[Sympatholytic drugs: inhibitors of sympathetic termination functioning and blockaders of adreno-receptors].
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Biomedical subjects
Publications and source records attributed to S Laurent.
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Blood pressure, brachial artery diameter and pulse wave velocity were determined before and after diuretic treatment in 2 groups of hypertensive patients treated either by indapamide (2.5 mg per d) or by canreonate (50 mg per d). Brachial artery diameter, measured from pulsed Doppler flowmetry, and pulse wave velocity, evaluated from mechanography, did not alter significantly despite a significant blood pressure reduction. The study indicates that, in hypertensive patients of middle age, diuretics did not change brachial artery diameter and distensibility, whether the drug caused an increase or a decrease in plasma potassium levels.
To investigate the mechanism by which the large T antigen (T-Ag) of polyomavirus and simian virus 40 can promote recombination in mammalian cells, we analyzed homologous recombination events occurring between two defective copies of the polyomavirus middle T (pmt) oncogene lying in close proximity on the same chromosome in a rat cell line. Reconstitution of a functional pmt gene by spontaneous recombination occurred at a rate of about 2 x 10(-7) per cell generation. Introduction of the polyomavirus large T (plt) oncogene into the cell line by DNA transfection promoted recombination very efficiently, with rates in the range of 10(-1) to 10(-2) per cell generation. Recombination was independent of any amplification of viral sequences and could even be promoted by the large T-Ag from simian virus 40, which cannot activate polyomavirus DNA replication. To explain the role of large T-Ag, we propose a novel mechanism of nonconservative recombination involving slipped-strand mispairing between the two viral repeats followed by gap repair synthesis.
Stimulation of receptors in the cardiopulmonary compartment produces a vasodilatation of forearm resistive vessels. A possible participation of large conduit arteries in such adjustments, studied in situ, has not been clearly documented in humans. We used a dual-crystal pulsed Doppler system to determine whether leg elevation in recumbent subjects is associated with changes in brachial artery diameter (BAD) and blood velocity (BV) in humans. BA diameter, velocity, and flow, together with arterial pressure and heart rate, were measured in 20 normal subjects in supine position and after passive leg raising. BAD increased immediately after leg elevation from 4.03 +/- 0.11 to 4.56 +/- 0.13 mm (P less than 0.001) parallel with an increase in BV from 6.05 +/- 1.18 to 7.1 +/- 1.36 cm/s (P less than 0.02). A positive correlation between BAD enlargement and BV increase was observed during the initial peak response (P less than 0.01). Subsequent measures indicated that BAD remained enlarged throughout the whole period of leg raising, whereas BV returned to the base-line values. Brachial artery volumic flow augmented during the initial phase of leg raising from 46 +/- 8 to 74 +/- 15.5 ml/min (P less than 0.01) and remained elevated throughout the whole period of leg elevation. This study shows that arteries participate in hemodynamic adjustments induced by positional changes associated with cardiopulmonary baroreflex activation.
Brachial artery hemodynamics including brachial artery diameter (D) and local blood flow velocity (V) was studied in 15 normotensive subjects (NT) and 19 age-matched hypertensive patients (HT) at rest using a bidimensional pulsed Doppler system during a 2-min period of distal circulatory occlusion and during reactive hyperemia. Kinetics of changes in V and D were determined during successive and reproducible maneuvers. V and D decreased significantly during distal circulatory occlusion in both groups. During reactive hyperemia, V reached similar maximum values in both groups, and D increased significantly in NT and HT. Changes in D during reactive hyperemia were positively and significantly correlated with changes in V recorded at the same level. No significant difference was found between the two groups. These results demonstrate noninvasively that there are velocity-dependent variations in the diameter of a large artery in humans and suggest that velocity-dependent vasodilation of the brachial artery is not impaired in essential hypertension.
There is very clear evidence that active changes in the arterial wall contribute substantially to the pathophysiology, prognosis and treatment of hypertension. Reduced aortic compliance independently affects the blood pressure through an increase in systolic pressure and a decrease in diastolic pressure at any given mean arterial pressure. With the subsequent increase in pulse pressure, arterial abnormalities may specifically influence cardiac morbidity and mortality, in particular by triggering coronary ischemic accidents. The pathophysiological and epidemiological results of these mechanisms clearly indicate that a severe decrease in diastolic blood pressure might precede some hypertensive coronary ischemic accidents.
The concept of vasodilatation has evolved with regards to the treatment of hypertension. Large multicentre trials have shown that decreasing mean arterial pressure alone does not reduce coronary morbidity and mortality related to hypertension. The authors suggest that the haemodynamic abnormalities related to hypertensive disease were not totally reversed by the antihypertensive agents used in these trials. Regression of structural arterial changes, regression of LVH without altering systolic function, reduction of the variability of blood pressure and maintenance of regional blood flow should all be objectives of any antihypertensive vasodilator therapy. Methods of studying vasodilators are described and the effects of the main classes of antihypertensive drugs on these parameters are analysed.
The changes of the cardiovascular system observed in hypertension are, on the one hand, functional (neurohumoral), and on the other hand, structural (cardiac and vascular hypertrophy). They affect the whole of the cardiovascular system (heart, arteries, arterioles, veins). Clinical studies using non-invasive methods suggest a close interaction between the heart and large arteries, independent of the degree of peripheral arteriolar constriction. Our understanding of the value of the mean arterial pressure which may damage target organs has been improved by automatic ambulatory blood pressure recordings over the 24 hour period. Finally, recent technological developments based on sophisticated computer systems have contributed to our appreciation of parameters of arterial distensibility, so giving a better understanding of arterial physiopathology in hypertension and helping orientate the choice of therapeutic strategy.
A randomised, double-blind study was conducted to assess the influence of intra-articular and subcutaneous prilocaine with adrenaline on postoperative pain in day case arthroscopy of the knee. The time to first dose of oral analgesia postoperatively was significantly prolonged in those patients receiving prilocaine but no significant difference in analgesic effect was demonstrated at 4, 8, and 12 h after operation between the two groups.
Studies based on non-invasive methods, using a pulsed Doppler flowmeter technique, show that, in hypertensive patients, the brachial artery reacts actively to posture changes and to a norepinephrin perfusion: in the latter situation, there is an abnormal constriction, and its vasodilation is more marked when the lower extremities are raised in a patient in decubitus. These modifications occur in the absence of any significant variation of the blood pressure and the heart rate, and the high output resulting from the vasodilation is not sufficient to explain these changes. According to the authors, the brachial artery reacts actively to alterations of the autonomous nervous system. Variation observed following elevation of the lower extremities would probably result from the stimulation of the mechanical receptors of a low pressure system.
The negative inotropic potencies (IC50) of the calcium channel blockers nicardipine (12 +/- 2 nM) and nifedipine (9 +/- 2 nM) measured in cultured chick embryo ventricular cells were not significantly different. Exposure of the cells to isoproterenol potentiated the negative inotropic effect of low concentrations of nicardipine (10(-9)-10(-8) M) and decreased the effect of higher concentrations (10(-7) M). In contrast, isoproterenol shifted the entire dose-response curve for nifedipine to the right. These results provide evidence that activation of beta-adrenoceptors modulates the negative inotropic effect of nifedipine and nicardipine differently.
The present study was undertaken in order to determine the effects of the dihydropyridine calcium channel blocker, nimodipine and the dihydropyridine calcium channel activator BAY k 8644, in the learned helplessness test in the rat. Nimodipine dose dependently (0.5-2 mg/kg per day) reversed the behavioral deficit induced by inescapable shocks. The reversal of helpless behavior by imipramine (32 mg/kg per day) was antagonized by BAY k 8644 (0.5 and 1 mg/kg per day), and the effects of imipramine 8 and 16 mg/kg per day) were potentiated by a subeffective dose (0.5 mg/kg per day) of nimodipine. These results suggest that central dihydropyridine binding sites may be specifically involved in the modulation of the imipramine reversal of helpless behavior and favor a physiological role for dihydropyridine binding sites in the brain.
To determine whether atrial natriuretic peptide (ANP) has an inotropic effect, the contractility of spontaneously beating cultured chick embryo ventricular cells was studied in response to rat-ANP (1-23) superfused at concentrations ranging from 10(-10) M to 2.5 x 10(-7) M. r-ANP reversibly decreased contractility with a threshold concentration of 10(-8) M; at the highest concentration, r-ANP decreased contractility to a moderate extent (-30 +/- 4%) r-ANP increased dose-dependently intracellular cGMP levels. Stimulation of contractility with [Ca2+], the calcium-channel agonist BAY K 8644 or isoproterenol attenuated to various degrees the inhibitory effect of r-ANP. By contrast, the inhibitory effect of r-ANP on contractility was unchanged or even enhanced after stimulation of contractility by angiotensin II. There was no difference in r-ANP-induced increase in cGMP whether cells were pre-incubated with angiotensin II or not. These results indicate that r-ANP was able to decrease contractility of cultured cardiac myocytes and suggest a preferential antagonism of the inotropic effect of angiotensin II.
A noninvasive evaluation of the aortic arch diameter was performed in 16 subjects with sustained essential hypertension and in 15 normal subjects of similar age, gender and body surface area. In all subjects, measurements were obtained of brachial mean arterial pressure and pulse pressure, cardiac mass (judged on echocardiography) and carotid-femoral pulse wave velocity together with ultrasound determinations of aortic arch diastolic and systolic diameter (suprasternal window). For each subject, pulsatile change in aortic diameter, strain and aortic arch elastic modulus were calculated. Compared with normal subjects, the hypertensive subjects showed an increase in aortic arch diameter (diastolic diameter 29.6 +/- 1.0 versus 25.4 +/- 1.0 mm, p less than 0.01), in elastic modulus (1.071 +/- 0.131 versus 0.526 +/- 0.045 10(5) N.m-2, p less than 0.001) and pulse wave velocity (11.8 +/- 0.5 versus 8.9 +/- 0.3 m/s, p less than 0.001). In the study group, a positive correlation was observed between diastolic aortic arch diameter and mean arterial pressure (r = 0.54, p less than 0.01) and between elastic modulus and cardiac mass (r = 0.60, p less than 0.01). Elastic modulus and age were positively correlated (r = 0.73, p less than 0.01) in hypertensive but not in normal subjects (r = 0.08, NS). This study is the first to demonstrate noninvasively that both the aortic arch diameter and the elastic modulus are increased in patients with sustained uncomplicated essential hypertension. These findings suggest that the increase in elastic modulus could influence the development of cardiac hypertrophy, and that both age and blood pressure act independently as factors that alter the arterial wall of subjects with sustained essential hypertension.
The cardiopulmonary baroreflex response was studied before and after 24 h bed rest with head-down tilt (-5 degrees) in six normal male subjects, through lower body negative pressure (-5, -10, -15 mmHg) and passive leg raising. The reflex response was assessed (using plethysmography) by changes in forearm vascular resistance. During the lower body negative pressure and leg raising, forearm vasoconstriction and vasodilation were similar before and after head-down tilt. The study shows that orthostatic intolerance following head-down tilt is not explained by an abnormality in the response of low pressure baroreceptors.
In order to investigate the reactivity to angiotensin II (Ang II) in large and small arteries in situ, brachial artery diameter, blood flow velocity, local volumic blood flow and local vascular resistance (mean arterial pressure divided by local blood flow) were determined non-invasively, using a pulsed Doppler system. Increasing doses of Ang II (0.5, 1.0 and 2.0 ng/kg per min) were given intravenously and double-blind to nine normotensive subjects (group I) and 10 hypertensive patients (group III); placebo (glucose) was given to nine hypertensives (group II). Angiotensin II did not change the brachial artery diameter, blood flow velocity, local blood flow or local resistance. Mean arterial pressure was increased slightly but significantly (P less than 0.05) by Ang II at 2 ng/kg per min in groups I and III. In contrast, we had shown previously, following the same procedure, that subthreshold doses (for the increase in mean arterial pressure) of noradrenaline reduced branchial artery diameter, velocity and local blood flow and increased local resistance in hypertensives. These results indicate that in hypertensives the vascular reactivity of the brachial circulation (1) is lower than that of other territories in response to Ang II and (2) is lower in response to Ang II than in response to noradrenaline.
To determine whether endothelin, a highly potent vasoconstrictor peptide, may affect cardiac myocyte contractility directly, we studied the effects of synthetic porcine endothelin-1 in cultured chick embryo ventricular cells. Endothelin-1 had a potent chronotropic effect (EC50 0.17 nmol/l) in spontaneously beating cells. The increase in the beating rate was accompanied by a frequency-dependent decrease in the amplitude of contraction. In electrically driven cells (1 Hz), endothelin-1 increased the amplitude of contraction dose-dependently, with an EC50 of 0.3 nmol/l, smaller than that of the calcium channel blocker BAY K 8644 (EC50 3.3 nmol/l), and with an efficacy close to that of BAY K 8644 and isoproterenol. Nicardipine (100 nmol/l) shifted to the right, by two orders of magnitude, the dose-response curve of endothelin-1 for inotropism. These results indicate that endothelin-1 is one of the most potent inotropic agents in cultured cardiac myocytes, and suggest that this effect involves, at least in part, a calcium ion influx through voltage-sensitive calcium channels.
An exaggerated reflex response of forearm resistance vessels following stimulation of cardiac mechanoreceptors has been observed in human hypertension. In the present study we analyze the possibility that such an increased response also involves the large brachial artery. For that purpose, the influence of leg elevation in subjects in a supine position on brachial artery diameter and blood flow velocity was studied in 12 healthy, normal males and 17 males of the same age with sustained essential hypertension. Brachial artery diameter and blood flow velocity were measured using a two-dimensional pulsed Doppler velocimeter, with subjects in a supine horizontal position, after passive elevation of the legs and again in a supine horizontal position. Blood pressure and heart rate remained unchanged throughout the study. Elevation of the legs induced an immediate increase in brachial artery diameter (P less than 0.001) and blood flow velocity (P less than 0.001) in both normal subjects and hypertensive patients. The maximal increase in these two parameters was similar in the two groups. In normal subjects, the increases were short-lived, with values returning to baseline levels even when leg elevation was maintained. In hypertensive patients, the increases persisted throughout the period of leg elevation, and brachial artery diameter remained significantly increased in comparison with normal subjects (P less than 0.01). This study provides evidence that loading cardiac mechanoreceptors causes a large dilation of the conduit arteries which is long-lasting in essential hypertensives and short-lived in normal subjects.