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Biomedical subjects

M A Devynck

Publications and source records attributed to M A Devynck.

At least 91 records · Page 5Linked to original sources

Platelet cyclic AMP in essential hypertensive and normotensive offspring.

Essential hypertension is accompanied by several modifications to platelet metabolism suggesting hyper-reactivity to various aggregating agents. As the platelet response is mediated by both cytosolic free calcium, which is stimulatory, and cyclic (c)AMP, which is inhibitory, this hyper-reactivity may be caused by a modification in cAMP metabolism. We therefore determined cAMP in unstimulated platelets from 19 patients with essential hypertension and 27 age-matched normotensive subjects, nine with and 19 without a family history of hypertension. The platelet cAMP content was reduced in the essential hypertensives and in the normotensives with a positive family history by 37.5% and 42%, respectively (P less than 0.001 for both). Platelet cAMP was inversely correlated with diastolic blood pressure (P = 0.036). After prostaglandin (PG) E1 stimulation, the platelet cAMP content remained lower in the patients with essential hypertension than in the normotensive subjects, whatever their hypertensive heredity. The rises in cAMP caused by inhibition of phosphodiesterase by 7-bromo-1,5-dihydro-3,6-dimethylimidazo-[2,1-b]quinazolin-2[ 3H]-one (Ro 15-2041) were similar in the three groups. These results indicate that cAMP, the platelet inhibitory messenger, is reduced in hypertensive patients and in their normotensive offspring and may affect the various platelet abnormalities previously described in this disease.

Adult↗

Platelet cytosolic proton and free calcium concentrations in essential hypertension.

Alterations in the metabolism of intracellular messengers, such as calcium and cyclic adenosine 5'-phosphate (cAMP), have been reported in essential hypertension. Since intracellular pH (pHi) participates in the control of fundamental cell functions, we looked for changes in platelet cytosolic H+ concentration [( H+]i) in hypertension and investigated whether or not its impaired metabolism is linked to the calcium handling abnormalities. The fluorescent pH indicator BCECF has been used to evaluate intracellular H+ concentration in platelets, unstimulated ex vivo, from normotensive (n = 20) and hypertensive patients (n = 20). Cytosolic [H+] was 20% lower in hypertensive than in normotensive subjects (49.5 +/- 3.4 and 61.8 +/- 2.2 nmol/l cells, respectively, P less than 0.005; mean pHi values were 7.21 and 7.33, respectively). Platelet cytosolic H+ and free Ca2+ concentrations ([Ca2+]i) were determined in parallel in 15 normotensive and 15 hypertensive patients. [Ca2+]i was found to be 19% higher (P less than 0.01), and [H+]i 22% lower (P less than 0.02), in the hypertensive patients compared with the normotensive subjects. Platelet pHi and [Ca2+]i were increased simultaneously in some hypertensive patients. These results are compatible with the hypothesis of an in vivo activation of platelets in hypertension. If a similar alkalinization exists in smooth muscle cells, it may participate in cell proliferation and in an enhanced sensitivity to agonists, two parameters thought to be involved in blood pressure elevation.

Adult↗

Platelet cyclic AMP in essential hypertension.

Various abnormalities in platelet metabolism, including increased sensitivity to several aggregating agents, have been described in essential hypertension. Platelet response is controlled by Ca2+ and cyclic AMP-dependent mechanisms (stimulatory and inhibitory, respectively) which oppose one another. In the present study, the cyclic AMP contents of unstimulated platelets were measured by radio-immunoassay and observed to be lower in hypertensive than in normotensive subjects, either in the basal state or after prostaglandin E1 (PGE1) stimulation. In the presence of 7-bromo-1,5,dihydro-3,6-dimethylimidazo [2,1-b] quinazolin-2(3H)-one (Ro 15-2041), a specific inhibitor of phosphodiesterase, the increases in cyclic AMP content were similar in platelets from both groups, indicating that this enzyme was not responsible for the alterations in cyclic AMP metabolism observed in hypertension. Low external Ca2+ reduced basal and PGE1-stimulated cyclic AMP content in both normotensive and hypertensive groups but cyclic AMP levels remained lower in hypertensive patients than in normotensive subjects, indicating that Ca2+ influx is not responsible for this altered metabolism of cyclic AMP in hypertension. These data suggest that the reduced platelet cAMP content may participate in the hyperreactivity to various aggregating agents previously reported to accompany essential hypertension.

Adult↗

Body fluid variations and endogenous digitalis-like compounds during chronic NaCl loading in Wistar rats.

Circulating digitalis-like compounds have been proposed to be raised in volume expanded hypertension and to participate in Na+ homeostasis. We have investigated the temporal relationships between the activity of these circulating digitalis-like compounds, blood pressure and body fluid volume variations during a chronic NaCl load in the Wistar rat. Characteristics of salt-loaded rats were compared to those of weight-matched controls. At one week, when extracellular fluid volume (ECFV) was elevated, the capacity of plasma extracts to inhibit the Na+K+ATPase activity begun to rise. At two weeks, ECFV remained elevated, and plasma volume, blood pressure and the activity of plasma digitalis-like compounds increased. After 13 weeks, the continuous rise in plasma digitalis-like activity and in blood pressure was accompanied by the return of body fluid volumes towards control values. These changes in plasma digitalis-like activity, body fluid volumes, and systolic blood pressure during a high NaCl diet are compatible with the proposed role of circulating digitalis-like compounds as natriuretic and hypertensive factors.

Animals↗

[Essential hypertension and platelet cytosolic concentrations of H(+) and Ca2(+)].

Essential hypertension is associated with various cell abnormalities, including alterations in the metabolism of intracellular messengers, such as cytosolic free Ca2+ and cyclic AMP or IP3. Intracellular pH is implicated in the regulation of number vital functions, including cell metabolism, division and response to various stimuli. We have measured cytosolic H+ concentration ([H+]i) in human platelets and investigated a possible relationship with free Ca2+ concentrations ([Ca2+]i) in hypertensive patients. [H+]i was determined with the pH sensitive fluorescent probe BCECF in platelets from 15 normotensive subjects and 15 patients with mild to moderate essential hypertension, free from medication, il any, for at least two weeks. Donor characteristics are indicated in the table. (table; see text) [H+] cytosolic from hypertensive patients was significantly lowered by 21 p. 100 compared to normotensive values (table). Cytosolic free Ca2+ concentrations, measured with the Ca2+ fluorescent probe Fura2, were significantly increased by 19 p. 100 in platelets from hypertensive patients when compared to those of normotensive donors. Taken all together, [H+]i and [Ca2+]i varied inversely (r = -0.421, p = 0.02) in these thirty donors and tends to be correlated in the essential hypertensive patients (r = 0.490, p = 0.06). This correlation remained significant at constant age systolic and diastolic blood pressures. The simultaneous rise in [H+]i and [Ca2+]i in platelets from essential hypertensive patients are compatible with their observed enhanced sensitivity to several aggregating agents. This alkalinisation, if present in the vascular smooth muscle cells, may also reflect facilitated cell proliferation and increased sensitivity to stimulating agents, two parameters implicated in the rise of arterial blood pressure.

Adult↗

[Endogenous compounds of the digitalis type in essential and arterial hypertension].

Endogenous digitalis-like compounds are present in biological fluids and in some tissues. Little is known, so far, about their chemical nature and the tissues where they originate. Plasma and urinary levels of these compounds are elevated in essential and experimental arterial hypertension, and this rise may contribute to the genesis and maintenance of an abnormally high blood pressure. This is explained by an increase in intracellular calcium concentration resulting from inhibition of the sodium/potassium pump and increase of intracellular sodium. Concerning the chemical nature of these endogenous digitalis-like compounds two hypotheses have been put forward: peptides or steroids. Precise identification of these compounds and a knowledge of their mechanism of action on the sodium/potassium pump will probably lead to the development of new drugs in the field of cardiovascular and renal diseases.

Animals↗

Fluorescence measurements of free Ca2+ concentration in human erythrocytes using the Ca2+-indicator fura-2.

We report here the use of the fluorescent Ca2+-chelator fura-2 to directly measure free Ca2+ concentration within intact human erythrocytes and the influence of viscosity on the fluorescence of this probe. The bright fluorescence of fura-2 has permitted the use of low concentrations of indicator and cells, thus minimizing the screening effect and the intrinsic fluorescence of haemoglobin. Erythrocytes (10(8) cells/ml) were loaded with 0.5 microM fura-2AM then diluted at 10(7) cells per ml for measurements. The extracellular signal was suppressed by addition of manganese ions just before recording spectra. Under these conditions, a blood sample of 100 microliter was sufficient for analysis. To study the influence of viscosity on fura-2 fluorescence, gelatin and polyvinylpyrrolidone at various concentrations were added to a physiological buffer to perform fura-2-Ca fluorescence standard curves. Fluorescence intensities and the apparent affinity constant for Ca2+ were modified by viscosity. When intra-erythrocytic viscosity was simulated with 21 g/l polyvinylpyrrolidone to obtain a mean viscosity of 14 mPa.s similar to that observed in human erythrocytes, the mean value of free Ca2+ concentration measured in erythrocytes from healthy subjects was 78 +/- 16 nM (mean +/- S.D., n = 29).

Benzofurans↗

Platelet 5-HT content and uptake in essential hypertension: role of endogenous digitalis-like factors and plasma cholesterol.

A decrease in platelet 5-HT content linked to partial inhibition of 5-HT uptake has been described in essential hypertension. Transport of 5-HT through platelet membrane is dependent upon transmembranal Na+ and K+ gradients. It is inhibited by Na+, K+-ATPase inhibitors such as ouabain and endogenous digitalis-like compounds isolated from hemodiafiltrate. The activity of such compounds in plasma extracts, measured by inhibition of Na+,K+-ATPase or ouabain binding to human erythrocytes, and platelet 5-HT content were determined in parallel in essential hypertensive patients. Significant negative correlations were observed between these parameters in men, suggesting that high levels of digitalis-like compounds can affect platelet 5-HT content. In addition, in essential hypertensive patients, total plasma cholesterol was inversely related to both platelet 5-HT content (n = 15, r = -0.594, P less than 0.02) and maximal velocity of 5-HT uptake (n = 15, r = -0.717, P less than 0.003). In normotensive control subjects, no variation of platelet 5-HT content with cholesterol was observed. This suggests that the platelet membranes of essential hypertensive patients are more sensitive to increases in plasma cholesterol than those of normotensive subjects.

Adult↗

Correlations between plasma levels of an endogenous digitalis-like substance and haemodynamic parameters measured during cardiac catheterization.

It has been postulated that one or more plasma digitalis-like compounds may play an important role in body fluid regulation and in essential hypertension, although very little is known about their possible role in general haemodynamics. We therefore measured plasma inhibition of human kidney Na+,K+-ATPase and plasma cross-reactivity with digoxin antibodies in 11 normotensive cardiopathic subjects admitted to our clinic for heart catheterization. Possible correlations with haemodynamic parameters were studied. Plasma digoxin-like activity correlated directly with left atrial pressure and with pulmonary circulation data. The ability of the plasma to inhibit Na+,K+-ATPase showed an inverse correlation with cardiac output and cardiac index. No correlations were found with any of the other parameters measured, notably systemic resistance, blood pressure and natriuresis. These findings suggest the presence of more than one substance sharing chemical properties with digitalis: (1) a substance cross-reacting with digoxin antibodies and dependent on pulmonary vascular congestion; and (2) a substance capable of inhibiting the Na+-K+ pump and present in large amounts in heart diseases with a reduced cardiac index.

Adult↗

Antihypertensive effect of canrenone in a model where endogenous ouabain-like factors are present.

The effect of canrenone, an antialdosterone and partial ouabain-agonist drug, was studied in rats that developed volume expansion and hypertension after renal mass reduction and excess Na+ intake (RRM-salt). The RRM-salt was characterized by: (1) increased endogenous "digitalis-like" compounds in plasma [cross reactivity with digoxin-antibodies (57.5 +/- 5.0 vs. 42.1 +/- 3.8 pg/ml, p less than 0.02); inhibition of kidney Na+, K+-ATPase activity (135 +/- 5 vs. 154 +/- 5 mumol/mg/h, p less than 0.01); and inhibition of Na+ extrusion from normal erythrocytes (5.96 +/- 0.40 vs. 7.68 +/- 0.34 mmol/L cells/h, p less than 0.01)]; (2) reduced Na+, K+-pump activity (7.34 +/- 0.29 vs. 10.88 +/- 0.41 mmol/L cells/h, p less than 0.001) and increased Na+ content (4.66 +/- .08 vs. 4.16 +/- 0.11 mmol/L cells, p less than 0.01) in erythrocytes; and (3) low plasma renin activity (2.1 +/- 0.9 vs. 12.6 +/- 1.6 ng/ml/h). Ninety minutes after the administration to RRM-salt of a single oral dose of 60 mg/kg of canrenone, the systolic blood pressure decreased by 36 +/- 4 mm Hg (mean +/- SEM). Chronic canrenone administration (60 mg/kg/day) resulted in a marked antihypertensive effect associated to a correction of volume expansion, a decrease in endogenous "digitalis-like" compounds, and a partial recovery of Na+, K+-pump activity and Na+ content in erythrocytes. Our results suggest that the antihypertensive effect in RRM-salt rats results, at least in part, from antagonism with endogenous "digitalis-like" compounds.

Animals↗

Red blood cell ionized calcium concentration in spontaneous hypertension: modulation in vivo by the calcium antagonist PN 200.110.

1. Altered calcium regulation has been observed in experimental and human hypertension. In this study erythrocyte (RBC) intracellular calcium concentration ([Ca2+]i) was compared in conscious spontaneously hypertensive rats (SHR) and their normotensive controls (WKY) at rest and after injection of the dihydropyridine calcium antagonist PN 200.110. 2. Resting [Ca2+]i was similar in SHR and WKY. 3. PN 200.110 administration induced a rapid decrease in blood pressure in SHR and WKY. Five minutes after the injection no change in [Ca2+]i was observed; at 1 h [Ca2+]i was significantly decreased in SHR, but not in WKY. 4. These results suggest that the mutual adaptation of the rate of calcium influx through calcium channels and the activity of the calcium extruding pump differ between WKY and SHR.

Animals↗

Endogenous digitalislike circulating substances in spontaneously hypertensive rats.

Circulating digitalislike compounds have been proposed to be involved in some Na+-dependent types of experimental hypertension and in human essential hypertension. The level of circulating Na+-K+ pump inhibitor(s) was investigated in the spontaneously hypertensive rat of the Okamoto strain (SHR), its normotensive control, Wistar-Kyoto rat (WKY), and the regular Wistar rat using the following criteria: the ability of whole plasma to inhibit the total active Na+ efflux from Wistar rat erythrocytes and to cross-react with digoxin antibodies and the ability of plasma extracts to inhibit Na+,K+-adenosine triphosphatase (ATPase) activity of membranes from rat kidney. SHR plasma inhibited the net Na+ efflux from Wistar erythrocytes by up to 27% compared with WKY or Wistar plasma. For a given number of cells, the inhibition increased with the amount of available plasma. Cross-reactivity with digoxin antibodies was twice as high in SHR as in WKY or Wistar plasma. It was already enhanced in 3- to 4-week-old rats. Plasma extracts from SHR significantly inhibited Na+,K+-ATPase activity when compared with WKY extracts (75.6 +/- 2.6 vs 89.3 +/- 2.4 mumol Pi/mg/hr; p less than 0.01) but did not differ from Wistar plasma extracts. These results strongly suggest that circulating digitalislike compound(s) are present in elevated amounts in SHR as early as 3 to 4 weeks of age, but their exact participation in blood pressure elevation or maintenance remains to be clarified.

Animals↗

[Hereditary resistance to salt-induced hypertension. What mechanisms?].

The Sabra hypertension resistant rats (SBN) have an outstanding ability to maintain normal blood pressure when exposed to procedures that ordinarily cause hypertension in normal rats. The following findings may be relevant to resistance to hypertension of these rats: 1) In SBN rats, cardiac norepinephrine content is not affected by DOCA-salt treatment. Since depletion of cardiac norepinephrine is an index of cardiac adrenergic nerve overactivity, the results suggest an attenuated cardiac sympathetic nerve activity in these rats. 2) In SBN rats, the sensitivity of the baroreflex control of the heart is markedly increased compared with other strains. Reduction of baro-receptor sensitivity by aortic-baroreceptor deafferentation renders them susceptible to DOCA-salt hypertension. The results suggest a strong relationship between baroreflex supersensitivity and resistance to hypertension in these rats. 3) The amount of alpha 2 adrenoreceptor densities in cerebral and renal cortical membranes of normal rats increased in vitro, in the presence of sodium and guanyl nucleotide (GTP). In SBN rats, the effect of sodium is markedly attenuated compared with SBH, while response to GTP is identical in the two strains. The demonstration of a similar pattern of response in the Dahl rats suggests that alpha 2 adrenoreceptor may be involved in the sensitivity or resistance to salt induced hypertension.

Animals↗

[Variations in the plasma concentrations of atrial natriuretic factor and endogenous digitalis compounds during acute volume expansion in the conscious rat].

Atrial natriuretic peptide (ANP) and Na+ pump inhibitor (digitalis-like substance, DLS) have both been proposed to participate in body sodium and water homeostasis. Plasma levels and ANP and DLS have been reported to be increased in physiological or pathological states characterized by volume expansion. In order to investigate possible mutual relationships, their concentrations were measured in parallel during acute volume expansion by injection of 25 ml/kg isotonic NaCl (A) or blood (B) in the conscious rat. ANP was measured by radioimmunoassay and DLS by inhibition of renal Na+, K+-ATPase activity and digoxin-like immunoreactivity (DLI). Five minutes after injection, plasma ANP increased to reach 700 pg/ml (A, n = 21) or 1,500 pg/ml (B, n = 5) but the ability of plasma extracts to inhibit the renal Na+, K+-ATPase activity was unchanged (16.6 +/- 2.5 vs 16.9 +/- 2.0 p. 100, A, n = 8 and 6). Digoxin-like immunoreactivity was slightly lowered after NaCl injection from (74.4 +/- 6.2 to 65.4 +/- 5.1 pg/ml, n = 21) and unchanged after blood injection (79.0 +/- 3.4 vs 81.2 +/- 5.0 pg/ml, n = 5). Plasma ANP concentrations then decreased and had returned to preinjection values before 30 (A) or 90 (B) minutes, whereas the capacity of plasma to inhibit the Na+, K+-ATPase tended to increase (25.9 +/- 4.7 p. 100 at 3 hours after injection, n = 12 compared to 17.6 +/- 1.6 p. 100, n = 20) and DLI remains stable.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Plasma levels of digitalis-like substance in Nigerians with essential hypertension.

A plasma Na+-K+ ATPase inhibitor, which is estimated by a technique in which it competes with ouabain for binding on red cells, was measured in three groups of individuals: (a) normotensive subjects without a family history of hypertension, (b) normotensive subjects with a family history of hypertension, (c) untreated essential hypertensive subjects. The mean value of the inhibitor in group (b) subjects was significantly higher than the mean value in group (a). The mean value in group (c) subjects was also significantly higher than in group (a) subjects. However, the means of the values in groups (b) and (c) were not significantly different. There was a significant positive correlation between the levels of the inhibitor and the urinary Na+ excretion in all subjects. However, there was no correlation between the inhibitor levels and mean arterial pressure. The relevance of these results to the pathophysiology of hypertension in the black African subject is discussed.

Adult↗

Evidence of an endogenous digitalis-like factor in the plasma of patients with acromegaly.

Evidence suggests that plasma-volume expansion leads to the release of a digitalis-like factor, which is thought to act on the renal tubular cells and cause natriuresis. We postulated that this factor might be present in patients with acromegaly (in whom plasma volume is elevated) and might return to normal levels when the disease was treated successfully. We measured the ability of plasma extracts from patients with acromegaly to inhibit the binding of ouabain to the sodium pump in normal red cells and to inhibit the enzymatic activity (sodium-potassium-ATPase) of the sodium pump in membrane preparations from normal kidneys. In 21 patients with active acromegaly, the mean (+/- SE) level of ouabain-binding inhibition (1.56 +/- 0.38) was higher (P less than 0.01) than that in either 11 successfully treated patients (0.18 +/- 0.05) or in 27 normal controls (0.19 +/- 0.03). The inhibition of sodium-potassium-ATPase activity by plasma was also greater in patients with active acromegaly (38.1 +/- 6.8 percent) than in successfully treated patients (18.4 +/- 5.6 percent, P less than 0.05) or controls (21.1 +/- 2.7 percent, P less than 0.05). Significant correlations were found between plasma volume and ouabain-binding inhibition in 23 patients (r = 0.72, P less than 0.01) and sodium-potassium-ATPase inhibition in 19 patients (r = 0.62, P less than 0.01). Pituitary adenomectomy decreased plasma volume and the inhibition by plasma of ouabain binding. We conclude that an endogenous digitalis-like factor is present in the plasma of patients with chronic volume expansion due to acromegaly. These results are consistent with the hypothesis that this natriuretic factor may have a physiologic role in water and sodium homeostasis.

Acromegaly↗

The role of antihypertensive drugs in counteracting adverse influence on large arteries.

Studies in humans have shown that chronic elevation of blood pressure induces early alterations in the large arteries, consisting mainly of increased diameter, increased pulse wave velocity, and decreased arterial compliance. Acute reduction of blood pressure, per se, does not necessarily correct these alterations homogeneously. For instance, cadralazine reduced brachial artery diameter and urapidil decreased pulse wave velocity, without accompanying changes in forearm arterial compliance. In contrast, acebutolol, isosorbide dinitrate, nicardipine, and nitrendipine, for the same acute decrease in blood pressure, improved forearm arterial compliance by a concomitant decrease in pulse wave velocity and increase in arterial diameter. To determine whether or not these vascular effects persist with long-term acebutolol therapy, nine hypertensive patients were treated for a period of 3 months. Forearm hemodynamic and cytosolic free calcium concentrations in platelets were simultaneously assessed before and after treatment. Compared with placebo baseline values, chronic acebutolol therapy significantly decreased mean arterial pressure (p less than 0.01), pulse wave velocity (p less than 0.01), and platelet free calcium concentration (p less than 0.05); forearm arterial compliance was increased (p less than 0.01), but brachial artery diameter did not change. Platelet calcium concentration correlated closely with pulse wave velocity even at constant mean arterial pressure. These findings suggest a relaxant effect of acebutolol on the smooth musculature of large arteries, which is independent of changes in blood pressure and arterial diameter, and possibly mediated by changes in cytosolic calcium levels.

Acebutolol↗

Endogenous digitalis-like compounds in essential and experimental hypertension.

The hypothesis that endogenous digitalis-like compounds might participate in body sodium and water homeostasis have led us to investigate the presence in plasma of compounds interacting with digoxin antibodies in man and rats. The apparent levels of digoxin-equivalents in plasma of control subjects (n = 21) and patients with essential hypertension (n = 48) or end-stage renal failure (n = 13) were 24.7 +/- 3.2, 34.4 +/- 4.4 and 98.7 +/- 17.4 pg/ml, p less than 0.05 and p less than 0.01 respectively. Positive correlations were observed between systolic and diastolic blood pressure and the apparent immunoreactivity of plasma. No relationship was found with the renal Na+ excretion or the plasma renin activity. The apparent digoxin-like immunoreactivity of the plasma was correlated with its ability to inhibit ouabain binding to the erythrocyte Na+ pump and to reduce the renal Na+,K+-ATPase activity. In rats with experimental hypertension, the plasma cross-reactivity with antidigoxin antibodies was also enhanced when compared to control rats (71.6 +/- 10.2 pg/ml, n = 12 and 57.3 +/- 5.0 pg/ml, n = 33 in Na+ loaded rats and in rats with reduced renal mass respectively compared to 43.4 +/- 3.7 pg/ml, n = 36, p less than 0.05). In spontaneously hypertensive rats (SHR), the apparent levels of digoxin- equivalents were higher than that of age-matched WKY normotensive rats. This increase was already present in prehypertensive SHR (3 week-old) (105.8 +/- 12.4 vs 40.0 +/- 6.5 pg/ml, n = 9 and 8, p less than 0.001) and persisted after hypertension has developed (134 +/- 12.6 vs 85 +/- 7.9 pg/ml, n = 7 and 8, p less than 0.005 in 30 week-old rats). The apparent affinity of the erythrocyte Na+,K+ cotransport for intracellular Na+ and the maximal rate of the Na+ pump were correlated with the plasma digoxin-like levels. These results confirm the presence in plasma of compounds possessing some of the functional and structural properties of cardioactive steroids, associated with a rise in blood pressure.

Adult↗