bradykinin may be involved in the control of blood pressure in the resting state in humans.

Comparison of the AT1-receptor blocker, candesartan cilexetil, and the ACE inhibitor, lisinopril, in fixed combination with low dose hydrochlorothiazide in hypertensive patients.

AIM: To compare candesartan cilexetil and lisinopril in fixed combination with hydrochlorothiazide with respect to antihypertensive efficacy and tolerability. METHODS: This was a double-blind (double-dummy), randomised, parallel group comparison in patients with a mean sitting diastolic blood pressure 95-115 mm Hg on prior antihypertensive monotherapy. Treatments were candesartan cilexetil/hydrochlorothiazide 8/12.5 mg once daily (n = 237) and lisinopril/hydrochlorothiazide 10/12.5 mg once daily (n = 116) for 26 weeks. The primary efficacy variable was change in trough sitting diastolic blood pressure. RESULTS: Changes in mean sitting diastolic blood pressure did not differ significantly between the groups (mean difference 0.5 mm Hg; 95% confidence interval -1.6, 2.7, P = 0.20). No significant differences between the groups was found for other haemodynamic variables (sitting systolic blood pressure, standing blood pressure, sitting/erect heart rate, and proportion of responders and controlled patients). Both drugs were well tolerated but the proportion of patients with at least one adverse event was significantly greater in the lisinopril group (80% vs 69%, P = 0.020). The proportion of patients spontaneously reporting cough (23.1% vs 4.6%) and discontinuing therapy due to adverse events (12.0% vs 5.9%) was also higher in the lisinopril group compared with the candesartan cilexetil group. CONCLUSIONS: The fixed combinations of candesartan cilexetil and hydrochlorothiazide 8/12.5 mg and lisinopril and hydrochlorothiazide 10/12.5 mg once daily are equally effective as antihypertensive agents. The fixed combination containing candesartan cilexetil is better tolerated than that containing lisinopril.

Left ventricular hypertrophy, blood pressure and ACE genotype in untreated hypertension.

It has been suggested that the deletion polymorphism of the angiotensin-converting enzyme (ACE) genotype may be important in the development of left ventricular hypertrophy (LVH). In order to test this hypothesis we investigated the interaction between blood pressure (BP), LVH and ACE genotype in 86 previously untreated hypertensive patients. Each underwent two-dimensional and Doppler echocardiography and ACE genotyping. There were no significant differences in BP, the parameters of left ventricular structure (including left ventricular mass index) or diastolic function between the three genotype groups. Additionally, there were no significant differences in the relationship between systolic BP and left ventricular mass index among the three genotype groups (II genotype, r = 0.46, P = 0.02; ID genotype, r = 0.42, P = 0.01; DD genotype, r = 0.34, P = 0.10; F = 0.38). In contrast to some previous studies, we have found in this group of previously untreated hypertensive subjects no evidence to suggest that the deletion polymorphism of the ACE genotype is important in the development of LVH.

The efficacy and tolerability of candesartan cilexetil in an elderly hypertensive population.

This study was performed to evaluate the antihypertensive efficacy and tolerability of candesartan cilexetil 8-16 mg once-daily in comparison with placebo in elderly hypertensive patients. Forty-one hospital and general practice centres in the Netherlands and in the United Kingdom enrolled 350 patients over 65 years of age with essential hypertension (WHO grades I or II). Patients with supine diastolic BP in the range 95-114 mm Hg after 4- to 8-week placebo run-in period (n = 193) were randomised to double-blind therapy with candesartan cilexetil or placebo. The initial dose of candesartan cilexetil 8 mg or placebo was doubled after 6 weeks if supine diastolic blood pressure (BP) exceeded 90 mm Hg. Mean (95% confidence interval) placebo-corrected reduction in supine diastolic BP after 12 weeks' treatment with candesartan cilexetil was 7.5 mm Hg (3.6-11.4; P < 0.001); the corresponding reduction in supine systolic BP was 13.6 mm Hg (6.9-20.2; P < 0.001). Placebo-corrected mean reduction in supine diastolic BP 2 and 4 h after the first dose of candesartan cilexetil were 2.2 mm Hg (-1.3 to +5.8; P = 0.219) and 4.0 mm Hg (-0.4 to +7.6; P = 0.027), respectively. Candesartan cilexetil had almost no influence on heart rate and did not affect the normal orthostatic changes in BP. Adverse events were equally common in the two treatment groups. Candesartan cilexetil 8-16 mg once-daily is an effective antihypertensive agent in elderly patients. The onset of action is smooth with no exaggerated response after the first dose and there is no postural hypotension. Candesartan cilexetil is very well tolerated in elderly hypertensives.

Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in humans.

BACKGROUND: Although local inhibition of the generation or actions of endothelin-1 has been shown to cause forearm vasodilatation, the systemic effects of endothelin receptor blockade in healthy humans are unknown. We therefore investigated the cardiovascular effects of a potent peptide endothelin ETA/B receptor antagonist, TAK-044, in healthy men. METHODS AND RESULTS: Two randomized, placebo-controlled, crossover studies were performed. In nine subjects, TAK-044 (10 to 1000 mg IV over a 15-minute period) caused sustained dose-dependent peripheral vasodilatation and hypotension. Four hours after infusion of the highest dose (1000 mg), there were decreases in mean arterial pressure of 18 mm Hg and total peripheral resistance of 665 AU and increases in heart rate of 8 bpm and cardiac index of 0.9 L x min(-1) x m(-2) compared with placebo. TAK-044 caused a rapid, dose-dependent increase in plasma immunoreactive endothelin (from 3.3 to 35.7 pg/mL within 30 minutes after 1000 mg). In a second study in eight subjects, intravenous administration of TAK-044 at doses of 30, 250, and 750 mg also caused peripheral vasodilatation, and all three doses abolished local forearm vasoconstriction to brachial artery infusion of endothelin-1. Brachial artery infusion of TAK-044 caused local forearm vasodilation. CONCLUSIONS: The endothelin ETA/B receptor antagonist TAK-044 decreases peripheral vascular resistance and, to a lesser extent, blood pressure; increases circulating endothelin concentrations; and blocks forearm vasoconstriction to exogenous endothelin-1. These results suggest that endogenous generation of endothelin-1 plays a fundamental physiological role in maintenance of peripheral vascular tone and blood pressure. The vasodilator properties of endothelin receptor antagonists may prove valuable therapeutically.

Tissue angiotensin generation and regulation of vascular tone.

The renin-angiotensin system is intimately involved in the control of sodium and water balance, the activity of the sympathetic nervous system, mitogenesis and the regulation of vascular tone. There is evidence that many of these effects may be controlled at a local level by independent tissue renin-angiotensin systems. Drugs that are specific inhibitors of the cascade have proved powerful tools for dissecting the physiology of the renin-angiotensin system, and are of major benefit in the treatment of hypertension and chronic heart failure. Recent evidence suggests that variations in the genes coding for components of the system may affect the risk of developing hypertension and ischaemic heart disease.

The relationship between blood pressure and left ventricular mass in essential hypertension is observed only in the presence of the angiotensin-converting enzyme gene deletion allele.

An insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) gene accounts for approximately 50% of the variance in plasma ACE concentration: deletion homozygotes (DD) have the highest, and insertion homozygotes (II) the lowest ACE concentrations. ACE is responsible for the generation of angiotensin II, which is implicated in the development of left ventricular hypertrophy, an independent risk factor for morbidity and mortality in hypertension. The aim of this study was to investigate the contribution of ACE genotype to the development of left ventricular hypertrophy in patients with essential hypertension. Eighty-five patients with essential hypertension underwent echocardiographic assessment of left ventricular mass index (LVMI) and determination of ACE genotype from leukocyte DNA by polymerase chain reaction. There was no significant difference in LVMI among the genotypes (II, ID, DD). Analysis of covariance modelled for LVMI showed a significant interaction with systolic blood pressure (p = 0.036) but not diastolic blood pressure (p = 0.453). The relationship between LVMI and systolic blood pressure was strongest in the deletion homozygotes (p = 0.002, R2 = 0.47), and also present in the heterozygotes (p = 0.013, R2 = 0.40). No relationship was seen in the insertion homozygotes (p = 0.914, R2 = 0.23). These findings suggest that the effect of blood pressure on LVMI in essential hypertension is expressed only in the presence of the ACE gene deletion allele.

Local L-NG-monomethyl-arginine attenuates the vasodilator action of bradykinin in the human forearm.

1. Studies in animals indicate that bradykinin relaxes blood vessels directly through an action on smooth muscle and indirectly through the release of endothelium-derived mediators. Its precise mechanism of action in the human arterial circulation is not yet known. 2. In this study the effects of a specific inhibitor of nitric oxide synthase, L-NG-monomethyl-arginine (L-NMMA) and noradrenaline on the vasodilator responses to bradykinin were examined in the forearm arterial bed of healthy volunteers. Noradrenaline was used as a control for vasoconstriction by L-NMMA; glyceryl trinitrate (GTN) as a control vasodilator acting independently of the NO synthase enzyme. 3. L-NMMA (4 mumol min-1; 5 min) alone reduced resting forearm blood flow by 44% (P < 0.01; n = 6) confirming that nitric oxide plays an important role in regulating vascular tone. 4. Bradykinin (10 and 100 pmol min-1; 3 min each dose) and GTN (2 and 5 nmol min-1; 3 min each dose) increased forearm blood flow in a dose-dependent manner (percentage changes 171 +/- 17% and 398 +/- 35%, and 176 +/- 21% and 268 +/- 42%, respectively; n = 6). 5. The response to bradykinin, but not that to GTN, was attenuated by L-NMMA compared with noradrenaline (P < 0.05; n = 6), suggesting that bradykinin-induced vasodilatation in the forearm is mediated, at least in part, by stimulating release of nitric oxide.