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Biomedical subjects

P Hamet

Publications and source records attributed to P Hamet.

At least 181 records · Page 10Linked to original sources
PubMed1989

Abnormalities in growth characteristics of aortic smooth muscle cells in spontaneously hypertensive rats.

Comparative studies have shown that cultured vascular smooth muscle cells from spontaneously hypertensive rats (SHR) proliferate to a higher cell number, grow to a greater density, and have greater specific growth rate, particularly at a higher saturation density, than those of the normotensive Wistar-Kyoto (WKY) control rats. The growth difference was not due to varying cell survival nor to attachment ability after passage. The degree of DNA synthesis was estimated by [3H]thymidine incorporation into newly synthesized DNA. [3H]thymidine uptake increased with escalating concentrations of calf serum and reached a plateau at 5% calf serum in WKY rats, whereas an excessive, continuous rise was observed in SHR with up to a 20% concentration. [3H]thymidine incorporation into newly synthesized DNA was tested after stimulation by platelet-derived growth factor and epidermal growth factor. A significantly higher amount of newly synthesized DNA in vascular smooth muscle cells from SHR was noted when the cells were stimulated by platelet-derived growth factor or epidermal growth factor alone, and their simultaneous addition did not significantly change the 50% effective concentration but heightened the maximal response. These data provide evidence of increased aortic smooth muscle cell proliferation from aortas of SHR after mitogen stimulation and suggest a defect in growth stimulatory-inhibitory control.

Animals↗
PubMed1989

Thermosensitivity, a possible new locus involved in genetic hypertension.

Spontaneously hypertensive mice have been characterized as more sensitive to environmental heat than normotensive mice. A breeding program was therefore initiated to examine the possible genetic link between thermosensitivity and hypertension. Crossbreeding of spontaneously hypertensive mice with randomly bred normotensive mice produced F1 hybrids, which were then intercrossed to create a F2 population. Thermosensitivity was measured with a noninvasive method. The rate of body temperature increase was significantly (p less than 0.001) higher in the hypertensive mice (1.74 +/- 0.04 degrees C/min) compared with normal controls (1.13 +/- 0.03 degrees C/min). The frequency distribution of the rate of body temperature increase among the progenies was consistent with the hypothesis that a single gene locus determines the observed difference in thermosensitivity between normal and hypertensive mice. The allele that determines the rate of body temperature increase in normal mice was dominant in relation to the allele contributed by hypertensive mice. In the F2 population, a bimodal distribution determined two phenotypes: less than 1.40 degrees C/min and greater than 1.40 degrees C/min. A significant difference (p less than 0.01) in blood pressure of 11 mm Hg was observed between these two phenotypes. In addition, a positive correlation (p less than 0.01) was noted between the rate of body temperature increase and blood pressure in the F2 progeny. We conclude that there is possibly a single locus controlling thermosensitivity, which exhibits additive-dominance inheritance. Alleles of this particular trait segregate in part with an increment in blood pressure. The results support the possibility that the increased thermosensitivity seen in hypertensive mice is associated with one of the genes that contributes to their high blood pressure.

Animals↗
PubMed1989

Dissociation of natriuresis and diuresis and heterogeneity of the effector system of atrial natriuretic factor in rats.

The hypotensive, natriuretic, and diuretic actions of human atrial natriuretic factor-(99-126) (hANF) are accompanied by an elevation of cyclic guanosine monophosphate (cGMP) in plasma and urine. However, the oxidized hANF analogue, human [Met-O110]ANF-(99-126) (Met-O-ANF), has been reported to be unable to increase cGMP (Biochem. Biophys. Res. Commun. 128: 538-546). We employed this oxidized peptide to evaluate the relationship between its biological effects and cGMP generation, with cGMP serving as a marker of the recognized property of ANF to stimulate particulate guanylate cyclase. Met-O-ANF appeared to be a partial agonist, exhibiting a decreasing order of relative potency of hypotensive, vasorelaxant, diuretic, and natriuretic functions compared to hANF. A lower degree of cGMP increases was achieved by this analogue in cultured smooth muscle and endothelial cells. Met-O-ANF doses, which led to a significant increase in diuresis, were neither natriuretic nor accompanied by an increase of urinary cGMP. We were thus able to dissociate the diuretic and natriuretic effects of ANF. High doses of the oxidized analogue were required to elevate cGMP levels in plasma and urine. In isolated kidney fractions, Met-O-ANF's action on cGMP was significantly lower in glomeruli (fivefold less), virtually absent in the collecting duct, yet only slightly different (20% less) in thick ascending limb. Our results indicate that the diuretic and natriuretic effects are exerted at distinct sites, with only the natriuresis being related to an increase of extracellular cGMP. The variability of differential potency of biological and biochemical effects from tissue to tissue of these two forms of human ANF support the notion of the heterogeneity of the ANF effector system.

Animals↗
PubMed1989

Echocardiographic measurements and plasma levels of atrial natriuretic factor.

Atrial distension and pressure have been reported to be important for the release of atrial natriuretic factor (ANF) into the circulation. However, in mild essential hypertension, we have been unable to demonstrate an increase in plasma levels of ANF. To evaluate more precisely the lack of increase of ANF, we measured echocardiographically the diameters of the cardiac chambers and correlated these measurements with ANF values in normal subjects (n = 25), in patients with untreated essential hypertension (n = 20), and in patients with treated essential hypertension (n x 27). The plasma values of ANF were 21.9 +/- 2.8 pg/ml in the normal controls, 20.4 +/- 2.2 pg/ml in patients with untreated mild essential hypertension, and 32.6 +/- 2.8 pg/ml in patients with treated but uncontrolled essential hypertension (p less than 0.05). The plasma values of cGMP were 4.53 +/- 0.56 pmol/ml in the normal, 5.41 +/- 0.57 pmol/min in the patients with untreated essential hypertension, and 6.76 +/- 0.58 pmol/ml in treated essential hypertension (p less than 0.05). There were no significant differences in the size of the cardiac chambers between the three groups, except for the size of the right atrium, but there was a correlation between the ANF values and the size of the left atria (r = 0.29, p = 0.01, n = 72), as well as with the size of the intraventricular septum (IVS) in systole (r = 0.36, p = 0.002, n = 72). Since ANF levels are similar in mild untreated essential hypertension and normal volunteers, the ANF plasma levels could be a better reflection of the impact of the blood pressure on the myocardium than the level of blood pressure itself and indicate in patients the degree of cardiac impairment. On the other hand, there seems to be definitely an effect of treatment on the levels of ANF.

Adult↗
PubMed1989

Atrial natriuretic factor, the kidney and high blood pressure.

The discovery of atrial natriuretic factor (ANF) constitutes a major advance in our knowledge of negative cell regulatory pathways leading to vasodilation. The biochemical mechanisms of the action of ANF at the cellular level appear to be mediated by the cGMP- particulate guanylate cyclase system. In the kidney, the main cGMP increasing effect of ANF occurs at the level of the glomeruli, but it appears that action of ANF at the lowest part of the distal tubule is required for its natriuretic activity. Although most current knowledge concerning ANF has been obtained with pharmacological doses of the hormone, it appears that endogenous manipulations of ANF, such as those occurring with postural change, are associated with physiological consequences including increases of cGMP, natriuresis, and diuresis. In both experimental and human hypertension, increased plasma levels of ANF are secondary to higher blood pressure. In hypertension, the administration of ANF leads to an exaggerated renal response. We propose as a hypothesis that an abnormality in the expression of a vasodilatory system, such as ANF-cGMP, may play a role in the pathogenesis of hypertension.

Atrial Natriuretic Factor↗
PubMed1989

Cardiovascular, renal and endocrine responses to low doses of atrial natriuretic factor in mild essential hypertension.

The purpose of this study was to evaluate the cardiovascular, renal and endocrine effects of human atrial natriuretic factor (ANF), infused at a rate of 0.8 microgram/min (about 4 pmol/kg/min) for three hours in normal subjects and patients with essential hypertension. This infusion rate was chosen to obtain a range of plasma ANF levels which can be generated by physiological manoeuvres and to reduce the likelihood of hypotension. Five patients and six healthy volunteers participated in the study. The infusion had to be prematurely discontinued in one patient and in one control because of hypotension with relative bradycardia. Blood pressure otherwise remained unchanged during infusion whereas heart rate rose transiently. Plasma ANF levels increased similarly during infusion from 8.9 +/- 2.6 to 23.9 +/- 6.4 pmol/l in patients and from 3.7 +/- 0.7 to 25.4 +/- 6.9 pmol/l in the controls, remained stable during the infusion, and decreased similarly in both groups after the infusion, with a half-life of 7 min. Plasma guanosine cyclic phosphate (cGMP) was augmented by about four-fold in both groups. In both groups, plasma aldosterone levels fell whereas plasma noradrenaline increased. The diuretic effect of ANF was similar in both controls and patients (1354 +/- 161 vs 1542 +/- 116 ml/3 hrs respectively), whereas its natriuretic effect was exaggerated in hypertensive patients (90 +/- 11 vs 62 +/- 9 mmol/3 hrs, P less than 0.05). In conclusion, this low infusion rate of ANF produced similar changes in plasma ANF, cGMP, aldosterone and noradrenaline levels but patients with mild essential hypertension demonstrated an exaggerated diuretic and natriuretic response to ANF infusion.

Adult↗
PubMed1988

Atrial natriuretic factor in experimental and human hypertension.

Plasma levels of immunoreactive atrial natriuretic factor (IR-ANF) were evaluated by radioimmunoassay in several models of experimental hypertension and in human hypertension. Plasma levels of IR-ANF are consistently increased in all models of experimental hypertension studied so far. This is accompanied by a decrease of IR-ANF levels in the left atrium at certain times. Plasma levels of IR-ANF are not increased in human essential hypertension, except in the severe form (diastolic blood pressure above 110 mmHg). Peripheral levels of IR-ANF in renovascular hypertension do not differ from normal but are increased above normal in aortic blood.

Animals↗
PubMed1988

Vascular smooth muscle cell hyper-responsiveness to growth factors in hypertension.

To understand the intrinsic mechanisms of vascular smooth muscle cell proliferation, we studied the growth of cultured rat aortic smooth muscle from spontaneously hypertensive rats (SHR) and their normotensive controls, Wistar-Kyoto rats (WKY), under basal conditions and after stimulation. Cell growth was assessed by the determination of cell number, and incorporation of 3H-thymidine into newly-synthesized DNA. We demonstrated that vascular smooth muscle cells from SHR proliferate faster and grow to a greater density, regardless of the initial plating number. The growth difference was not due to different plating efficiencies. Significantly higher 3H-thymidine incorporation was observed in vascular smooth muscle cells from SHR when the cells were stimulated by calf serum, platelet-derived growth factor or epidermal growth factor. Exposure to calf serum elicited an excessive expression of c-myc and c-fos in the first hour after stimulation. These results provide evidence of the hyper-responsiveness of vascular smooth muscle cells from SHR aortae to growth stimuli.

Animals↗
PubMed1988

Genetic and molecular characteristics of thermosensitivity in hypertension.

Acute heat exposure is more lethal to spontaneously hypertensive mice (SHM) than to normal mice, whereas chronic heat treatment appears to be more beneficial in SHM, in that it normalizes blood pressure. By genetic breeding experiments, we demonstrated that the gene responsible for thermosensitivity segregates with an increment of blood pressure in the F2-generation and represents a genetic locus of hypertension. The molecular response to heat characterized by the induction of heat stress genes is abnormal in hypertension. There is an earlier accumulation and decline of heat-stress proteins (HSP70) and their messenger (m) RNA following heat exposure in tissues obtained from hypertensive mice. Our results indicate that thermosensitivity is genetically linked with hypertension and characterized by an abnormality in the synthesis of stress proteins as well as in the expression of their mRNA following heat exposure, which implies that a genetic defect is present in response to environmental stress in spontaneous hypertension.

Animals↗
PubMed1988

Effects of dietary calcium on the development of salt hypertension in young and adult Dahl rats.

The effect of dietary calcium on the development of salt hypertension was studied in young and adult Dahl rats. Age-dependent development of blood pressure was compared in salt-sensitive (DS) and salt-resistant (DR) Dahl rats that were fed either a low-calcium (0.15%) or a high-calcium (2.5%) diet. Systolic blood pressure was consistently higher in DS rats than in a comparable group of DR rats. In young DS rats the high-calcium diet transiently attenuated the development of hypertension, whereas in adult rats this diet potentiated the development of hypertension. In young DS rats total plasma calcium was increased by the high-calcium diet, but in adult rats it was significantly decreased. Our results suggest that the effects of dietary calcium supplementation on calcium metabolism and the development of salt hypertension in DS rats depend on the age at which calcium supplementation is started.

Age Factors↗
PubMed1988

Effects and pharmacokinetics of bolus injections of atrial natriuretic factor in normal volunteers.

The aim of this study was to examine the hemodynamic, renal, and endocrine effects of exogenous human atrial natriuretic factor (ANF), together with its pharmacokinetics, in healthy volunteers. Ten subjects participated in this study, in which the effects of a single bolus dose of ANF and of a matched vehicle injection were compared under a 135 mmol/day sodium intake. Doses of 3, 12.5, and 25 micrograms of ANF were given to 1 subject each, and doses of 50 and 100 micrograms were given to 4 and 3 subjects, respectively. Significantly, hemodynamic changes occurred at the 100 micrograms dose, when mean blood pressure decreased by 15% and heart rate increased reciprocally. Diuresis and natriuresis tended to increase following 50 micrograms but increased significantly and in a prolonged fashion following 100 micrograms of ANF. Atrial natriuretic factor did not cause significant changes in plasma catecholamine, renin activity, and aldosterone levels at any dose, although aldosterone tended to decrease. Plasma arginine-vasopressin concentrations decreased significantly following 100 micrograms. Plasma cyclic GMP levels increased in all subjects and in a dose-dependent fashion. Plasma ANF concentrations peaked 3-5 min following the bolus injection and returned toward baseline values within 10-60 min. Although with doses of less than or equal to 50 micrograms plasma ANF levels increased up to 8 to 50-fold, compared to baseline values, the only significant change was the increase in plasma cyclic GMP levels, perhaps because the effects of ANF were successfully masked by counter-regulatory mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Abnormality of calmodulin activity in hypertension. Evidence of the presence of an activator.

An apparent increase of calmodulin (CaM) activity was previously observed in the heart and kidney but not in the liver of spontaneously-hypertensive rats (SHR) and mice compared with their corresponding normotensive controls. As this change was due to an elevated recovery of CaM in the organs of the hypertensive animals, the present study was designed to evaluate its activity in hypertension. A CaM activator, detected in heart and kidney supernatants from hypertensive animals, was found to be responsible for this enhanced recovery. Similar results were obtained with passaged, cultured aortic smooth muscle cells from SHR, indicating that the anomaly was not a mere consequence of elevated blood pressure but rather a genetic expression of cells of hypertensive origin. The activator was heat stable, nondialyzable, and recovered in the fraction precipitated with 30-50% ammonium sulfate. Preliminary extraction studies suggest that the activator is contained in a glycolipid fraction. The stimulation of phosphodiesterase by this activator was calcium and CaM dependent. The activator appears to affect the affinity of the phosphodiesterase for CaM rather than the maximal stimulation. The activator was also present at a low concentration in the heart and kidney of normotensive animals. These findings indicate that at least some of the calcium abnormalities implicated in the pathogenesis of hypertension could be the result of interactions between CaM, calcium, and this activator.

Animals↗
PubMed1988

ANF in experimental congestive heart failure.

The plasma and cardiac levels of immunoreactive (IR) atrial natriuretic factor (ANF) were measured during the entire lifespan of cardiomyopathic hamsters, which eventually develop spontaneous congestive heart failure, and were correlated with immunohistochemical, ultrastructural, and immunocytochemical changes in the secretory apparatus of atrial and ventricular cardiocytes. Plasma IR-ANF rose in the early stages of the disease, reached a maximum in moderate heart failure, and declined thereafter but remained above control values. The peptide decreased constantly in the atria during the evolution of the disease but increased markedly in the ventricles. Its highest levels were found in the inner half of the left ventricle. In atrial cardiocytes, the size and complexity of the Golgi complex increased with the progression of the disease, whereas the number, size, and IR-ANF content (as assessed by the immunogold technique) of secretory granules decreased constantly. In ventricular cardiocytes, the size of the Golgi complex increased, and typical secretory granules were present in approximately 20% of these cells, regardless of their localization in the myocardium. The results suggest that stimulation of ANF secretion in atrial cardiocytes leads to a dissociation between synthesis and release, the latter being maximal according to ultrastructural and immunocytochemical criteria. In ventricular cardiocytes, the same stimulation culminates in increased synthesis and the possibility of release via two pathways: one constitutive, the other regulated. Thus, the elevated plasma levels of IR-ANF in congestive heart failure may be derived from secretion by both atrial and ventricular cardiocytes.

Animals↗
PubMed1988

[Effects of phenylephrine on atrial natriuretic factor and the renin-aldosterone axis in normal patients and essential hypertensive patients].

Phenylephrine infusions enhance diuresis and natriuresis both in normal subjects and patients with essential hypertension, whereas they have an opposite effect on urinary aldosterone excretion, decreasing it in normal subjects and enhancing it in hypertensive patients. With the new knowledge concerning the atrial natriuretic factor (ANF), it seemed a strong possibility that in normal subjects phenylephrine infusions should exert its effect through the increased release of ANF, as suggested by in vitro studies. Phenylephrine infusions at high pressor dose (to increase diastolic pressure by 25 mmHg) in six healthy volunteers increased plasma ANF and cGMP and decreased plasma renin activity and aldosterone concentrations. Urinary volume, sodium, and cGMP excretion were also increased. Phenylephrine infusions at low pressor dose (to increase diastolic pressure by 12-15 mmHg), in healthy subjects and in five patients with mild essential hypertension, significantly increased plasma ANF concentrations and decreased plasma renin activity to the same degree in both groups. But, whereas in normal subjects plasma aldosterone decreased significantly, it increased in patients with mild essential hypertension despite the simultaneous rise in plasma ANF concentration.

Adult↗