Biomedical subjects
Publications and source records attributed to M Burnier.
Hypertension is a multifactorial disease. Various antihypertensive drugs can lower arterial pressure in a given patient in a more or less efficient way. The sequential testing of several drugs is most promising for lowering blood pressure by monotherapy. If necessary a drug combination is preferable to dose adjustments of a single substance because of the risk for side effects growing with the dose.
Human autoantibodies were used to localize centromere proteins by immunoelectron microscopy, immunofluorescence, and confocal microscopy in isolated cells and in cryosections of rabbit testis. A computer-assisted three-dimensional reconstruction of the positions and sizes of fluorescent spots allowed us to follow their movements during the different phases of spermiogenesis. In very young spermatids, the centromeres were distributed within a space separated from both the external nuclear limits and the nuclear core. They moved towards the nuclear center in cap phase spermatids, where they clustered into a few large centromeric masses. In preelongating spermatids, the immunolabeled proteins were dispersed within an equatorial area, where they formed one large mass. In late spermatids, the mass moved towards the posterior part of the nucleus, and, in the spermatozoon, the two basal knobs located at the base of the nuclei were the only strongly immunolabeled structures, while no labeling of the main part of the nucleus was observed. Since the number of centromeres remained close to the number of chromosomes until the cap phase of spermatid differentiation, we hypothesize that the labeling of young spermatids corresponds to centrometric proteins associated with their specific DNA counterparts, while the centromere proteins, possibly detached from their DNA loci, were released from nuclei of old spermatids in the same way as are histones and transition proteins.
Human neuropeptide Y (hNPY) is a potent vasoconstrictor peptide of 36 aminoacid residues. We isolated hybridomas secreting four monoclonal antibodies directed against various epitopes of neuropeptide Y and studied their cross-reactivity with peptide YY (PYY) and the pancreatic polypeptide (PP), two peptides sharing sequence homologies with hNPY (respectively 70% and 50%). The antibody NPY02 is an IgG1 with a Ka of 5.5 x 10(10) liters/mol. It binds to the 11-24 region of NPY (IC50 = 2 x 10(-7)M), does not recognize PP but cross-reacts weakly with PYY. Antibodies NPY03 and NPY05 are IgG2 with respective Ka's of 6.7 x 10(9) and 2.5 x 10(10) liters/mol. They interact with a C-terminal epitope on NPY (NPY 27-34, IC50 = 2 x 10(-9) M for NPY03 and NPY 32-36, IC50 = 1 x 10(-9) M for NPY05). These two antibodies cross-react with PYY whereas only NPY05 binds PP. NPY05 is unable to bind the free acid form of neuropeptide Y. The 32-36 COOH free subpeptide is recognized 50,000 less efficiently by NPY05 than its amidated form. Antibody NPY04 is an IgG3 with a Ka of 3.8 x 10(8) liters/mol. It recognizes a N-terminal epitope between aminoacids 1 and 12 (IC50 = 2.5 x 10(-6) M). NPY04 interacts weakly with PYY but not detectably with PP. These results obtained with 4 different monoclonal antibodies demonstrate the presence of at least four epitopes on hNPY, two of them being continuous. These antibodies will be used to study the interaction of NPY with its receptor and to develop sensitive and specific assays for determination of NPY concentrations in biological fluids.
Diuretics have long been used to lower blood pressure in hypertensive patients or to control body fluid and electrolyte homeostasis in diseases such as congestive heart failure, chronic renal failure or cirrhosis. The initial response to diuretics is a negative sodium and fluid balance. The diuretic-induced loss of salt and water activates several hormonal systems such as vasopressin, the renin-angiotensin-aldosterone system or the sympathetic nervous system which tend to compensate for the changes in sodium and water balance. This neurohormonal response may have important clinical implications. Thus, the activation of the renin-angiotensin-aldosterone cascade appears to be partially responsible for the flat dose-blood pressure response curve of thiazides in hypertensive patients. It may also be responsible for the difference between responders and non-responders to diuretic therapy and for the development of side-effects such as hypokalaemia, metabolic alkalosis or hyponatraemia. There are several ways to prevent the undesirable consequences of the neurohormonal responses to diuretics. The first is to use low doses of these agents. It is also possible to combine them with agents that block the activity of the renin-angiotensin-aldosterone system such as ACE inhibitors or in combination with drugs that reduce aldosterone secretion such as calcium antagonists. The development of drugs able to enhance urinary sodium excretion and to reduce simultaneously the activity of the renin-angiotensin-aldosterone system may offer a new interesting alternative. This might perhaps be achieved in the future with the administration of neutral endopeptidase inhibitors which interfere with the enzymatic degradation of atrial natriuretic peptide.
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Angiotensin converting enzyme (ACE) inhibitors are increasingly used to treat hypertension and congestive heart failure. Recently, several new ACE inhibitors with pharmacokinetic features different from earlier agents such as captopril or enalapril have come into use. This review discusses the use of pharmacokinetics to optimise ACE inhibitory therapy in various patient groups. Among the pharmacokinetic characteristics of ACE inhibitors the route of excretion and to a lesser degree the half-life appear to be the most clinically relevant. There is no evidence that being a prodrug offers a significant clinical advantage. The importance of varying tissue penetration also remains to be determined. Knowledge of ACE inhibitor pharmacokinetics is particularly important in patients with renal or hepatic dysfunction in whom the major route of excretion of these agents is impaired. This might also be the case in elderly patients or those with severe congestive heart failure. However, for most ACE inhibitors, major changes in the drug dosage (amount or interval) are necessary only when the glomerular filtration rate falls below 30 ml/min (1.80 L/h). The occurrence of adverse effects due to overdosage or drug interactions may be prevented by adapting the prescription of an ACE inhibitor to its pharmacokinetic characteristics.
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The effects of anoxia or hypoxia on Ca++ uptake and lactic dehydrogenase (LDH) release were examined in freshly isolated rat proximal tubules (rPT). Both Ca++ uptake and LDH release were increased above control after only 10 min of either anoxia or hypoxia in rPT. The increase in Ca++ uptake was through voltage-sensitive, slow Ca++ channels, because pretreatment with chemically dissimilar calcium channel blockers (CCB), either verapamil or flunarizine, prevented the increased Ca++ uptake and reduced the LDH release from the anoxic and hypoxic rPT. After 20 min of hypoxia, however, verapamil pretreatment did not significantly reduce the high Ca++ uptake rate, thus, suggesting that this increase in Ca++ permeability was occurring through pathways other than the slow Ca++ channels. The increase in LDH release was only slightly decreased by verapamil after 20 min of hypoxia. After 20 min of anoxia in rPT, Ca++ uptake was no longer increased, but the increased LDH release persisted. These effects of anoxia were unaltered by verapamil. These results, thus, suggest that early membrane injury to isolated rPT in suspension, which is associated with 10 min of either anoxia or hypoxia, involves increased cellular Ca++ uptake through voltage-sensitive Ca++ channels and protection is afforded by CCB. In contrast, after 20 min of anoxia or hypoxia, rPT membrane damage persisted and was only partially reversed by CCB. The rPT injury induced by 20 min of O2 deprivation, thus, involves factors independent of voltage-sensitive Ca++ channels.
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Neuropeptide Y (NPY) is a 36 amino acid peptide present in the brain, the adrenal medulla and peripheral sympathetic nerves. The localization and mode of release of NPY led to the proposal that this peptide plays an important role in modulating the contribution of the sympathetic nervous system to blood pressure control. In this paper Bernard Waeber and colleagues review the current knowledge about the mechanisms involved in NPY signal transduction and the different mechanisms whereby NPY, released by the peripheral nervous system, may influence vascular tone and cardiac function.
Two patients who had similar clinical presentations of bilateral multiple chorioretinal lesions and needed a correct diagnosis underwent chorioretinal biopsy. The biopsy from one patient demonstrated mainly a B cell infiltrate in choroidal and subretinal nodules, while the biopsy from the second patient showed mainly macrophages in the retina. These findings directed the therapeutic approach taken in each patient. Although chorioretinal biopsy is an invasive procedure with the potential for serious complications, the resultant finding may aid in the diagnosis and guide the subsequent management of certain patients presenting with serious ocular findings of undefined etiology.
Dracunculiasis, an infection caused by the nematode parasite, Dracunculus medinensis, usually affects the skin and subcutaneous tissue. The authors studied two cases of dracunculiasis involving the orbit and eyelid in African children. In the first case, the patient presented with proptosis and the clinical diagnosis was Burkitt's lymphoma. In the second patient, the eyelid lesion was diagnosed as a dermoid cyst. Histopathologically, the orbital lesion showed a degenerated and partially calcified worm within a large intraconal abscess. The eyelid lesion contained a well-preserved gravid female worm filled with larvae. The results of transmission and scanning electron microscopic studies are discussed.
Atrial natriuretic peptide is cleared from plasma by clearance receptors and by enzymatic degradation by way of a neutral metalloendopeptidase. Inhibition of neutral metalloendopeptidase activity appears to provide an interesting approach to interfere with metabolism of atrial natriuretic peptide to enhance the renal and haemodynamic effects of endogenous atrial natriuretic peptide. In this study, the effects of SCH 34826, a new orally active neutral metalloendopeptidase inhibitor, have been evaluated in a single-blind, placebo-controlled study involving eight healthy volunteers who had maintained a high sodium intake for 5 days. SCH 34826 had no effect on blood pressure or heart rate in these normotensive subjects. SCH 34826 promoted significant increases in excretion of urinary sodium, phosphate, and calcium. The cumulative 5-hour urinary sodium excretion was 15.7 +/- 7.3 mmol for the placebo and 22.9 +/- 5, 26.7 +/- 6 (p less than 0.05), and 30.9 +/- 6.8 mmol (p less than 0.01) for the 400, 800, and 1600 mg SCH 34826 doses, respectively. During the same time interval, the cumulative urinary phosphate excretion increased by 0.3 +/- 0.4 mmol after placebo and by 1.5 +/- 0.3 (p less than 0.01), 1.95 +/- 0.3 (p less than 0.01), and 2.4 +/- 0.4 mmol (p less than 0.001) after 400, 800, and 1600 mg SCH 34826, respectively. There was no change in diuresis or excretion of urinary potassium and uric acid. The natriuretic response to SCH 34826 occurred in the absence of any change in plasma atrial natriuretic peptide levels but was associated with a dose-dependent elevation of urinary atrial natriuretic peptide and cyclic guanosine monophosphate.(ABSTRACT TRUNCATED AT 250 WORDS)
These experiments were designed to assess the ability of the new nonpeptide angiotensin II antagonist DuP 753 to inhibit the binding and, particularly, to antagonize the cellular response to angiotensin II in human platelets and primary cultures of rat aortic smooth muscle cells (SMC). The binding of 125I-angiotensin II was competitively inhibited by DuP 753 with a 50% binding inhibition (IC50) of 5 to 6 x 10(-8) mol/L in platelets and 1 x 10(-8) mol/L in vascular SMC as compared to an IC50 of 5 to 7.5 x 10(-9) mol/L with nonlabeled angiotensin II. In vascular SMC, DuP 753 completely abolished the effects of angiotensin II on 45CaCl2 efflux and 45CaCl2 uptake. Moreover, in these latter cells, DuP 753 prevented the angiotensin II but not the vasopressin induced increase in cytosolic calcium. These results demonstrate that DuP 753 competes with angiotensin II binding to its receptor in both animal and human cells and selectively blocks the cellular response to angiotensin II.
A new high-precision ultrasonic device was developed to determine noninvasively arterial compliance as a function of blood pressure. Because of the nonlinear elastic properties of arterial walls, measurements of compliance can be appropriately compared only if obtained over a range of pressures. This apparatus was used to evaluate in a double-blind, parallel fashion the effect of three different antihypertensive drugs and of a placebo on radial artery compliance. Thirty-two normotensive volunteers were randomly allocated to an 8-day, once-a-day oral treatment with either a placebo, 100 mg atenolol, 20 mg nitrendipine, or 20 mg lisinopril. Blood pressure, heart rate, radial artery diameter, and arterial compliance were measured immediately before as well as 6 hours after dosing on the first and last days of the study. On the eighth day of administration, within 6 hours after dosing, lisinopril induced an acute increase in radial artery diameter, from 2.99 +/- 0.06 to 3.28 +/- 0.09 mm (mean +/- SEM, p less than 0.01). The compliance-pressure curve was shifted upward on day 1 (p less than 0.01) as well as on day 8 (p less than 0.05). None of the other drugs induced any significant modification of these parameters. Arterial compliance has a strong nonlinear dependency on intra-arterial pressure and therefore has to be defined as a function of pressure. Antihypertensive drugs acting by different mechanisms may have different effects on the mechanical properties of large arteries.
The normal kidney can increase its rate of glomerular filtration in response to an acute protein load. It has been suggested that this acute hyperfiltration represents a renal functional reserve (RFR). The RFR has also been proposed to reflect the chronic hyperfiltration found in diabetic patients and animal models of chronic renal failure. The physiologic role of the RFR is still unclear. On the one hand, the availability of an RFR may retard the progression towards end-stage renal failure. On the other hand, sustained hyperfiltration has been implicated as a potential deleterious factor in the progression of renal disease. Antihypertensive drugs used in the management of hypertensive patients with chronic renal disease modify both the systemic and the renal hemodynamics. Depending on their hemodynamic effects, they may thereby alter the ability to mobilize RFR. Today, it is still not clear whether an ideal compound should increase, decrease, or not affect RFR to preserve long-term renal function. Evaluation of the effects of various antihypertensive agents on RFR could become an important aspect of consideration in order to optimize both the control of blood pressure and the capacity of the therapy to prevent deterioration of renal function.
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