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Biomedical subjects

H R Brunner

Publications and source records attributed to H R Brunner.

At least 145 records · Page 8Linked to original sources

Modern strategies to prevent coronary sequelae and stroke in hypertensive patients differ from the JNC V Consensus Guidelines.

In recent years, government agencies of many countries have established consensus guidelines for the evaluation and treatment of hypertension. Once published, guidelines tend to be perceived as directives by a variety of health care providers. Unfortunately, these guidelines often do not reflect the practices of most hypertension experts. This report summarizes the opinions of seven hypertension experts concerning the impact of "official" guidelines on clinical practice. In addition, the individual therapeutic recommendations of these panel members are summarized. Their different treatment strategies reflect the diversity of first rate treatment plans that aim to reduce the cardiovascular sequelae in individual patients with essential hypertension. Most importantly, not one of these seven treatment strategies followed the "preferred" treatment of the U.S. guidelines, which recommend diuretics and beta-blockers as first-line therapy. The present authors approach the treatment of hypertension as a means to reduce cardiovascular events. Thus, reduction of blood pressure is not the most important therapeutic endpoint. The panel believes that whereas many different drugs can produce effective blood pressure reduction, the modern primary goal of antihypertensive drug therapy is to select a regimen most likely to prolong the quality and duration of life. In real terms, this means that the primary goal of treatment is the prevention of the major vascular sequelae of hypertension (heart attack, ventricular remodeling, hypertrophy, heart failure, and stroke) that shorten useful life. There are a number of effective hypertensive treatments, which can be selected based on individual patient requirements. However, many consensus guidelines do not allow the flexibility required to optimize individual patient treatment. As a result, health care providers should not feel compelled to regard the preferences of "official" guidelines as the best, modern, state-of-the-art therapy for an individual patient. All seven experts who are deeply involved in the daily care of patients preferred drugs other than beta-blockers and diuretics (the Joint National Committee [JNC] choices) for first-line therapy of hypertension.

Cardiovascular Diseases↗

Dose-related effects of ACE inhibition in man: quinapril in patients with moderate congestive heart failure. The Study Group on Neurohormonal Regulation in Congestive Heart Failure: Lausanne, Switzerland; Berlin, Düsseldorf, Munich, Germany.

Early treatment with ACE inhibitors of even moderate heart failure is clinically beneficial, even though haemodynamic measurements cannot adequately quantitate such improvement. Neurohumoral assessment is, however, supposed to be more accurate. In 55 patients with moderate heart failure (ejection fraction < or = 35%), we investigated the dose-dependent effects of ACE inhibition with quinapril taken orally (2.5, 5 or 10 mg b.i.d.) following a placebo-controlled, parallel design protocol over 12 weeks. Plasma components of the renin angiotensin system, catecholamines and ANF were measured together with haemodynamics both at rest and during exercise. Before ACE inhibitor treatment, median PRA, Ang I and II and catecholamines were normal, while ANF was increased. All these parameters, including ACE activity, rose during exercise. Chronic inhibition of ACE activity was dose-dependent and the maximal fall in Ang II occurred with quinapril 20 mg.day-1. Humoral changes appeared more assessible than haemodynamic alterations even though many of these changes were reasonably correlated. The effects of chronic ACE inhibition on circulating neurohumoral components in patients with moderate heart failure are small and dose-dependent. Since humoral changes are related to haemodynamics they should account for the clinical benefit. Appropriately high doses of ACE inhibitors should be chosen for treatment of heart failure.

Administration, Oral↗

Dose-response relationships of ACE inhibitors and angiotensin II blockers.

It is difficult to establish dose-response relationships for ACE inhibitors in patients with hypertension or congestive heart failure. This has led to the widely held opinion that the effects of ACE inhibitors are hardly dose dependent. The purpose of this short discussion is to demonstrate that this class of compounds, as well as the more recent angiotensin II receptor antagonists, exhibit some very clear dose-response relationships when these are evaluated in normal volunteers based on the mechanisms for which they were designed. Characterization of these dose-response curves is important in order to use these drugs at their optimal dose and to obtain the maximal therapeutic benefit.

Angiotensin II↗

Value of different clinical and biochemical correlates to assess angiotensin converting enzyme inhibition.

In a double-blind study, we compared the value of different approaches to assess blockade of angiotensin (Ang) II generation in 10 normal volunteers treated with the new Ang-converting enzyme (ACE) inhibitor temocapril. Plasma concentration of the diacid active metabolite of temocapril, plasma Ang I and II levels, plasma ACE activity, and inhibition of the pressor response to repeated intravenous (i.v.) doses of Ang I were measured before and repeatedly after different doses of tempocapril or placebo. In vivo ACE activity, estimated by the plasma Ang II/Ang I ratio, correlated well with temocapril diacid concentration (r = 0.85, n = 148) and with systolic and diastolic blood pressure (SBP, DBP) responses to Ang I (r = 0.76 and r = 0.79, n = 148). SBP and DBP responses to Ang I were also strongly related to temocapril diacid concentration (r = -0.81 and r = -0.88, n = 148). ACE activity measured in vivo reliably predicts the decrease in Ang-dependent BP to be achieved by ACE inhibitors.

Administration, Oral↗

Neuropeptide Y infusion decreases plasma renin activity in postmyocardial infarction rats.

We wished to determine if chronic neuropeptide Y (NPY) infusion (1 ng/min for 1 week by Alzet minipump) could decrease plasma renin activity (PRA) and norepinephrine (NE) in a rat myocardial infarction (MI) model of moderate compensated congestive heart failure (CHF). CHF was produced by prior (6-8 weeks) ligation of the left coronary artery; control rats were sham-operated. Carotid arterial blood was drawn for PRA and NE in conscious unrestrained rats that had been instrumented 24 h earlier. MI rats had increased PRA as compared with sham-operated rats [8.73 +/- 1.27 vs. 5.10 +/- 0.91 ng angiotensin (AI) I/ml.h, mean +/- SE]. During chronic NPY infusion, PRA was reduced to normal in the MI group (4.78 +/- 0.91) but was not affected in the sham group (5.65 +/- 0.51). Plasma NE was altered similarly, but the changes did not reach statistical significance. These data suggest that NPY has the capacity to restrain renin release in moderate compensated CHF.

Animals↗

Angiotensin II receptor antagonists and the kidney.

The kidney is not only the source of circulating renin, which determines the plasma concentration of angiotensin II, but it is also one of the main targets of angiotensin II. Thus, angiotensin II exerts an important physiologic influence on renal function through its ability to modulate renal hemodynamics as well as glomerular and tubular functions. Moreover, angiotensin II appears to contribute to the progressive deterioration of renal function commonly observed in renal diseases. The availability of new orally active, nonpeptide angiotensin II receptor antagonists lacking agonistic or kinin- and prostaglandin-inducing properties has offered the possibility of investigating further the renal influence of angiotensin II. Thus, it is now clear that most if not all renal effects of angiotensin II are mediated by the activation of AT1 receptors, although the AT2 subtype is present in the kidney. Furthermore, increasing experimental evidence indicates that the long-term renal protective effect of angiotensin-converting enzyme inhibitors is indeed due to the inhibition of the renin-angiotensin system rather than to the activation of non-angiotensin II mechanisms.

Angiotensin Receptor Antagonists↗

Mechanisms of the pressor response to intravenous thyrotropin-releasing hormone in the rat.

1. The purpose of this study was to examine the contribution of the sympatho-adrenomedullary system to the blood pressure response to an intravenous bolus of thyrotropin-releasing hormone (TRH) in conscious medullectomized and sham-operated rats. 2. The peak pressor effect of 0.5 mg TRH was significantly increased in rats having no adrenal medulla (+24.2 +/- 1.6 mmHg, mean +/- s.e.m., P < 0.01) as compared to sham-operated animals (+12.2 +/- 3.0 mmHg). 3. Blockade of alpha-adrenergic receptors with phentolamine abolished the pressor effect of TRH in control rats (+2.1 +/- 1.9 mmHg) but did not attenuate the blood pressure response of medullectomized rats (+21.5 +/- 4.7 mmHg). In contrast, beta-blockade with propranolol blunted the blood pressure responsiveness of rats subjected to adrenal medullectomy (+12.4 +/- 2.6 mmHg) but did not modify the effect of TRH in sham-operated controls (+10.9 +/- 2.9 mmHg). 4. The direct in vitro effect of TRH on isolated mesenteric rat arteries was also evaluated. TRH did not induce contractions of isolated arteries. 5. These results suggest that in rats with intact adrenals, the pressor effect of intravenous TRH is mediated primarily by a stimulation of alpha-adrenergic receptors. Adrenal medullectomy appears to enhance the blood pressure response to intravenous TRH. Activation of cardiac beta-adrenoceptors seems to contribute to the blood pressure increasing effect of intravenous TRH in medullectomized animals.

Acetylcholine↗

Confocal microscopy to analyze cytosolic and nuclear calcium in cultured vascular cells.

With the development of calcium-sensitive fluorescent dyes and videomicroscopic imaging, several investigators have located the changes in intracellular calcium in the cytoplasm, in the perinuclear region, and possibly in the nucleus. However, the presence of calcium in the nucleus is often difficult to ascertain because the fluorescence derived from the perinuclear area interferes with that of the nucleus. We have used confocal microscopy together with two calcium-sensitive dyes [acetoxymethyl esters of fluo 3 (fluo 3-AM) and rhod 2 (rhod 2-AM)] to analyze the cytosolic and nuclear calcium distribution in vascular smooth muscle and endothelial cells studied at rest and after stimulation with receptor-dependent (angiotensin, vasopressin) and receptor-independent (KCl) stimuli. With fluo 3-AM, the baseline fluorescence was located in the cytoplasm but was slightly higher in the nucleus. With all stimuli, the fluorescence intensity increased in both compartments but remained more pronounced within the nucleus. Yet, after calibration, the cytosolic calcium concentration was greater than that of the nucleus at rest and was equally high after stimulation, suggesting different properties of fluo 3 in the cytosol and in the nucleus. With rhod 2-AM, baseline fluorescence was low in the nucleus and high in the cytosol. Cell stimulation caused an initial increase in cytosolic calcium with no change in the nucleus followed by a rise in both compartments. Thus the stimulation of vascular cells is associated with marked increases in cytosolic and nuclear calcium. Fluo 3-AM seems to be a better indicator of nuclear calcium than rhod 2-AM. The increases in nuclear calcium induced by angiotensin II and vasopressin may contribute to their cell proliferative effect.

Aniline Compounds↗

Renal sodium handling in patients with untreated hypertension and white coat hypertension.

Renal tubular sodium handling was investigated prospectively in 48 normotensive subjects, 53 untreated hypertensive patients, and 13 patients with white coat hypertension using endogenous trace lithium as a marker of proximal sodium reabsorption. A 12-hour daytime ambulatory blood pressure recording was performed in all patients to confirm the diagnosis of hypertension. Patients were included in the white coat hypertension group if their office blood pressure was above 160/90 mm Hg but the mean value of their 12-hour ambulatory recording was lower than 140/90 mm Hg. All participants were studied on their normal diet and ate salt freely. Fractional excretions of sodium (FENa), lithium (FELi), and potassium (FEK) were measured simultaneously before blood pressure recording. FENa was significantly higher in hypertensive patients (0.84 +/- 0.05%, P < .05) than in normotensive control subjects (0.60 +/- 0.06%), and FELi was comparable in the two groups (15.4 +/- 0.65% in hypertensive patients and 17.0 +/- 0.9% in control subjects). However, the relation between FENa and FELi was significantly different in normotensive subjects and hypertensive patients (P < .001), so that for a given increase in FENa a smaller increase in FELi was observed in hypertensive patients. In addition, the ratios of urinary lithium to sodium and urinary potassium to sodium were significantly reduced in hypertensive patients, suggesting an increased proximal reabsorption of sodium. Similar alterations in renal tubular sodium handling were observed in patients with white coat hypertension. These results suggest that an increased sodium reabsorption in the proximal tubule may contribute to the maintenance of hypertension and that white coat hypertension might represent a prehypertensive state.

Absorption↗

Long-term nitric oxide synthase inhibition and distensibility of carotid artery in intact rats.

The goal of the present study was to evaluate the effect of long-term nitric oxide synthase inhibition by NG-nitro-L-arginine-methyl ester (L-NAME) on the morphology and viscoelastic properties of the carotid arteries in rats. Twelve-week-old Wistar-Kyoto rats were treated for 6 weeks with either the nitric oxide synthase inhibitor L-NAME (0.4 g/L in drinking water; L-NAME rats, n = 13) or tap water (control rats, n = 13). Age-matched spontaneously hypertensive rats (SHR, n = 14) received tap water for the same period. The internal diameter of the common carotid artery was measured continuously with an echo-tracking device with the rats under anesthesia with halothane. Intra-arterial pressure was monitored on the contralateral side. L-NAME rats exhibited arterial pressures similar to those of SHR. The distensibility pressure-curve determined in L-NAME rats was a direct continuation of that obtained in control rats. In contrast the distensibility in SHR was increased (P < .01, SHR versus L-NAME rats). Carotid artery cross-sectional area and left ventricular weight index were increased similarly in SHR and L-NAME rats compared with control rats. Thus the hypertension caused by long-term nitric oxide synthesis inhibition was not associated with the increased arterial distensibility observed in SHR despite similar blood pressure elevations, similar arterial hypertrophy, and consequently similar wall stress. This suggests a role for nitric oxide in regulating the mechanical behavior of arteries exposed to high blood pressure.

Amino Acid Oxidoreductases↗

Clinical utility of ambulatory blood pressure monitoring in the evaluation of patients with borderline hypertension.

Blood pressure measured in the physician's office often differ considerably from those recorded during everyday activities away from the medical environment. This fact is particularly important in patients whose office blood pressures are only mildly elevated because, in a large proportion of these people, the elevation is observed only when blood pressures are measured in the physician's office and not when they are measured during normal activities. There is little evidence that this 'white-coat' hypertension is associated with increased cardiovascular risk, but patients with the condition are prone to develop sustained hypertension over time. It is therefore advisable to monitor these individual regularly so that antihypertensive therapy can be initiated when appropriate.

Antihypertensive Agents↗

Angiotensin-converting enzyme inhibition by hydroxamic zinc-binding idrapril in humans.

The new angiotensin-converting enzyme (ACE) inhibitor idrapril acts by binding the catalytically important zinc ion to a hydroxamic group. We investigated its pharmacodynamic and pharmacokinetic properties in 8 healthy men: Increasing doses of 1, 5, and 25 mg idrapril as well as placebo or 5 mg captopril were administered intravenously (i.v.) at 1-week intervals. Six of the subjects received 100 mg idrapril orally (p.o.) last, and two ingested oral placebo as a double-blind control. Blood pressure (BP) and heart rate (HR) remained unchanged. No serious side effects were observed. ACE inhibition in vivo was evaluated by changes in the ratio of specifically measured plasma angiotensin II (AngII) and AngI concentrations determined by high-performance liquid chromatography/radioimmunoassay (HPLC/RIA) techniques. Plasma ACE activity in vitro was estimated by radioenzymatic assay; it was suppressed by > or = 93% at 15 min after injection of 25 mg idrapril or 5 mg captopril and by 96% 2 h after idrapril intake. Mean AngII levels were decreased dose dependently at 15 min after idrapril injections. At the same time, plasma renin activity (PRA) and AngI increased according to the doses. The AngII/AngI ratio was clearly related to plasma idrapril levels (r = -0.88, n = 60). Oral idrapril inhibited ACE maximally at 1-4 h after dosing, when < 7% of initial ACE activity was observed in vitro and in vivo. Idrapril is a safe and efficient ACE inhibitor in human subjects. It is well absorbed orally. Besides having a slightly slower onset of action, idrapril has pharmacodynamic effects comparable to those of captopril.

Adult↗

Angiotensin II antagonists DuP 753 and TCV 116.

BACKGROUND: Acute blockade of the renin-angiotensin system with the parenterally active angiotensin II antagonist saralasin has been shown to effectively lower blood pressure in a large fraction of patients with essential hypertension and to improve haemodynamics in some patients with congestive heart failure. It is now possible to chronically antagonize angiotensin II at its receptor using non-peptide angiotensin II inhibitors such as losartan (DuP 753/MK-954) or TCV 116. EFFECT OF NON-PEPTIDE ANGIOTENSIN II ANTAGONISTS: When administered by mouth, DuP 753 and TCV 116 induce dose-dependent inhibition of the pressor response to exogenous angiotensin II. This effect is closely related to circulating levels of the corresponding active metabolites E3174 and CV11974. Preliminary studies performed in hypertensive patients suggest that losartan lowers blood pressure to an equivalent extent to an angiotensin converting enzyme (ACE) inhibitor. CONCLUSIONS: Further investigation is required to show whether these new angiotensin II antagonists compounds compare favourably with ACE inhibitors.

Administration, Oral↗

The advantages of angiotensin II antagonism.

New approaches to renin-angiotensin blockade: The successful use of angiotensin converting enzyme (ACE) inhibitors in the treatment of hypertension and congestive heart failure has generated a great deal of research interest in developing new pharmacological approaches to block the renin-angiotensin system. In recent years, several new non-peptide angiotensin II antagonists have been synthesized and some of them are available for experimental and/or clinical investigations. Now that experience with the antagonist losartan is accumulating, it is important to compare the effects, the efficacy and the side effects of this agent with those of ACE inhibitors. Effects of losartan compared with ACE inhibitors: So far, ACE inhibitors and the angiotensin II antagonist losartan appear to have similar systemic and regional hemodynamic effects. The impact of ACE inhibition and angiotensin blockade on the various components of the renin-angiotensin system is also comparable except for a marked increase in plasma angiotensin II levels during angiotensin II blockade. This increase in circulating angiotensin II might theoretically lead to an excessive stimulation of the AT2 receptor subtype, but since the function of this receptor is not known it is impossible to evaluate the implications of this reactive rise. Renal effects of losartan: The renal effects of angiotensin II antagonists are also very similar to those of ACE inhibitors. However, a marked increase in uric acid excretion has been observed with the administration of losartan. This uricosuric effect of losartan might represent a clinical advantage unless a state of urinary supersaturation of undissociated uric acid is achieved.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

Endothelial dysfunction in chronic heart failure. Experimental and clinical studies.

The endothelium plays an important role in the control of human vascular tone by releasing endothelium-derived nitric oxide. Therefore, endothelial dysfunction could be involved in the increased peripheral vasoconstriction of patients with chronic congestive heart failure (CHF). To investigate endothelial function in humans in vivo, agents such as acetylcholine are used to stimulate the release of endothelium-derived nitric oxide (EDRF). Conversely, N-mono-methyl-L-arginine (L-NMMA), a specific inhibitor of nitric oxide synthesis from L-arginine decreases forearm blood flow by inhibiting the basal release of nitric oxide. Consistent with experimental studies, the blood flow response to acetylcholine is blunted in patients with chronic heart failure as compared to healthy age-matched volunteers. In contrast, the decrease in blood flow induced by L-NMMA appears to be exaggerated in CHF. The blood flow response to nitroglycerin or sodium nitroprusside, endothelium-independent vasodilators, is usually preserved in patients with chronic, non-edematous heart failure, indicating a normal response of the vascular smooth muscle of resistance vessels to exogenous nitric oxide. In contrast, the dilator response of the radial artery diameter to nitroglycerin and flow-dependent dilation are impaired in patients with chronic heart failure, indicating that the abnormal flow-mediated relaxation of large arteries may be due to both endothelial and vascular smooth muscle alterations. Thus, impaired endothelium-dependent dilation of peripheral resistance vessels emerges in chronic heart failure, suggesting a reduced release of nitric oxide upon stimulation. Thus, endothelial dysfunction may be involved in the impaired vasodilator capacity in the peripheral circulation, e.g. during exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Arginine↗

[The importance of therapy compliance in the treatment of arterial hypertension].

The hypertensive patient remains mostly asymptomatic and requires medication over his entire life. A sufficient follow-up may sometimes be difficult. Poor control of blood pressure is frequently due to inadequate compliance with the prescribed medication. This compliance is therefore a factor to be considered in any instance of a follow-up consultation of a hypertensive patient.

Antihypertensive Agents↗