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Biomedical subjects

J B Michel

Publications and source records attributed to J B Michel.

At least 19 recordsLinked to original sources
PubMed1992

Species specificity of renin kinetics in transgenic rats harboring the human renin and angiotensinogen genes.

The renin-angiotensin system (RAS) is the most important regulatory system of electrolyte homeostasis and blood pressure. We report here the development of transgenic rats carrying the human angiotensinogen TGR-(hAOGEN) and human renin TGR(hREN) genes. The plasma levels and tissue distribution of the transcription and translation products from both genes are described. A unique species specificity of the enzyme kinetics was observed. The human RAS components in the transgenic rats did not interact with the endogenous rat RAS in vivo. Instead, infusions of exogenous human RAS components specifically interacted with human transgene translation products. Thus, infusion of human renin in TGR(hAOGEN) led to an increase of angiotensin II and an elevation of blood pressure, which could not be antagonized by the human-specific renin enzyme inhibitor Ro 42-5892. Rat renin also elevated blood pressure and angiotensin II in TGR(hAOGEN); however, this effect was not antagonized by the human renin inhibitor. Compared to mice, rats offer the advantage of chronic instrumentation and repetitive, sophisticated, hemodynamic, and endocrinological investigations. Thus, transgenic rat models with human-specific enzyme kinetics permit primate-specific analyses in non-primate in vivo and in vitro experimental systems.

Angiotensin II↗
PubMed1992

[Signals regulating arterial vasomotricity and vasotrophicity].

Second messengers regulating the level of free intracellular calcium and the level of phosphorylation (kinase activities) transduce within the cells the mechanical and biochemical (endocrine, paracrine and autocrine) signals detected by the arterial wall. In arterial smooth muscle cells two signalling pathways produce opposite functional and structural effects: the breakdown of phosphoinositol leading to an increase in intracellular calcium level, and the cyclic guanosine monophosphate (GMP) pathway resulting in a decrease in calcium level. The arterial cyclic GMP pathway is predominantly under control of the endothelial function to secrete no rather than influenced by the atrial natriuretic factor. These two intracellular second messenger pathways are involved not only in the regulation of motricity, but also in the control of arterial wall trophicity, including hypertrophy, hyperplasia and collagen hypersecretion. Inactivation of the cyclic GMP pathway and activation of phosphoinositol breakdown predominate in vascular adaptation to the ageing process.

Angiotensin II↗
PubMed1992

Effect of atrial natriuretic factor on the water permeability of endothelial cells.

Atrial natriuretic factor increases the water permeability of the whole endothelium. This study investigates how it would affect the transcellular osmotic water permeability of bovine artery endothelial cells. The cyclic-GMP production by the isolated cells was maximal for 10(-6)M atrial natriuretic factor within 30 minutes at 37 degrees C. The cyclic-GMP protein kinase cell concentration was 1.87 +/- 0.15 ng/mg protein. The control apparent water permeability of the cells measured by light scattering was 195 +/- 11 microns/sec (n = 5). Membrane folding revealed by light and scanning electron microscopy indicated that their true water permeability values would be close to 20-40 microns/sec, similar to the values for lipid membranes. The energy activation calculated from the temperature dependence of water permeability between 15 degrees C and 37 degrees C was 9.3 kcal/mol. This value suggests water movement through the lipid bilayer and not through water channels. Atrial natriuretic factor 10(-6)M did not significantly increase the water permeability of the cells. Hence, atrial natriuretic factor-stimulated increase in water permeability of the endothelium is more related to changes in paracellular water pathways than in transcellular water flux.

Animals↗
PubMed1992

Effect of perindopril on the immune arterial wall remodeling in the rat model of arterial graft rejection.

A model of arterial graft arteriosclerosis is described in which arterial wall immune injury was induced by grafting segments of abdominal aorta between two histologically incompatible strains of rats. The effect of hypertension and its treatment with the angiotensin-converting enzyme (ACE) inhibitor perindopril was tested using inbred spontaneously hypertensive rats (SHR) and their normotensive controls (Wistar-Kyoto [WKY]). Each of the grafted hypertensive and normotensive rats was randomly allocated to placebo treatment (10 SHR, 10 WKY) and perindopril treatment (2 mg/kg/day) (10 SHR, 10 WKY). The immune injury and the arterial wall response were quantified morphometrically 2 months after the grafting using specific stains for collagen, elastin, and nuclei. Hypertension was associated with a significant increase in intimal thickness. Treatment with perindopril greatly reduced intimal proliferation, decreasing the intimal thickness and the collagen content within the intimal layer. In contrast, hypertension and ACE inhibition had little effect on the arterial wall injury. We conclude that hypertension and its treatment with perindopril significantly affect graft arteriosclerosis. These effects seem to be independent of their effects on arterial wall injury, but not independent of blood pressure.

Analysis of Variance↗
PubMed1992

A fatal case of acute splenic sequestration in a 53-year-old woman with sickle-hemoglobin C disease.

Acute splenic sequestration crisis (ASSC) is a common complication in infants and young children with homozygous sickle cell disease, but it is infrequent in patients with sickle-hemoglobin C (SC) disease. When it does occur in such patients, it is often associated with exposure to high altitude, either by air travel or mountainous environment. Since 1970, only 15 cases of ASSC have been reported in patients with SC disease who were not exposed to a high altitude. Nine of these were children and adolescents aged 11 to 18 years, while six were adults aged 21 to 44 years. A review of these cases shows only two fatalities from ASSC: a 12-year-old West Indian girl living in England and a 13-year-old black girl in the United States. In this report, we describe the sudden death from ASSC of a 53-year-old black woman with SC disease at low altitude. To our knowledge, death from ASSC has not been previously reported in an adult patient with SC disease.

Acute Disease↗
PubMed1992

Effects of the selective neutral endopeptidase inhibitor, retrothiorphan, on renal function and blood pressure in conscious normotensive Wistar and hypertensive DOCA-salt rats.

Atrial natriuretic peptide (ANP) is degraded by neutral endopeptidase (NEP) mainly in the proximal tubule of the kidneys. We studied the effects of retrothiorphan, a potent and highly specific NEP inhibitor on renal function and blood pressure (BP). A 25-mg/kg bolus injection (group bolus), or bolus injection plus infusion 25 mg/kg + 25 mg/kg/h (group infusion), was given to conscious normotensive Wistar and hypertensive DOCA-salt rats. Bolus and infusion produced increases in diuresis (110 +/- 15 vs. 103 +/- 15 vs. 42 +/- 9 microliters/min) and natriuresis (10.6 +/- 3.0 vs. 7.0 +/- 1.0 vs. 5.4 +/- 1.0 mumol/min) in normotensive rats, with a maximum change at 30 min. Change in kaliuresis was not significant. These renal effects were associated with nonsignificant increases in urinary cyclic GMP and ANP. Arterial pressure and heart rate (HR) were not affected. Bolus or infusion of retrothiorphan also induced increases in diuresis (92 +/- 16 vs. 124 +/- 13 vs. 38 +/- 6 microliters/min) and natriuresis (10.3 +/- 2.0 vs. 12.5 +/- 1.0 vs. 5.0 +/- 1.0 mumol/min) in DOCA-salt hypertensive rats, with a maximum change at 30 min. The changes in diuresis and natriuresis induced by retrothiorphan were correlated with a significant increase in urinary cyclic GMP excretion (r = 0.89, p < 0.001 and r = 0.91, p < 0.001). Urinary ANP did not change in controls but significantly increased in the treated rats; urinary immunoreactive bradykinin (BK) also tended to increase. Plasma ANP and hematocrit did not change after retrothiorphan, but plasma cyclic GMP increased significantly after infusion. Only infusion caused a decrease in arterial pressure in DOCA-salt rats (-20 mm Hg at 120 min). Renal clearance studies in DOCA-salt rats showed that retrothiorphan has a transient effect on renal hemodynamics, with increases in glomerular filtration and renal blood flow (RBF) and a decrease in renal vascular resistance (RVR). Its renal action was also tubular, with an increase in fractional sodium excretion. We also compared the effects of retrothiorphan in normotensive Brown-Norway kininogen-deficient rats (BN-Kat) and DOCA-salt hypertensive kininogen-deficient rats. The NEP inhibitor induced increases in diuresis and natriuresis in both groups, with increased urinary cyclic GMP. Urinary immunoreactive BK did not change significantly in normotensive or DOCA-salt hypertensive kininogen-deficient rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Adaptation to sodium restriction in renin-immunized spontaneously hypertensive and normotensive rats.

The influence of active immunization against renin on the systemic and renal adaptation to abrupt suppression of dietary sodium was assessed in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. Very low level of plasma renin activity and no response of circulating renin to sodium restriction were observed in immunized rats. The final systolic arterial pressure achieved in immunized SHR (144 +/- 3 mmHg) was similar to that observed in nonimmunized WKY (137 +/- 4 mmHg), and no influence of renin immunization on renal blood flow was observed in both strains maintained on ad libitum sodium intake. Dietary sodium restriction was associated with a consistent decrease in arterial pressure in immunized rats, whereas no change occurred in sham-immunized rats. No impairment in the renal adaptation was detected in immunized rats (6-day cumulative sodium excretion of 1.67 +/- 0.2 and 1.65 +/- 0.3 mmol in immunized SHR and WKY, respectively, and 1.50 +/- 0.2 and 1.21 +/- 0.2 mmol in sham-immunized SHR and WKY rats). These studies indicate that renin immunization decreases arterial pressure but does not affect renal adaptation to dietary sodium restriction in hypertensive and normotensive rats.

Adaptation, Physiological↗
PubMed1992

Determinants of aortic cyclic guanosine monophosphate in hypertension induced by chronic inhibition of nitric oxide synthase.

Nitric oxide (NO) and atrial natriuretic factor (ANF) cause vascular relaxation by generating cyclic guanosine monophosphate (cGMP) via activation of the soluble and particulate guanylate cyclases, respectively. The chronic effects of NG-nitro-L-arginine methyl ester (L-NAME), an L-arginine antagonist and NO synthase inhibitor, on the blood pressure and plasma and aortic cGMP levels of rats were tested. Wistar rats (n = 10 per group) were given doses of L-NAME (0, 1, 5, 10, 20, 50, and 100 mg/kg.d) by gavage twice a day for 4 wk. Chronic L-NAME induced a time- and dose-dependent increase in blood pressure. The total heart weight/body weight ratio did not change in any group, despite the hypertension. The plasma levels of cGMP did not change significantly in any group, and were correlated with the plasma ANF levels (r = 0.51, P less than 0.0001). Aortic cGMP decreased in negative correlation with increasing L-NAME from 0 to 10 mg/kg.d, culminating in a 10-fold drop arterial wall cGMP. The aortic cGMP content of rats in the four highest dose groups (from 10 to 100 mg/d) tended to increase slightly and was positively correlated with endogenous ANF (r = 0.48, P less than 0.002, n = 40). Intravenous L-arginine decreased arterial blood pressure and reversed the decline in aortic cGMP. Exogenous ANF and sodium nitroprusside both significantly increased aortic cGMP. Neither the arterial wall concentrations of cGMP-dependent kinase nor cAMP was changed by L-NAME. Thus, chronic blockade of NO synthase with L-NAME induces a dose-dependent increase in blood pressure and decrease in aortic cGMP. The in vivo basal aortic cGMP seems to be mainly dependent on NO synthase: soluble guanylate cyclase activity and to a minor extent on particulate guanylate cyclase activity.

Amino Acid Oxidoreductases↗
PubMed1992

[Effects of angiotensin II on intrinsic contractibility of the myocardium in the guinea pig].

Analysis of the contraction-relaxation coupling of guinea pig left ventricular papillary muscle was performed with and without angiotensin II (Ang II 10-6 M). The inotropic and lusitropic properties of Ang II were evaluated at 20 degrees C, 30 beats/min, CaCl2 6H20 2 mM and pH 7.4, under low load (isotonic conditions) and high load (isometric conditions). The maximum velocity of contraction (max Vc) and relaxation (max Vr) were calculated from isotonic contraction having as its only load that corresponding to the imposed preload at Lmax. The maximum positive (+dF/dtmax) and negative values (-dF/dtmax) of the derivative of the force were calculated during isometric contraction. The coefficients, R1 = max Vc/max Vr and R2 = (+dF/dtmax)/(-dF/dtmax), were calculated. These two coefficients allow the contraction-relaxing coupling to be assessed at low and high loads respectively. In the presence of Ang II, the increase in the isotonic velocity of relaxation (1.93 +/- 0.26 vs 3.15 +/- 0.35 Lmax/sec; p < 0.001) was greater than that of the isotonic velocity of contraction (0.74 +/- 0.05 vs 1.02 +/- 0.07 Lmax/sec; p < 0.001). This results in a decrease in the ratio of the velocities of isotonic contraction and relaxation (R1) (0.44 +/- 0.06 vs 0.35 +/- 0.05; p < 0.01). Under isometric conditions, Ang II induced a proportional increase in the parameters of contraction and relaxation. Consequently, there was no significant change in the R2 coefficient (1.22 +/- 0.06 vs 1.12 +/- 0.08). Moreover, Ang II did not induce any change in the sensitivity of the relaxation with respect to load.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1992

A 94-kDa protein, identified as neutral endopeptidase-24.11, can inactivate atrial natriuretic peptide in the vascular endothelium.

Neutral endopeptidase 24.11 (EC 3.4.24.11) inactivates atrial natriuretic peptide by cleaving the hormone between Cys7 and Phe8, and inhibitors of the enzyme have consequent natriuretic and diuretic properties. The in vivo sites of degradation of this peptide by the zinc-metallopeptidase, however, remain to be established. Because an endopeptidase-24.11-like activity has recently been reported in the rat mesenteric artery, we have further investigated the degradation of atrial natriuretic peptide in vascular tissue. Endopeptidase-24.11 activity was detected in solubilized membrane preparations from rat and rabbit vascular tissue, using [3H]D-Ala2-leucine enkephalin as substrate, and both rabbit and rat aorta preparations were also found to cleave atrial natriuretic peptide between Cys7 and Phe8. In both cases, hydrolysis was inhibited by neutral endopeptidase inhibitors, with Ki values close to their Ki values for the pure enzyme. In preparations of rabbit aorta denuded of endothelium by saponin treatment, the hydrolysis of the Gly3-Phe4 bond of [3H]D-Ala2-leucine enkephalin and the Cys7-Phe8 bond of atrial natriuretic peptide was reduced by greater than 90%. The high performance liquid chromatography method used to follow the degradation of atrial natriuretic peptide differed from previously published procedures, in that samples to be injected were first treated with excess dithiothreitol to reduce the Cys7-Cys23 disulfide bridge. This facilitated the separation of the intact peptide and its metabolites. The presence of the 94-kDa neutral endopeptidase in rabbit aortic tissue was definitively established using a new potent 125I-labeled inhibitor, [125I]RB104 [2-[(3-[125I]iodo-4-hydroxy)phenylmethyl]-4-N-[3- hydroxyamino-3-oxo-1-phenylmethyl propyl]amino-4-oxobutanoic acid] (Ki, 30 pM), which selectively labeled the enzyme after sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the membrane preparations. Therefore, despite its low concentrations in the vasculature, the presence of endopeptidase-24.11 almost exclusively in endothelial tissue suggests that the enzyme is ideally localized to inactivate circulating atrial natriuretic peptide.

Amino Acid Sequence↗
PubMed1992

Arterial hypertension and aneurysmal dilatation.

Hemodynamic parameters and especially systemic hypertension are considered to be significant factors in the progression of aortic aneurysmal dilatation. We have recently described an original experimental model of aortic aneurysm induced by transparietal infusion of elastase in the rat abdominal aorta. In order to evaluate the effect of hypertension on the aneurysmal remodeling of the arterial wall induced by perfusion of elastase activity, this experimental model was applied to renovascular hypertensive (N = 17), spontaneously hypertensive (N = 18) and normotensive rats (N = 17). The aneurysms were induced by infusion of 15 units of hog pancreatic elastase of a one centimeter isolated aortic segment in anesthetized rats which were sacrificed two weeks later. The aneurysmal length and diameter were measured in vivo using a micrometer in a surgical microscope. The aortas were then fixed in formalin and embedded in paraffin for standard histological study. The animals which died during the experimental period were examined. All rats presented a macroscopic aneurysm two weeks after the infusion of elastase. Histologically, the aneurysmal area was characterized by the disappearance of the normal elastic network and by the presence of a collagenic wall. The dimensions of the aneurysms (transversal diameter and length) were greater in hypertensive than in normotensive animals (F = 11, P less than 0.001) and aneurysmal dimensions were positively correlated with the level of blood pressure (r = 0.56, P less than 0.001). Moreover, the frequency of aortic rupture was greater in renovascular hypertensive (4/17) than in spontaneously hypertensive (1/18) and normotensive (0/17) rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

[Acquired aneurysms of the infrarenal abdominal aorta].

Abdominal aortic aneurysms (AAA) are the result of a degenerative process of the aortic wall. The incidence of AAA has increased during the last three decades. Computerized axial tomography is the best method for investigating AAA. For aneurysms of 4-5 cm or more in antero-posterior diameter, the risk of rupture is definitely high and justifies a preventive surgery. Precise evaluation of myocardial function and of coronary circulation may limit the operative risk and may improve the life expectancy. Screening of AAA in populations at risk will allow to survey the natural history of aneurysmal disease and limit the incidence of rupture which keeps a high mortality rate.

Age Factors↗
PubMed1991

[Pathogenesis of acquired abdominal aortic aneurysms].

Abdominal aortic aneurysms are the result of a destructive process of the aortic media. The incidence of abdominal aortic aneurysms is increasing but the reasons remain unknown. The mechanical and structural characteristics of the abdominal aorta explain the frequency of acquired aneurysms at this location. Classically, atherosclerosis is the main etiologic factor, but the abdominal aortic aneurysm is distinguishable from the aged aorta and occlusive atherosclerotic disease by the apparent absence of a reparative process. Some authors have tried to differentiate aneurysmal disease from occlusive atherosclerotic disease. Atherosclerosis could lead to plaque and stenosis or, in some unknown circumstances, to atrophy of the media and aneurysmal dilation. Proteolytic enzymes within the aortic wall play an important role in the destruction of the extracellular matrix of the aortic wall. Plasmin could locally worsen the proteolysis. Inflammatory cells might be responsible for these proteolytic activities. Calcium could play a role in the activation of inflammatory cells. Genetic markers and familial grouping have been reported by several authors. The discovery of constitutional or acquired factors that could lead to activation of degradative phenomena within the aortic wall will facilitate the identification of patients at risk, and improve screening of asymptomatic aneurysms.

Aneurysm↗
PubMed1991

Low angiotensinogen levels are related to the severity and liver dysfunction of congestive heart failure: implications for renin measurements.

PURPOSE: To compare the determination of plasma renin activity (PRA) and the direct measurement of active renin by immunoradiometric assay (IRMA) as methods of assessing the renin system in patients with congestive heart failure. PATIENTS AND METHODS: The status of the renin-angiotensin system in congestive heart failure was assessed by measuring the plasma renin substrate concentration, PRA, and plasma concentration of active renin in 37 patients with mild to severe congestive heart failure. Natremia and plasma levels of atrial natriuretic factor (ANF) were determined as biologic indexes of the severity of heart failure, and concentrations of prealbumin and retinol-binding protein were used as indexes of liver dysfunction. RESULTS: The PRA and the concentrations of active renin and ANF were markedly higher in patients with New York Heart Association class IV heart failure than in patients with class II to III heart failure, while natremia and the concentrations of renin substrate, prealbumin, and retinol-binding protein were markedly lower in the class IV patients than in the class II to III patients. Plasma renin substrate concentration was negatively correlated with active renin concentration (n = 37, r = -0.45, p = 0.005), and positively related to natremia (r = 0.56, p less than 0.0005), prealbumin (r = 0.54, p less than 0.001), and retinol-binding protein (r = 0.60, p less than 0.0001). CONCLUSIONS: Low levels of plasma renin substrate can be considered as an indirect index of the severity of heart failure that reflects both the high level of circulating active renin and the decrease in hepatic protein output. In patients with class IV heart failure, low levels of renin substrate led to a marked underestimation of active renin concentration from measurements of PRA. In contrast, direct IRMA of active renin measures the true plasma active renin concentration, independent of plasma renin substrate, and closely reflects renin secretion.

Adult↗
PubMed1991

Remodeling of heart and arteries by chronic converting enzyme inhibition in spontaneously hypertensive rats.

Hemodynamic and structural changes of the heart and large arterial vessels were studied in normotensive and spontaneously hypertensive rats following 12 weeks administration of converting enzyme inhibitor (perindopril, 2 mg/kg daily by gavage). In both strains, a significant blood pressure reduction was observed. In normotensive rats, the hemodynamic changes involved significant increase in systemic arterial compliance whereas slight changes in left ventricular weight and aortic medial thickness were observed. In hypertensive rats, the increase in compliance was relatively small, whereas there was a major reduction in medial thickness. Furthermore, the reduction of the media thickness was much more pronounced than that of the left ventricular hypertrophy. The present results suggest that the cardiac and arterial changes observed following long term converting enzyme inhibition do not strictly parallel the blood pressure changes in hypertensive rats. Dissociation between cardiac and arterial changes may be observed.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Effect of converting enzyme inhibition on allograft-induced arterial wall injury and response.

Converting enzyme inhibition (CEI) can prevent myointimal proliferation after arterial wall balloon injury. Because intimal proliferation is the main long-term complication of chronic vascular rejection, we tested the effect of CEI (perindopril, 1 mg/kg twice a day) on arterial rejection-induced intimal proliferation, using a model of aortic allograft in normotensive Wistar-Kyoto and spontaneously hypertensive rats. Eight-week-old rats were grafted and studied 2 months later. The structural parameters of the transplanted aortic wall were measured by morphometric analysis of specifically stained, formol-fixed sections. CEI did not prevent adventitial inflammatory infiltration but significantly increased the number of living cells and prevented the partial destruction of elastic laminae in the media, thereby increasing medial thickness to close to that of sham-operated controls. CEI significantly decreased intimal thickness and intimal collagen density, without changing the absolute number of intimal smooth muscle cells. The intimal thickness and the intimal collagen density were significantly correlated with the effect of CEI on blood pressure. CEI partially prevented the consequences of immune injury to the media within the arterial wall, probably by suppressing the proinflammatory activity of angiotensin II. It also decreased the recipient arterial wall response by acting more on the trophicity of intimal cells and on their ability to produce collagen rather than by directly inhibiting smooth muscle cell proliferation in our model of arterial allograft.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

[Evaluation of urinary excretion of cyclic guanosine monophosphate in clinical cardiology].

The prognostic importance of levels of urinary excretion of cyclic GMP (cGMPu), the second messenger of the atrial natriuretic factor (ANF) was studied in different cardiac pathologies in 31 patients (19 males and 12 females, average age 66 +/- 15 years) and compared with 31 control subjects of the same age (+/- 4 years) and sex. In the control group, the average cGMPu was 0.35 +/- 0.17 mumoles/24 hours/m2, and, with respect to urinary creatinine, increased with age (r = 0.54, p = 0.002). In the 16 patients with cardiac failure, the cGMPu was very high (1.03 +/- 0.59 mumoles/24 hours/m2, p less than 0.001) without any significant correlation with NYHA functional class although it fell after treatment. After myocardial infarction (8 cases including 3 with cardiac failure), the cGMPu was also high (0.49 +/- 0.33 mumoles/24 hours/m2) but it did not differ significantly from the control values in the 9 atrial arrhythmias without cardiac failure. The cGPMu was related to the cardiothoracic ratio but not to any blood gas parameter or echocardiographic measurement. In conclusion, the cGMPu is more stable and easier to measure than the ANF. It would seem to be a sensitive marker of cardiac failure complicating the most common cardiac pathologies observed in clinical practice.

Adult↗