beta-Endorphin: possible involvement in the antihypertensive effect of central alpha-receptor activation.

Clonidine and L-alpha-methylnoradrenaline (but not D-alpha-methylnoradrenaline) increase the release of a substance with beta-endorphin immunoreactivity from slices of brainstem of spontaneously hypertensive rats, but not that of normotensive rats. It was reported earlier that opiate antagonists inhibit the hypotensive action of clonidine and alpha-methyldopa in spontaneously hypertensive but not in normotensive rats and that beta-endorphin has hypotensive effects of its own. Together, these findings indicate that release of beta-endorphin by central alpha-receptor agonists may contribute to the antihypertensive action of these drugs.

Effect of individualizing starting doses of a statin according to baseline LDL-cholesterol levels on achieving cholesterol targets: the achieve cholesterol targets fast with atorvastatin stratified titration (ACTFAST) study.

AIMS: To investigate whether selecting the starting dose of atorvastatin according to baseline and target (<2.6 mmol/L) LDL-cholesterol (LDL-C) values would allow high-risk subjects to achieve target LDL-C concentration within 12 weeks, with the initial dose or a single uptitration. METHODS AND RESULTS: Twelve-week, prospective, open-label trial that enrolled 2117 high-risk subjects (statin-free [SF] or statin-treated [ST]). Subjects with LDL-C >2.6 mmol/L (100mg/dL) but

A comparison of the tolerability of the direct renin inhibitor aliskiren and lisinopril in patients with severe hypertension.

Patients with severe hypertension (>180/110 mm Hg) require large blood pressure (BP) reductions to reach recommended treatment goals (<140/90 mm Hg) and usually require combination therapy to do so. This 8-week, multicenter, randomized, double-blind, parallel-group study compared the tolerability and antihypertensive efficacy of the novel direct renin inhibitor aliskiren with the angiotensin converting enzyme inhibitor lisinopril in patients with severe hypertension (mean sitting diastolic blood pressure (msDBP)>or=105 mm Hg and <120 mm Hg). In all, 183 patients were randomized (2:1) to aliskiren 150 mg (n=125) or lisinopril 20 mg (n=58) with dose titration (to aliskiren 300 mg or lisinopril 40 mg) and subsequent addition of hydrochlorothiazide (HCTZ) if additional BP control was required. Aliskiren-based treatment (ALI) was similar to lisinopril-based treatment (LIS) with respect to the proportion of patients reporting an adverse event (AE; ALI 32.8%; LIS 29.3%) or discontinuing treatment due to AEs (ALI 3.2%; LIS 3.4%). The most frequently reported AEs in both groups were headache, nasopharyngitis and dizziness. At end point, ALI showed similar mean reductions from baseline to LIS in msDBP (ALI -18.5 mm Hg vs LIS -20.1 mm Hg; mean treatment difference 1.7 mm Hg (95% confidence interval (CI) -1.0, 4.4)) and mean sitting systolic blood pressure (ALI -20.0 mm Hg vs LIS -22.3 mm Hg; mean treatment difference 2.8 mm Hg (95% CI -1.7, 7.4)). Responder rates (msDBP<90 mm Hg and/or reduction from baseline>or=10 mm Hg) were 81.5% with ALI and 87.9% with LIS. Approximately half of patients required the addition of HCTZ to achieve BP control (ALI 53.6%; LIS 44.8%). In conclusion, ALI alone, or in combination with HCTZ, exhibits similar tolerability and antihypertensive efficacy to LIS alone, or in combination with HCTZ, in patients with severe hypertension.

Bilateral axillobrachial and external carotid artery manifestation of giant cell arteritis: important role of color duplex ultrasonography in the diagnosis.

A 76-year-old man was admitted to our hospital with vertigo. Previously he had been extensively examined because of an increased erythrocyte sedimentation rate without any clinical symptoms. Physical examination revealed 60 mmHg blood pressure difference between the two arms. Color duplex ultrasound examination revealed bilateral extreme narrowing of the external carotid and axillobrachial artery with a dark, hypo-echoic halo around the lumen. This condition was recognized as a specific sign for giant cell arteritis (GCA), described originally in cases of temporal arteritis. The diagnosis was confirmed by biopsy of the temporal artery. In contrast to the typical cranial form of GCA -- our patient showed an unusual, bilateral large-vessel manifestation. The diagnosis was based on ultrasound images rather than on symptoms that characterize the well-known temporal form. This observation emphasizes the role of color duplex ultrasonography in the diagnosis and follow-up of GCA.

Thyrotropin releasing hormone and naloxone attenuate the antihypertensive action of central alpha 2-adrenoceptor stimulation through different mechanisms.

In various forms of shock, TRH is equivalent to naloxone in reversing the hypotension and improving the survival rate. The present findings indicate that in spontaneously hypertensive rats (SHR), TRH has another naloxone-like effect in antagonizing the antihypertensive response to clonidine and alpha-methyldopa. When given during the hypotensive response to alpha-methyldopa, both naloxone and TRH produce a pressor response. While this effect of naloxone is blocked by prazosin, the effect of TRH is not influenced by prazosin or hexamethonium but is inhibited by a vasopressin pressor antagonist. This suggests that the pressor response to naloxone is mediated by the sympathetic nervous system, whereas the similar action of TRH is independent of sympatho-adrenomedullary functions and it is mediated by vasopressin.

Diurnal rhythm of beta endorphin in normotensive and hypertensive patients: the effect of clonidine.

Diurnal rhythm of plasma beta endorphin was established with the highest level in the morning and the lowest one at midnight in normotensive subjects and also in patients with essential hypertension. Clonidine (300 micrograms daily) significantly increased plasma beta endorphin concentrations only in the hypertensive patients. The significant linear correlation between the increase in plasma beta endorphin concentration and the decrease in blood pressure (both systolic and diastolic) in these patients may point to the role of this endogenous opioid in the antihypertensive action of clonidine.

Effects of clonidine and guanfacine in essential hypertension.

Daily doses of 0.3 mg clonidine and 3 mg guanfacine were equiactive in decreasing blood pressure and heart rate in 17 subjects with essential hypertension. Clonidine decreased cardiac output and guanfacine decreased total peripheral resistance, while clonidine had no effect on stroke volume but guanfacine increased it. Both clonidine and guanfacine decreased plasma renin activity. Naloxone, 0.4 mg iv, reversed the antihypertensive effect of clonidine but was ineffective even at higher doses (1.6 mg iv) when subjects were treated with placebo or guanfacine. It is suggested that the hemodynamic differences between the two centrally acting alpha 2-adrenoceptor agonist antihypertensive drugs may at least in part result from the involvement of opioid mechanisms only in the action of clonidine.

The efficacy and tolerability of losartan versus atenolol in patients with isolated systolic hypertension. Losartan ISH Investigators Group.

OBJECTIVE: To compare the efficacy and tolerability of angiotensin II (Ang II) antagonist losartan and the beta-blocker atenolol in the treatment of patients with isolated systolic hypertension (ISH) after 16 weeks of treatment. METHODS: A double-blind, randomized, multi-country study was carried out in 273 patients with ISH. Patients with a sitting systolic blood pressure (SiSBP) of 160-205 mmHg, and a sitting diastolic blood pressure (SiDBP) < 90 mmHg at screening and at placebo baseline were subjected to a 4-week placebo period and then randomly grouped to receive 50 mg losartan or 50 mg atenolol once daily for 16 weeks. At 8 and 12 weeks, patients not controlled (SiDBP > or = 160 mmHg) were given additional treatment of 12.5 mg hydrochlorothiazide (HCTZ) once daily. RESULTS: Similar significant reductions in SiSBPs (mean +/- SD) were obtained with 50 mg losartan and 50 mg atenolol, from 173.7 +/- 10.3 and 173.5 +/- 10.7 mmHg at baseline to 149.0 +/- 15.5 and 148.2 +/- 15.3 mmHg after 16 weeks of losartan or atenolol treatment respectively. Sixty-seven percent of the losartan-treated and 64% of the atenolol-treated patients remained on monotherapy throughout the study. Only 1.5% of the losartan-treated patients withdrew because of a clinical adverse event (CAE) compared with 7.2% in the atenolol-treatment group (P= 0.035). Drug-related CAEs were observed significantly more frequently with atenolol than with losartan treatment (20.3 versus 10.4%; P = 0.029). CONCLUSION: It is concluded that 50 mg losartan and 50 mg atenolol produced comparable reductions in SiSBP in patients with ISH but losartan was better tolerated. This is the first demonstration of the therapeutic value of selective Ang II receptor blockade with losartan in the treatment of ISH.

Naloxone reverses the antihypertensive effect of clonidine.

In unanesthetized, spontaneously hypertensive rats the decrease in blood pressure and heart rate produced by intravenous clonidine, 5 to 20 micrograms/kg, was inhibited or reversed by nalozone, 0.2 to 2 mg/kg. The hypotensive effect of 100 mg/kg alpha-methyldopa was also partially reversed by naloxone. Naloxone alone did not affect either blood pressure or heart rate. In brain membranes from spontaneously hypertensive rats clonidine, 10(-8) to 10(-5) M, did not influence stereoselective binding of [3H]-naloxone (8 nM), and naloxone, 10(-8) to 10(-4) M, did not influence clonidine-suppressible binding of [3H]-dihydroergocryptine (1 nM). These findings indicate that in spontaneously hypertensive rats the effects of central alpha-adrenoceptor stimulation involve activation of opiate receptors. As naloxone and clonidine do not appear to interact with the same receptor site, the observed functional antagonism suggests the release of an endogenous opiate by clonidine or alpha-methyldopa and the possible role of the opiate in the central control of sympathetic tone.

Antihypertensive effect of the calcium antagonist isradipine and lipid profile.

The hypothesis that plasma lipids may modulate the antihypertensive effect of the calcium antagonist isradipine was tested in 85 patients who had essential hypertension. Significant linear correlations were found between the antihypertensive effect of isradipine and plasma levels of total cholesterol and high-density lipoprotein (HDL2 or HDL3) in normotriglyceridemic (n = 63), but not in hypertriglyceridemic (n = 22), patients. From this, we conclude that normal levels of plasma lipids may modulate the function of calcium channels and their interaction with calcium antagonists.

Hungarian Isradipine Study (HIS): long-term (3-year) effects on blood pressure and plasma lipids.

These are the preliminary data of an open multicenter trial of antihypertensive treatment with isradipine as monotherapy (dose, 4.55 +/- 0.56 mg twice daily; n = 11) or isradipine (7.5 +/- 0.63 mg twice daily) in combination with bopindolol (1.16 +/- 0.12 mg once daily; n = 30) administered for 3 years to patients with essential hypertension (WHO classification I or II). Blood pressure was significantly decreased in both treatment groups and there was no indication of resistance to therapy. Plasma levels of total cholesterol and triglycerides were decreased by the end of the second year of treatment, and there was a tendency toward increase in plasma levels of high-density lipoprotein cholesterol (HDL2 or HDL3). The atherogenic index (ratio between total cholesterol and HDL2 plus HDL3) was also decreased. Blood glucose levels remained unchanged in both normoglycemic patients and those with non-insulin-dependent diabetes mellitus (NIDDM) during 3 years of therapy. It is concluded that isradipine is safe and effective when administered long-term in the treatment of hypertensive patients with either hyperlipidemia or NIDDM.

Presynaptic alpha 2-adrenoceptors exclusively sensitive to agonists of phenylethylamine structure on the sympathetic nerves of the human gall bladder artery.

The influence of alpha 2-adrenoceptor agonists and antagonists on the release of noradrenaline was studied in human gall bladder (cystic) artery preparations, in which transmitter stores were labelled with [3H]noradrenaline. The preparations were stimulated at 2 Hz for 3 min (360 shocks each of 1 ms duration two times (S1 and S2)). Both the L-noradrenaline and alpha-methylnoradrenaline (10(-6) M) significantly reduced (S2/S1 = 0.27 +/- 0.05; 0.43 +/- 0.04, respectively), whilst clonidine, xylazine and guanfacine at 10(-6) M failed to affect the stimulation evoked release of [3H]noradrenaline. Yohimbine (10(-6) M), CH-38083, which is a new, selective alpha 2-adrenoceptor antagonist (10(-7) M) and prazosin (10(-6) M) enhanced the evoked release of radioactivity, where S2/S1 were 2.50 +/- 0.19; 2.99 +/- 0.32; 1.48 +/- 0.05, respectively. Administering the alpha 2-antagonists and prazosin together, we were unable to demonstrate an additive effect. Yohimbine and CH-38083 prevented, while prazosin reduced, the inhibitory effects of L-noradrenaline or alpha-methylnoradrenaline on the release of radioactivity. Our results suggest that one type of presynaptic alpha 2-adrenoceptor modulates the release of noradrenaline evoked by electrical stimulation of the human cystic artery. This receptor is sensitive to alpha 2-adrenoceptor agonists which have a phenylethylamine structure, but is insensitive to imidazolines and guanfacine.

Beta-endorphin contributes to the antihypertensive effect of clonidine in a subset of patients with essential hypertension.

Naloxone [0.4 mg iv.] increased blood pressure and heart rate of 13 clonidine-treated [0.3 mg per os for 3 days] patients with essential hypertension [reacting group] while it has no such effect in 11 clonidine-treated patients [non-reacting gr.] Clonidine increased plasma beta-endorphin concentration of the reacting patients by 17.53 +/- 1.68 pM/1 and in the non-reacting ones by 5.91 +/- 0.88 pM/1. Significant linear correlation was found between the clonidine-induced increase in plasma beta-endorphin level and the naloxone-induced change in mean blood pressure [r = 0.9572, n:24, p less than 0.001]. In another group of 8 patients clonidine [0.15 mg iv.] decreased mean blood pressure but naloxone, 30 min after the clonidine injection, did not reverse the clonidine hypotension. We suggest that beta-endorphin, released by chr. clonidine therapy, contributes to the anti-hypertensive effect only in the reacting group.

Imidazoline receptors: from discovery to antihypertensive therapy (facts and doubts).

The hypothesis and indirect evidence of imidazoline receptors has been promoted since some 15 years ago and it gave a substantial impetus for research in this field, resulting in a better understanding of neuronal and cardiovascular regulatory processes. The nomenclature of the imidazoline receptors has been accepted by international forums but no direct proof for the existence of these receptors has been published. Authors summarise the most important available data, including facts and doubts as far as the discovery, characterisation, and function of imidazoline receptors and their subtypes, the differences between imidazoline receptors and alpha-2 adrenoceptors, and also on their participation in regulatory processes.

Antihypertensive effect of bopindolol: a multi-centre study.

The objective of the study was to investigate the efficacy of different dose levels of bopindolol monotherapy in hypertension. This potent nonselective beta-adrenergic receptor blocker has intrinsic sympathomimetic activity and long duration of action. Forty-four patients with essential hypertension of mild (n = 40) or moderate (n = 4) severity (90 less than DBP less than or equal to 115 mmHg at the end of the placebo period) entered and completed the single-blind, placebo-controlled trial. The study lasted 14 weeks: 2 weeks on placebo, and 12 weeks on active treatment during which the initial dose of bopindolol, 1 mg daily, was augmented up to 1.5 mg, then to 2 mg at four-week intervals until BP normalized or a maximum dose of 2 mg/day bopindolol was reached. The bopindolol was administered once a day in the morning. Patients were seen every other week in the morning before drug taking, when BP and heart rate, supine and standing, a twelve lead ECG and side-effects were recorded. Compared with placebo, supine BP was significantly reduced by bopindolol: from 169 +/- 2/103 +/- 1 mmHg to 148 +/- 3/92 +/- 1, 144 +/- 3/90 +/- 1 and 136 +/- 2/85 +/- 0.6 mmHg at the end of 4, 8 and 12 weeks of treatments, respectively (P less than 0.01 for each). BP changes during standing were similar. Bopindolol lowered the supine heart rate from 84 +/- 2 to 75 +/- 1, 74 +/- 1, 72 +/- 1 beats/min (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Effective control of hypertension: a project of the Hungarian Society of Hypertension, baseline data.

The aim of the project is to assess the quality and improve the preventive and curative practices at the primary care level in Hungary. A total of 50 general practitionaires were selected on a voluntary basis in Budapest, Hungary, and from them, 30 were randomized to the intervention (I) group and 20 to the reference (R) group. The members in the I group have been trained for the official hypertension guideline and their everyday work is monitored. Those in the R group have only been monitored to measure the efficacy of the training. In all, 10% from the known hypertensive persons (N=10,799) and 5% of the remaining (nonhypertensive) patients (N=60,341) were selected randomly from the GP's computer files and invited for screening investigation performed by trained medical students. They measured the blood pressure of patients, assessed the cardiovascular risk status and the quality of education of patients by standardized questionnaires. In total, 4083 patients were invited, but only 39.2% attended the screening visit. The prevalence of undetected hypertension was 34.6%. This prevalence was significantly higher in the older (>60 years: 46.8%) than in the younger (<50 years: 20.8%, P<0.0001) age group and it was higher in men (41.5%) than in women (30.1%, P<0.001). The proportion of H patients on drug treatment was 85.3% and the frequency of patients under effective blood pressure control (eg<140/90 mmHg) was 27.8%. Counselling to patients for a healthier lifestyle (exercise, smoking, alcohol consumption, diet) was very rare. In conclusion, our data represent the primary care of Budapest and may not be relevant to the whole country. As a consequence of this study, education of primary care physicians and patients is a must for further improvement of hypertension care.

Metoclopramide decreases baroreflex sensitivity in patients with essential hypertension.

The effect of metoclopramide (10 mg, iv.) or physiological saline on the exercise-induced (standardized bicycle ergometry) increase in blood pressure and heart rate of patients with essential hypertension was investigated in a double blind, randomized, self controlled study. Metoclopramide had no effect on the exercise-induced increase in blood pressure but significantly enhanced the tachycardia due to ergometry after 4-6 min exercise. The mean slope of linear regression lines calculated from the systolic blood pressure and the corresponding heart rate measured before and during (at 1,2,3,4,5 min) exercise after metoclopramide was significantly steeper than after physiological saline (1.1 +/- 0.12 vs 0.79 +/- 0.09; mean +/- SEM), indicating the decrease in baroreflex sensitivity after metoclopramide. On the basis of results the possible role of endogenous dopaminergic mechanisms in suppressing some components of pressor effect of physical exercise can be hypothesized.

An open-label study investigating the efficacy and safety of 12-96 weeks of telmisartan treatment in patients with hypertension.

This open-label, multicentre, multinational trial evaluated the efficacy and safety of telmisartan used alone or as add-on therapy in 2121 adults with mild-to-moderate essential hypertension. Patients received telmisartan 40-80 mg once daily for 12 weeks and could participate in the study for up to 96 weeks, or until a marketed supply of telmisartan became available. Mean change from baseline in mean seated trough diastolic blood pressure (DBP) after 12 weeks' treatment, the primary endpoint, was -11.8 mmHg in the intent-to-treat population. The corresponding mean change in mean seated trough systolic blood pressure (SBP) was -20.2 mmHg. Both changes were statistically significant. Mean DBP and SBP reductions were apparent from week 4 and maintained throughout the treatment period. Telmisartan was well tolerated; the most common adverse events were headache (6%) and dizziness (3%), and 10% of adverse events were considered drug-related. In conclusion, telmisartan is an effective and well-tolerated drug when used as monotherapy or add-on treatment in this broad population of patients.

[Blood pressure lowering effect of nifedipine in smokers and non-smokers]. / A nifedipin vérnyomáscsökkentö hatása dohányzókban és nemdohányzókban.

The authors summarized the relationships between the cardiovascular diseases and smoking. In their retrospective study they studied the acute antihypertensive effect of nifedipine in patients with essential hypertension who were smokers and nonsmokers. They suggest that the antihypertensive effect of nifedipine did not decrease in smokers. Therefore the nifedipine can be the first choice in the antihypertensive therapy in smokers with essential hypertension.

[The "white coat effect" in hypertensive patients]. / A "fehérköpeny-jelenség" vizsgálata hipertóniás betegekben.

The "white coat effect" has been investigated by non-invasive automatic blood pressure monitoring in patients with hypertension, defined by casual blood pressure readings. A significant "white coat effect" has been demonstrated in 30 (32%) of the 93 patients: the average values were 17/9 mmHg and 6 beat/min, the highest values were 37/29 mmHg and 13 beat/min. The examination has been repeated after 24 hours in 11 cases and the phenomenon was reproducible. The "white coat effect" did not disappear even when the changes were compared to the averages of three subsequent automatic blood pressure measurements. There were significantly more women, than men among the "white coat" positive patients. However, no difference was found in age, occupation and the known duration of hypertension. Neither was any correlation between the "white coat effect" and the blood pressure reaction to mental arithmetic test. It is emphasized that the casual readings can significantly overestimate the blood pressure. This finding must be considered especially in the diagnosis of borderline hypertension.