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Biomedical subjects

A Pletscher

Publications and source records attributed to A Pletscher.

At least 37 records · Page 2Linked to original sources
PubMed1988

Low-density lipoprotein enhances platelet activation in parallel with the height of blood pressure.

The platelet-activating effect of low-density lipoprotein, ADP and collagen was investigated in 45 essential hypertensive patients (27 men, 18 women) and 45 healthy normotensive subjects strictly matched for age and sex. No differences in mean values were found between essential hypertensive and normotensive subjects. However, in essential hypertensive patients platelet sensitivity to low-density lipoprotein correlated positively whereas ADP and collagen correlated negatively with blood pressure (P less than 0.05). Diminished platelet sensitivity to ADP and collagen may reflect receptor desensitization. The pressure-dependent increase in platelet response to low-density lipoprotein possibly contributes to enhanced thrombo-embolic complications and platelet-mediated vasoconstriction as well as to low-density lipoprotein-related vascular damage in essential hypertension.

Adenosine Diphosphate↗
PubMed1988

Serotonin metabolism and age-related effects of antihypertensive therapy with ketanserin.

Concentrations of serotonin and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in platelet rich plasma, the urinary 5-HIAA excretion rate, and serotonin-induced platelet aggregation were measured in 17 patients with essential hypertension before, and at the end of, 8 weeks of oral ketanserin therapy at 20 to 40 mg twice daily. Ketanserin lowered systolic and diastolic blood pressure (p less than 0.01) and led to a reduction of serotonin concentration in platelet rich plasma in all patients (p = 0.05), as well as a decrease in 5-HIAA excretion rates in patients older than 55 years (p less than 0.05). Changes in 5-HIAA concentration in platelet rich plasma correlated with the fall in diastolic blood pressure (r = 0.67, p less than 0.05). Serotonin-induced platelet aggregation was inhibited by ketanserin (p less than 0.05), and this was more pronounced in older patients. Thus, antihypertensive therapy with ketanserin reduced platelet aggregation and serotonin metabolism in relation to the age of patients, and this may contribute to the reduction of their elevated rates of thromboembolic complications.

Adult↗
PubMed1987

The 5-hydroxytryptamine system of blood platelets: physiology and pathophysiology.

The 5-hydroxytryptamine (5HT)-system of human blood platelets consists of a relatively specific uptake mechanism for 5HT at the plasma membrane, intracellular storage organelles (dense bodies), a metabolizing enzyme (monoaminoxidase B) and a 5HT2-receptor whose stimulation leads to activation of the phosphatidylinositide turnover, a rise in free cytoplasmic Ca2+, phosphorylation of proteins and a shape change reaction. There is neither a relevant 5HT-biosynthesis nor a marked physiological 5HT-turnover in platelets. Under physiological conditions the platelet 5HT-system may have a role as a scavenger for free extracellular 5HT and in hemostasis. Disturbances which have been described in pathophysiological states include impairment of 5HT-uptake (hypertension, migraine), impairment of 5HT-storage (storage pool deficiencies, thromboembolic disorders, hypertension) and increased sensitivity to activating agents like 5HT (cardiovascular disorders, diabetes). Besides their role in physiology and pathophysiology platelets may be useful partial models for vascular smooth muscle cells.

Blood Platelets↗
PubMed1986

Interaction of vasopressin with human blood platelets: dependency on Mg2+.

Arginine-vasopressin (AVP) in the presence of Mg2+ but not in the absence of bivalent cations led to accumulation of [32P]-phosphatidic acid [( 32P]-PA) in human blood platelets. Mg2+ also enhanced the specific binding of [3H]-AVP to intact platelets. The concentrations of the cation which enabled AVP to cause half maximal rise of [32P]-PA and those inducing half maximal [3H]-AVP-binding were of the same order. It is concluded that the stimulation of phosphatidyl inositide breakdown by AVP in presence of Mg2+ is at least partially due to a Mg2+-induced enhancement of specific AVP-binding to the platelet membranes.

Arginine Vasopressin↗
PubMed1986

Smoking-induced increases in plasma vasopressin and reduced platelet hormone sensitivity.

Cigarette smoking is a major risk for coronary atherosclerosis, but the mechanism of this is still unclear. The present study demonstrates that smoking produces a variable increase in plasma vasopressin concentration but that sensitivity of platelets to this elevated endogenous vasopressin release is blunted. This suggests that cigarette smoking contributes to atherosclerosis through the vascular effects of the hormones whose release it stimulates rather than by platelet activation. The mechanism for this blunted responsiveness to vasopressin was also investigated in vitro. The rise in intracellular free calcium concentration of platelets was markedly reduced following a second administration of vasopressin, whereas the in vitro shape change response was usually unaltered and could only be reduced with specific procedures for platelet preparation. This suggests that only a small increase of intracellular free calcium is necessary for a complete shape change response induced by vasopressin. The results indicate that the shape change is mediated by an increase in intracellular free calcium which is independent from the phosphoinositol pathway and the calcium is released from intracellular pools other than by those activated by serotonin or thrombin.

Adult↗
PubMed1985

Verapamil, an antagonist at 5-hydroxytryptamine receptors of human blood platelets.

In human blood platelets verapamil and D600 (2-methoxyverapamil) in therapeutic concentrations inhibited the shape change reaction induced by 5-hydroxytryptamine (5HT) but not that induced by ADP. The N-methylated derivatives (D575 and D890) had much less effect. The inhibitory action of verapamil was independent of external Ca2+. Nitrendipine and diltiazem (20 microM) had no effect on the 5HT- and the ADP-induced shape change reactions. Since both these shape change reactions are mediated by a rise in cytoplasmic free Ca2+, it is concluded that the inhibition of the 5HT effect by verapamil and D600 was not due to their interference with calcium channels but rather to an antagonistic action on 5HT2-receptors. This view is supported by the finding that verapamil but not D575 competed with [3H]ketanserin and [3H]spiroperidol for their specific binding sites on membranes of rat cerebral cortex.

Adenosine Diphosphate↗
PubMed1985

Vasopressin-induced activation of human blood platelets: prominent role of Mg2+.

Arginine-vasopressin (AVP) caused a marked shape change reaction and rise in [Ca2+]i in human blood platelets only when the extracellular buffer contained Mg2+ or Ca2+. At physiological concentrations of the cations the potency of AVP was higher in the presence of Mg2+ than of Ca2+. The amplitude of the shape change reaction was also greater with Mg2+ than with Ca2+, although the [Ca2+]i-rise was slightly more marked with extracellular Ca2+. The concentration of Mg2+ at which AVP showed half of its maximal effects was below the physiological plasma level of the cation, whereas the corresponding value for Ca2+ was higher. Addition of Ca2+ to the Mg2+ containing medium did not further enhance the action of AVP on platelet shape. In platelet-rich plasma the potency and efficacy of AVP in causing a shape change were similar in the presence and absence of EGTA, whereas with EDTA in the medium AVP had no effect. In conclusion, Mg2+ has an essential physiological role in AVP-induced platelet activation, which is brought about partly by release of intracellular calcium and partly by some other intracellular mechanism.

Arginine Vasopressin↗
PubMed1985

Rapid intracellular release of calcium in human platelets by stimulation of 5-HT2-receptors.

The concentration of intracellular free Ca2+ ( [Ca2+]i) in human blood platelets was measured by use of the fluorescent probe quin-2. 5-Hydroxytryptamine (5-HT) caused a rapid increase of [Ca2+]i in the presence or absence of Ca2+ in the medium. The [Ca2+]i-rise was less marked in the absence of Ca2+ and could be antagonized by 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate-hydrochloride (TMB-8), an inhibitor of calcium release from internal stores. 5-HT induced a shape change reaction in the presence or absence of extracellular Ca2+, but the pEC50 of 5-HT was slightly higher in the presence of the cation. Shape change reaction and [Ca2+]i-rise showed similar time courses. Various 5-HT-agonists caused a rise of [Ca2+]i, whereas 5-HT-antagonists, but not the 5-HT-uptake inhibitor desmethylimipramine and the alpha 2-adrenoceptor antagonist yohimbine, counteracted the 5-HT-induced rise of the cation in a stereospecific manner. The antagonists were more potent than the agonists. The orders of potencies of the drugs affecting [Ca2+]i and platelet shape were similar. It is concluded that stimulation of 5-HT2-receptors of platelets causes a rapid release of intracellular calcium which, by activation of the contractile system, mediates the shape change reaction.

Aminoquinolines↗
PubMed1985

Activation of human blood platelets by arginine-vasopressin. Role of bivalent cations.

Arginine-vasopressin caused platelet activation, i.e., a shape change reaction and a rise in intracellular free Ca2+ ([Ca2+]i) only in the presence of certain bivalent cations. The EC50 of arginine-vasopressin (concentration causing half-maximal shape change) decreased with rising concentrations of Mn2+, Mg2+, or Ca2+ in the medium, but was at least an order higher with Ca2+ than with Mn2+ or Mg2+. The EC50 of the active bivalent cations (concentrations enabling 100 nM arginine-vasopressin to exert half-maximal shape change and rise in [Ca2+]i) varied with the individual cations, being by far the highest for Ca2+. The KD of [3H]arginine-vasopressin binding to platelet membranes and intact platelets markedly decreased when extracellular Mg2+ or Mn2+ were present, and the KD values were inversely related to the concentration of the cations. Ca2+ also lowered the KD values; however, the effect was less marked than that of Mg2+ or Mn2+ and, in physiological conditions, significant only in intact platelets. Vasopressin-1 antagonists counteracted arginine-vasopressin binding and the shape change reaction and [Ca2+]i rise induced by arginine-vasopressin. In the presence of Mn2+ in the medium, administration of arginine-vasopressin led to quenching of the intracellular fluorescence of 2-methyl-6-methoxy-8-nitroquinoline-loaded platelets, possibly due to influx of Mn2+. In conclusion, the dependency of the arginine-vasopressin-induced platelet activation on bivalent cations is at least partly due to an enhancement by these cations of the affinity of the vasopressin-1 receptor for arginine-vasopressin. Thereby, under physiological conditions, Mg2+ seems to be of primary importance. Other mechanisms may be involved, too, e.g., an enhancement by arginine-vasopressin of the influx of bivalent cations into the platelets.

Aminoquinolines↗
PubMed1984

Ca2+ as messenger of 5HT2-receptor stimulation in human blood platelets.

In blood platelets of man, both 5-hydroxytryptamine (5HT) and 80 nM of the Ca2+-ionophore A23187 led to rapid shape change reactions which were inhibited by prostaglandin E1 (PGE1), forskolin, 2-methyl-6-methoxy-8-nitroquinoline ( quin2 ) and chlortetracycline. The IC50-values of the inhibitors were similar in the 5HT- and the A23187-experiments. Higher amounts of A23187 abolished the inhibitory actions of PGE1 and forskolin. Furthermore, 5HT and A23187 enhanced adrenaline-induced platelet aggregation their effects showing similar time dependence. Ketanserin, an antagonist of 5HT2 -receptors, and 8-(N,N-diethyl-amino)octyl-3,4,5-trimethoxybenzoate (TMB-8), an intracellular Ca2+-antagonist, counteracted the effects of 5HT much more than those of A23187, whereas acetylsalicylate and indomethacin did not influence the actions of either 5HT or A23187. In addition, 5HT caused a concentration-dependent rise of intracellular free Ca2+ in platelets which was counteracted by ketanserin. PGE1 and forskolin reduced the resting Ca2+-levels. 5HT did not affect either the basal or the PGE1-stimulated activity of adenylate cyclase, whereas the Ca2+-ionophore A23187 slightly raised the basal activity of the enzyme. In conclusion, the functional effects of 5HT2 -receptor stimulation in human blood platelets (shape change reaction and enhancement of adrenaline aggregation) seem to be mediated by a rise of intracellular free Ca2+.

Adenylyl Cyclases↗
PubMed1983

Solubilization of imipramine-binding protein from human blood platelets.

Various procedures for the solubilization of the imipramine-binding protein (IBP) of human platelets were compared. An IBP of a molecular weight of 300 000-400 000, as determined by exclusion chromatography on Sepharose 6B, was obtained with high amounts of digitonin and with lysolecithin. With smaller amounts of digitonin the molecular weight varied between more than 1 million and about 550 000 depending on the batch of detergent. The KD values and the IC50 values of drugs inhibiting imipramine binding were similar in the soluble preparation and in intact membranes. CHAPS and CHAPSO, even in high amounts, yielded solubilized IBP of high molecular weight (greater than 1 million). Membrane preparations of human platelets solubilized with high amounts of digitonin and with lysolecithin would therefore seem to be the most suitable for further purification of IBP.

Blood Platelets↗
PubMed1983

The 5-hydroxytryptamine receptor of blood platelets.

Blood platelets show specific, high affinity binding of 3H-5-hydroxytryptamine, 3H-ketanserin and 3H-D-lysergic acid diethylamide. 5-HT-antagonists are considerably more potent than agonists regarding both the displacement of specifically bound 3H-ketanserin and the shape change reaction mediated by the 5-HT-receptor. The latter depends on a rise of free intracellular Ca2+. The binding site for 3H-ketanserin and the site at which the 5-HT-induced shape change is triggered show the characteristics of a 5-HT2-receptor whose intracellular mediator seems to be Ca2+. The 5-HT2-receptor of platelets may be used as a partial model for that in neurons; however, it remains to be elucidated whether Ca2% is a mediator of the latter.

Animals↗
PubMed1983

Storage of biogenic amines in guinea-pig brain synaptosomes: influence of proton gradient and membrane potential.

1 The effects of K(+), NaCN and the ionophores monensin, nonactin and carbonyl-cyanide-p-trifluoro-methoxyphenylhydrazone (FCCP) on the contents of [(3)H]-5-hydroxytryptamine ([(3)H]-5-HT), [(3)H]-dopamine and [(3)H]-noradrenaline ([(3)H]-NA) in guinea-pig synaptosomes preloaded with these amines were measured.2 In the presence of Ca(2+), K(+) markedly reduced the amine content of the synaptosomes, indicating an acceleration of spontaneous amine release. In the absence of Ca(2+), K(+) had much less effect.3 Monensin, nonactin and FCCP caused a release of all the three labelled amines. This release was considerably faster and more marked than that induced by K(+) and showed no dependence on Ca(2+). The ionophores did not release lactate-dehydrogenase from synaptosomes.4 NaCN, a blocker of oxidative energy production, did not enhance the spontaneous release of [(3)H]-5-HT nor did it influence the monensin-induced release of [(3)H]-5-HT.5 It is concluded that (a) the intragranular storage of 5-HT, dopamine and NA is dependent on the maintenance of a pH-gradient across the granular membrane as well as on the granular membrane potential; (b) the ionophores cause a non-exocytotic release of granular amines, and (c) blood platelets are partial models for aminergic brain neurones as far as intragranular amine storage is concerned.

Animals↗