Platelet hypoaggregability in hereditary hypertriglyceridemic rats: relation to plasma triglycerides.

To define better the relationships between lipid metabolism disturbances and platelet aggregation we have examined these parameters in hereditary hypertriglyceridemic and control Lewis rats. Hereditary hypertriglyceridemic rats are hypertensive and have high plasma triglycerides but not elevated plasma total cholesterol. In the present study, we have demonstrated that platelets from hereditary hypertriglyceridemic rats have lowered initial rate and maximal aggregation after stimulation with thrombin or ADP in comparison with controls. These two strains did not differ significantly in the inhibition of platelet aggregation by the thromboxane A2 receptor inhibitor, SQ 29 548. In hereditary hypertriglyceridemic rats, the thrombin response, as well as the contribution of the thromboxane A2-sensitive pathway, were positively associated with the plasma level of triglycerides. Similar trend was found in Lewis rats. However, the slopes of these relationships were reduced in hereditary hypertriglyceridemic rats. These alterations of the aggregatory responses in hereditary hypertriglyceridemic rats were independent of blood pressure and plasma cholesterol level. In conclusion, our results showed a clear-cut platelet hypoaggregability to both thrombin and ADP in hypertensive hypertriglyceridemic rats. This hypoaggregability was not due to an impaired function of the thromboxane A2 pathway but could be connected with disturbances of lipid metabolism.

Platelet aggregation and in vivo shear forces.

Haemodynamic shear forces have been reported to exert direct and indirect effects on platelet reactivity. In vitro, they activate platelets leading to spontaneous or facilitated aggregation. In vivo, they stimulate the production of endothelium-derived anti-aggregatory agents. This study was designed to evaluate in hypertensive patients, before and after antihypertensive treatment, the possible role of these haemodynamic forces, determined at the brachial artery level on the ex vivo platelet aggregatory response to ADP and collagen. Platelet reactivity, evaluated by EC50 for ADP and collagen, was found to be related to blood velocity, shear rate and shear stress (p < 0.01 for each). These inverse correlations of platelet aggregation with stress levels did not depend on age, body mass index, mean blood pressure, serum cholesterol and triglycerides or haematocrit. They were also independent of platelet cytosolic Ca2+ and cyclic AMP. The changes in shear forces and in aggregatory responses to ADP and collagen induced by nitrendipine treatment for 6 months remained negatively correlated, confirming the relationships existing between haemodynamic shear forces and platelet reactivity. These results indicate that the shear antiaggregant effects, likely mediated by flow-dependent endothelium-derived factors, prevail over its direct platelet aggregating effects.

Biochemical and functional alterations associated with hypercholesterolemia in platelets from hypertensive patients.

Hypercholesterolemia and hypertension are two of the major risk factors associated with increased atherosclerotic vascular disease. An abnormal platelet function is one of the mechanisms proposed to participate in atherogenesis. This study was undertaken to find out whether hypercholesterolemia in hypertensive patients can change platelet lipid composition and reactivity. Twenty-nine untreated hypertensive patients were distributed into 3 age, body mass index and blood pressure-matched groups according to their plasma cholesterol levels (normal, borderline or elevated, group NC, BC and HC respectively). Their platelet lipid composition, cytosolic Ca2+ concentration, cyclic AMP content and aggregating response to ADP and collagen were determined. Platelet from group HC patients were characterized by reduced cyclic AMP content (evaluated in the presence and absence of a platelet phosphodiesterase inhibitor) and aggregating responses to ADP and collagen, increased palmitic acid content and decreased arachidonic, eicosapentaenoic and docosatetraenoic and pentaenoic acid content, resulting in a lowered polyunsaturated to saturated fatty acid ratio (P less than 0.001). In contrast, platelet cytosolic Ca2+ concentration, DPH steady-state anisotropy and cholesterol to phospholipid molar ratio were not significantly changed. This indicates that hypercholesterolemia is accompanied in hypertensive patients by marked changes in platelet fatty acid composition, cyclic AMP content and response to aggregating agents. These changes, which clearly differ from those induced by in vitro cholesterol loading, could reflect not only the balance between LDL and HDL stimulation but also an adaptation to hemodynamic perturbations.

Hypercholesterolemia modulates the effects of nitrendipine on blood pressure and platelet function in essential hypertension.

Both marked hypercholesterolemia and severe hypertension have been reported to be associated with an enhanced sensitivity of blood platelets to activating agents. To investigate a possible mutual synergistic effect of moderate hypercholesterolemia and mild hypertension on platelet reactivity, we studied in 29 patients the response to aggregating agents, ADP and collagen, and the intracellular cyclic AMP content and cytosolic Ca2+ concentration that participate, respectively, as inhibitory and stimulatory mediators in platelet responses. When compared to age- and blood pressure-matched patients with normal or slightly elevated plasma cholesterol, the patients with total platelet cholesterol higher than 6.4 mM were characterized by a decreased response to collagen and ADP (14.5 +/- 3.0 vs. 23.8 +/- 2.0 a.u. and 17.7 +/- 4.5 vs. 26.9 +/- 2.7 a.u., respectively), a tendency to a reduced cAMP content both in the basal state and after phosphodiesterase inhibition by Ro-15 2041 (2.83 +/- 0.18 vs. 3.26 +/- 0.22 mumol/10(8) cells and 4.57 +/- 0.29 vs. 5.38 +/- 0.36 mumol/10(8) cells, respectively), and no change in cytosolic Ca2+ concentration (190 +/- 11 vs. 203 +/- 13 nM). After a chronic treatment with nitrendipine (20 mg/day for 6 months), blood pressure, platelet [Ca2+]i and cAMP content decreased in the patients with normal or moderately elevated hypercholesterolemia (p less than 0.001, less than 0.001, and less than 0.05, respectively), but these effects were attenuated or absent in the patients with higher hypercholesterolemia. Plasma lipids and the platelet-aggregating response to ADP and collagen were unchanged by this long-term nitrendipine treatment in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

Effects of adrenaline on ionic equilibria in red blood cells of rainbow trout (Salmo gairdneri).

Effects of adrenaline on the equilibrium distributions of Na(+) , K(+) , H(+) , Cl(-) , and H2O across the cell membrane of rainbow trout (Salmo gairdneri) erythrocytes were determinedin vitro, as a function of P CO2 (1.76-7.77 torr). CO2-carrying capacity of the blood was also examined. Plasma catecholamine concentrations inunanaesthetized, unrestrained trout were 3.1 nM adrenaline and 1.2 nM noradrenaline. Elevation of the plasma adrenaline concentrationin vitro to 4.6 × 10(3) nM resulted in net gains of Na(+) , Cl(-) and H2O by red cells, a net loss of H(+) from red cells, and a pronounced red cell swelling. Adrenaline also reduced the CO2-carrying capacity of trout bloodin vitro. The magnitudes of these effects increased with PCO2 and, thus, were sensitive to blood HCO3 (-) concentrations. The distribution of K(+) between red cells and plasma was unaffected by adrenaline. Adrenergic-mediated ion movements and red cell swelling were sensitive to both propranolol and SITS. These results are consistent with the symport NaCl uptake model for adrenergic-mediated swelling of Baroinet al. (1984). The adrenergic response of fish erythrocytes may function to ameliorate the effects of blood acidoses on O2-carrying capacity by maintaining red cell pH in the face of a decrease in plasma pH.

Effects of saltwater adaptation on serotonin metabolite concentrations in the cerebrospinal fluid of rainbow trout (Salmo gairdneri).

A new procedure was applied to rainbow trout for collecting cerebrospinal fluid (CSF). CSF was withdrawn continuously from the third ventricle at a flow rate of 0.7 microliter/min for up to 6 hr. The 5-HIAA concentrations in trout CSF are temperature-dependent and decrease exponentially after pargyline injection. The computed half-life of 5-HIAA production in CSF is 78 min at 15 degrees C. 5-HIAA concentrations in CSF are considered to reflect serotonin (5-HT) metabolism. The 5-HIAA content in the CSF of trout held in freshwater for several weeks is significantly higher than in trout held in either 1.6 or 3.0% saltwater while sodium content only exhibits a very slight change in the CSF of trout held in 3.0% saltwater. It is hypothesized that 5-HT could participate in the neurally-mediated adaptation to various osmotic conditions.