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N Senn

Publications and source records attributed to N Senn.

14 recordsLinked to original sources
PubMed1994

Erythrocyte ion transport as indicator of sensitivity to antihypertensive drugs.

Multiple ion transport defects have been characterized in red blood cell membranes from essential hypertensive patients. These seem to be biochemical markers of at least three different types of essential hypertension. A first type is characterized by low pump, low cotransport fluxes in erythrocytes. These hypertensive patients are apparently identical to the salt-sensitive, low-renin hypertensive patients, in whom low pump and cotransport seem to result from the presence of circulating endogenous ouabain-like and bumetanide-like factors. These hypertensive patients are sensitive to diuretic drugs and to vaso-relaxants with salidiuretic activity, as expected from a reduction in plasma volume and circulating levels of endogenous ion transport inhibitors. A second type of essential hypertension is characterized by increased red cell Na+:Li+ countertransport and [Na+, K+, Cl-] cotransport. These hypertensive patients tend to present normal or high plasma renin activity, disorders in lipid metabolism, and left ventricular hypertrophy. Hypertensive patients belonging to this group seem to be resistant to diuretic drugs but sensitive to vasorelaxants. A third type of essential hypertension is characterized by both high membrane sodium leak and high [Na+, K+, Cl-] cotransport in erythrocytes. Hypertensive patients in this group are resistant to diuretics, angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists, and centrally acting drugs.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1993

Opposite effects of cell growth factors and cicletanine sulfate on the sodium-independent [Cl-/HCO3-] exchange in cultured vascular smooth muscle.

Cicletanine sulfate was tested on bicarbonate-dependent pHi changes in cultured vascular smooth muscle (A10 line). Cicletanine sulfate exhibited double reactivity with regard to the cell alkalinization induced by bicarbonate uptake. The analysis of 11 concentration-response curves revealed a high reactivity component (IC50 approximately 3.5 x 10(-8) mol/L) and a weak reactivity component (IC50 approximately 4 x 10(-4) ml/L). Regarding the cell acidification induced by bicarbonate extrusion, cicletanine sulfate exhibited a single high reactivity component (IC50 = 5.9 +/- 2.9 x 10(-7) mol/l; mean +/- SD, n = 7). The high and weak reactivity sites were both sensitive to DIDS. Analysis of the data strongly suggested that the highly reactive site corresponds to a sodium-independent (Cl-/HCO3-] exchanger, which catalyzes net bicarbonate efflux, and the weak-reactivity site corresponds to the inwardly directed sodium-dependent [Cl-/HCO3-] exchanger. Three cell growth factors--epidermal growth factor, arginine-vasopressin, and insulin--were able to stimulate the sodium-independent [Cl-/HCO3-] exchanger in A10 cells. Finally, cicletanine sulfate (30 mumol/L) partially inhibited serum-dependent A10 cell growth. In conclusion, cicletanine sulfate and cell growth factors exert opposite effects (inhibition and stimulation, respectively) on the sodium-independent [Cl-/HCO3-] exchanger in cultured vascular smooth muscle. The effect of cicletanine sulfate on the sodium-independent [Cl-/HCO3-] exchanger may account for the ability of cicletanine to favorably alter vascular pathology in spontaneously hypertensive rat (SHR) models.

Animals↗
PubMed1991

Action of azelastine on intracellular Ca2+ in cultured airway smooth muscle.

Azelastine, a novel antiasthmatic/antiallergic agent, was tested for Ca2+ antagonistic properties in cultured rabbit airway smooth muscle, vascular smooth muscle and cardiocytes. In airway smooth muscle cells, the basal cytosolic free calcium content was 195 +/- 72 nM (mean +/- S.D., n = 18). These basal values were decreased by azelastine with an IC50 value of 1.1 +/- 0.3 x 10(-4) M. Endothelin-1 (10(-7) M) induced a rapid increase in free cytosolic calcium up to 806 +/- 314 nM, which returned to normal levels in 3-5 min. This was fully blocked by azelastine in a concentration-dependent manner, with an IC50 value of 6.7 +/- 2.9 x 10(-5) M. Moreover, azelastine fully blocked histamine-induced calcium mobilization (IC50 = 7 x 10(-5) M). In cultured vascular smooth muscle cells and cardiocytes, azelastine was unable to decrease the basal cytosolic free calcium content or inhibit agonist-induced calcium mobilization. Therefore, at therapeutic levels, a specific, mild inhibition of calcium mobilization in airway smooth muscle may be one component of the antiasthmatic action of azelastine.

Animals↗
PubMed1990

Kinetic study of the Ca2+ pump in erythrocytes from essential hypertensive patients.

Ca2+ pump kinetics were investigated in erythrocytes from 22 essential hypertensive patients and 20 normotensive controls (under initial-rate and steady-state conditions, using Sr2+ as a Ca2+ analogue). The mean value of the apparent dissociation constant for total internal Ca2+ (KCa) was slightly but significantly increased in the hypertensive population (73 +/- 7 versus 55 +/- 3 mumol/l cells, mean +/- s.e.m., P = 0.042 Mann-Whitney U-test). The statistical analysis showed that this was due to six essential hypertensives who exhibited a dissociation constant for Ca2+ that was higher than the upper 95% normal confidence limit (KCa = 116 +/- 7 mumol/l cells), and abnormally high maximal pump rates (7.7 +/- 0.6 versus 5.0 +/- 0.2 mmol/l cells per h in normotensives, P less than 0.001). In addition, the apparent dissociation constant for Ca2+ was inversely correlated with plasma renin activity, although the correlation was only borderline (P = 0.076). In the remaining 16 hypertensive patients, all kinetic parameters of the Ca2+ pump were within the normal range. Finally, a simultaneous study of Na+ transport kinetics suggested that erythrocyte Ca2+ and Na+ transport abnormalities were independent phenomena. Our results do not support the concept that primary hypertension (as a whole entity) is associated with a ubiquitous defect in the plasma membrane Ca2+ pump. However, in some essential hypertensive patients (about 25%) the erythrocyte Ca2+ pump exhibited an apparent decreased affinity for internal Ca2+. A similar defect in vascular smooth muscle may induce a delayed Ca2+ extrusion after the opening of Ca2+ channels, a disturbance likely to be translated into increased vascular reactivity.

Adenosine Triphosphate↗
PubMed1989

Regulation of Na+ and K+ contents in rat thymocytes.

A modified nystatin technique allowed the investigation of the initial rate of Na+ efflux as a function of internal Na+ content under steady-state conditions in rat thymocytes. This kinetic study showed that 1) ouabain-sensitive Na+ efflux as a function of internal Na+ can be adjusted by a three-sites kinetic model, with a maximal pump rate of 581 +/- 79 mmol.l cells-1.h-1 and an apparent dissociation constant for internal Na+ of 10.0 +/- 1.0 mmol/l cells (mean +/- SE of 3 experiments), 2) bumetanide-sensitive Na+ efflux was extremely low compared with the pump efflux (approximately 1%), and 3) ouabain- and bumetanide-resistant Na+ efflux was almost a linear function of internal Na+ content (as expected for a Na+ leak). This "all-pump" mechanism of thymocyte Na+ regulation was confirmed by non-steady-state experiments showing that 1) ouabain induced a rapid net Na+ gain and K+ depletion in fresh thymocytes and completely blocked the recovery of normal cation contents in Na+-loaded-K+-depleted thymocytes, and 2) bumetanide was unable to modify thymocyte Na+ and K+ contents. Na+ extrusion by Na+-loaded thymocytes was unaffected by prostaglandin E2, isoproterenol, or platelet-aggregating factor (PAF) and was slightly impaired in the adult spontaneously hypertensive rat of the Okamoto strain (10% lower rate constant for net Na+ extrusion, P less than 0.05). Concerning cell Na+ regulation, our results do not support the concept that rat thymocytes are more representative of vascular cells than enucleated erythrocytes.

Animals↗
PubMed1989

[Decrease in the regulatory capacity of the calcium pump in a subgroup of essential hypertensive patients].

We developed a new flux technique, useful for the clinical investigation of Ca2+ pump kinetics in intact erythrocytes. The initial rate of Sr2+ efflux (mediated by the Ca2+ pump) was studied as a function of steady state erythrocyte Sr2+ and Ca2+ contents in 22 Caucasian essential hypertensive patients (8 females, 14 males), aged 39-66 years (mean 51) and compared with 20 normotensive control subjects (10 females, 10 males), aged 22-57 years (mean 41). Kinetic analysis of the data (by using a two-sites model) allowed the determination of the apparent dissociation constants for internal Ca2+ (KCa) and for internal Sr2+ (KSr) and the maximal rate of Sr2+ efflux (Vmax). Mean values of these kinetic parameters were slightly increased in the hypertensive population. However, only the increase in KCa reached statistical significance (73 +/- 7 vs 55 +/- 3 mumol/l.cells, Mann-Whitney U test; p = 0.042). Individual analysis of the data showed that 6 essential hypertensives had a KCa higher than the upper normal limit (95 p. 100 confidence limit) of the normotensive group. In addition, mean values of Vmax and KSr were also significantly higher in these six essential hypertensives. In conclusion, about 25 p. 100 of the hypertensive patients had a decreased apparent affinity of the Ca2+ pump for internal Ca2+, which appears to be compensated (in the basal state) by an increased maximal pump rate. A similar abnormality in vascular smooth muscle cells may induce increased contractility by transitory cell Ca2+ retention after the opening of Ca2+ channels.

Adult↗
PubMed1988

[Na+, K+, Cl-]-cotransport function and dysfunction in different forms of primary hypertension.

We investigated the effect of an increase in cell Na+ content on outward and inward unidirectional fluxes catalyzed by the [Na+, K+, Cl-]-cotransport system in human erythrocytes (incubated in Li-Rb media). Erythrocytes with low Na+ content exhibited an uncoupled K+ efflux. The increase in cell Na+ content resulted in a more marked stimulation of outward Na+, K+ than of inward Li+, Rb+ cotransport fluxes (with stoichiometries not very different from one-to-one). These results suggest that in human erythrocytes and in nonepithelial cells with small but outwardly directed electrochemical Cl- gradients, the [Na+, K+, Cl-]-cotransport system may behave as a "second pump" by using the extra energy supplied by an additional net [K+, Cl-] efflux. The [Na+, K+, Cl-]-cotransport system (of vascular cells and/or noradrenergic endings) may play two different roles in primary hypertension: (a) "defective second pump" in some essential hypertensive patients with decreased cotransport affinity for internal Na+ and (b) "compensatory second pump" in other forms of primary hypertension where abnormalities in the Na+, K+ pump or in other ion transport systems may predispose the cell to a defective extrusion of excess cell Na+ content.

Biological Transport↗
PubMed1988

High sensitivity of the Na+, K+-pump of human red blood cells to genins of cardiac glycosides.

1. Four different cardiac glycosides (ouabain, digitoxin, digoxin and gitoxin) and their corresponding genins were tested on Na+, K+-pump fluxes measured under steady-state and initial rate conditions (non equilibrium conditions) in human and rat erythrocytes and in mouse macrophages. 2. In human red cells, Na+, K+-pump fluxes exhibited up to 8 fold higher sensitivity to genins than to glycosides. In addition genins, but not the corresponding glycosides, exhibited double reactivity with regard to the erythrocyte Na+, K+-pump (with the exception of gitoxigenin). A weak reactivity component was similar to the one of the corresponding glycosides (IC50 of about 10(-6) M) and a high reactivity component exhibited IC50 values varying from 0.1 to 0.5 X 10(-6) M for digitoxigenin and ouabagenin respectively. 3. In contrast with human red cells, the initial rate of Na+, K+-pump fluxes in rat erythrocytes and mouse macrophages was less sensitive to genins than to the corresponding cardiac glycosides. 4. Dihydroouabain was 3, 10 and 75 times less active than ouabain in inhibiting the initial rate of Na+, K+-pump fluxes in human and rat erythrocytes and in mouse macrophages respectively. 5. In conclusion, Na+, K+-pump fluxes measured under initial rate conditions in human erythrocytes exhibit an unusually high sensitivity to genins of cardiac glycosides. This property probably results from the fast binding rate constants of genins and the slow association rates of glycosides to human red cells.

Animals↗
PubMed1988

[Antihypertensive effects of captopril, hydrochlorothiazide, alone or in combination, with different categories of essential hypertensive patients].

30 male essential hypertensive patients were submitted to a "washout" of 8 days and at D (0) divided into two groups receiving 25 mg/day of Hydrochlorothiazide or 50 mg/day of Captopril. At D (45) the treatment was crossed, at D (90) all the patients received both drugs and at D (135) the treatment was stopped. According to the antihypertensive response, the patients were divided into: (i) R: responders, PAS (systolic arterial pressure) less than or equal to 140 mmHg and PAD (diastolic) less than or equal to 90 mmHg, ii) M: moderate responders, 140 less than PAS less than or equal to 160 mmHg and/or 90 less than PAD less than or equal to 100 mmHg and (iii) F: therapeutic failure, PAS greater than 160 mmHg and/or PAD greater than 100. A parallel study was carried out in erythrocytes. At D (0), 40 ml of blood were drawn and the hypertensive patients were classified in: (i) (+)NaT patients, 19 patients having one or more of the following erythrocyte abnormalities: increased Na+: Li+ counter-transport, increased Na+ leak, decreased affinity of the Na+, K+-pump and/or Na+, K+ cotransport system for internal Na+ and (ii) (-)NaT patients, 11 patients without the above erythrocyte abnormalities. During monotherapy treatment (with captopril or hydrochlorothiazide) 8 out of 11 (-)NaT patients normalized blood pressure (responders) against only 5 out of 19 (+)NaT patients (p less than 0.05, chi 2 test).(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Transport↗
PubMed1986

Inhibition of the erythrocyte Na+, K+-pump by mammalian lignans.

Several mammalian lignans, particularly enterolactone, 3-oxy-methyl enterolactone and prestegane B are able to inhibit Na+, K+-pump activity in human red cells with IC50 of about 1 mM. The inhibition of Na+, K+-pump activity by mammalian lignans have the following properties: the IC50 for ouabain remains unchanged suggesting a noncompetitive inhibition. The apparent affinity for internal Na+ and maximal rate of cation translocation are both diminished. The above inhibition of the Na+, K+-pump was obtained at doses 2-3 orders of magnitude higher than those required for ouabain. However we cannot exclude that a glycosyl- (and/or butenolide)-derivative of enterolactone could be one endogenous ouabain-like factor.

Cross Reactions↗
PubMed1986

Endogenous lignans--a potential endogenous digitalis.

Lignans are natural products formed by oxidative dimerization of monomeric phenols. A few were recently discovered in human and animal urine, semen and blood plasma but their role has never been assessed. We investigated the actions of mammalian lignans obtained by total synthesis or extracted from the urine of pregnant women, on the Na+K+-pump in human red cells. Some of the tested lignans (enterolactone, prestegane B and 3-O-methylenterolactone) inhibited the Na+K+-pump activity with IC50 ranging from 5 to 9 X 10(-4) mol/l. The IC50 for ouabain (7 X 10(-7) mol/l) was not modified by addition of lignans suggesting a non-competitive inhibition.

4-Butyrolactone↗
PubMed1986

[Mammalian lignans: possible involvement in endogenous digitalis activity].

Lignans are natural products, some of which were recently discovered in animal urines, semen and blood plasma. We investigated the actions of animal lignans obtained by total synthesis or extracted from urines of pregnant women on Na+, K+-ATPase in human red cells and human and guinea-pig heart cell membranes. Some of the tested lignans (enterolactone, prestegane B and 3-O-methyl enterolactone) inhibited Na+, K+-pump activity in human red cells with IC50 ranging from 5 to 9 X 10(-4) M. The IC50 for ouabain (7 X 10(-7) M) was not modified by addition of lignans. Enterolactone inhibited Na+, K+-ATPase activity in human and guinea pig heart membranes. It also displaced [3H]-ouabain binding from human heart with IC50 = 1.5 X 10(-4) M. The apparent dissociation rate constants (kd) of [3H]-ouabain were not different in presence of digoxin or enterolactone. Enterolactone exhibited a poor cross reactivity against antidigoxin antibodies. The aglycones of the lignans studied here were slight inhibitors of the Na+, K+-ATPase. However, we cannot exclude that a glycosyl- (and/or butenolide-) derivative of enterolactone could be one "endogenous ouabain-like" factor.

Animals↗
PubMed1985

[Acute effects of ethanol on the performance and metabolism of the isolated working heart, both normal and failing].

The direct effects of ethanol on cardiac contractility are controversial, probably because of methodological reasons in relation to the choice of appropriate experimental models. We studied the direct effects of 1, 2, 5 and 10 g/l ethanol on myocardial performance and metabolism in the isolated perfused working guinea-pig heart. In the normal heart ethanol induced a dose-dependent, fully reversible depression of cardiac contractility without significant changes of heart rate or cardiac metabolism. In the post-anoxic failing heart this effect was more pronounced. Ethanol had no arrhythmogenic effect even at high concentrations. Finally, it had no measurable effect on anoxic-induced alterations or post-anoxic recovery after a period of 20 minutes of anoxic perfusion. However anoxic-induced lactate production was decreased in hearts pretreated with 10 g/l ethanol. These results demonstrate the direct negative inotropic effect and the lack of chronotropic effect of ethanol. They suggest the lack of effect on excitability. The mechanism of the negative inotropic effect does not seem to be metabolically related since cardiac oxygen consumption and lactate production remained unaltered.

Animals↗