Effects of Anglotensin II and Endothelin-1 on Platelet Aggregation and Cytosolic pH and Free Ca2+ Concentrations In Essential Hypertension

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Abstract

The aims of this study were to determine the relations between platelet free calcium concentrations ([Ca2+1), intracellular pH (pH1), and aggregation and to assess the effects of angiotensin II (Ang II) and endothelin-1 on these platelet parameters in normotensive subjects and hypertensive patients. Seventeen normotensive subjects, 25 untreated hypertensive patients, and 34 treated hypertensive patients were studied. Platelet cytosolic free [Ca2+]1 and pH1 were measured spectrofluorometrically using specific fluorescent probes (fura 2-AM and BCECF-AM, respectively) in unstimulated and Ang II- and endothelin-1-stimulated platelets. Aggregation was measured by a turbidometric technique. Basal [Ca2+]1 (141±11 nmol/L) and pH (7.16±0.01) were higher (P<.05) in the untreated hypertensive group compared with the normotensive (118±9 nmol/L, 7.11±0.01, respectively) and treated hypertensive (121±11 nmol/L, 7.12±0.01, respectively) groups. In the combined normotensive and hypertensive groups, there were significant correlations between [Ca2+]1 and mean arterial pressure (r=.7S, P<.01), pH1 and mean arterial pressure (r=.72, P<.01), [Ca2+]1 and pH1 (r=.71, P<.01), [Ca2+]1 and aggregation (r=.69, P<.02), and pH1 and aggregation (r=.56, P<.05). Ang II stimulation significantly increased [Ca2+]1 and pH1 in the untreated hypertensive and normotensive groups. The net change in [Ca2+]1 induced by Ang II was significantly higher (P<.05) in the untreated hypertensive group compared with the other groups (67±6 nmol/L for the untreated hypertensive group versus 54±5 and 29±8 nmol/L for the normotensive and treated hypertensive groups, respectively). In the presence of Ang II, thrombin-induced aggregatory responses were increased in all three groups, but the maximal response was significantly higher in the untreated hypertensive group compared with the other groups (P<.05). Endothelin-1 increased pH1 through endothelin A-receptors (effect blocked by the specific antagonist BQ-123) but had no significant effect on [Ca2+]1 or aggregation. However, endothelin-1 blunted thrombin-induced platelet aggregation in normotensive subjects but not in hypertensive patients. In conclusion, increased Ang II-stimulated [Ca2+]1 and pH1 in platelets of essential hypertensive patients may be associated with increased aggregatory responses. The stimulatory effect of endothelin-1 on pH1 but not on [Ca2+]1 or aggregation suggests that in platelets endothelin-induced signaling pathways other than phospholipase C may be involved. The significant correlations between platelet aggregation, [Ca2+]1, pH1, and blood pressure may suggest a possible link between altered platelet cation status and platelet function in hypertension.

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