Effects of angiotensin II and endothelin-1 on platelet aggregation and cytosolic pH and free Ca2+ concentrations in essential hypertension.

Abstract

The aims of this study were to determine the relations between platelet free calcium concentrations ([Ca 2+ D, intracellular pH (pH,), 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 [Ca 3+ ]| and pH, 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 [Ca 2+ ], (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 [ ]; 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 pH, through endothelin A-receptors (effect blocked by the specific antagonist BQ-123) but had no significant effect on lCa 2+ ], or aggregation. However, endothelin-1 blunted thrombin-induced platelet aggregation in normotensive subjects but not in hypertensive patients. In conclusion, increased Ang H-stimulated [Ca 2+ j| and pH, in platelets of essential hypertensive patients may be associated with increased aggregatory responses. The stimulatory effect of endothelin-1 on pH, but not on [Ca 2+ ], or aggregation suggests that in platelets endothelin-induced signaling pathways other than phospholipase C may be involved. The significant correlations between platelet aggregation, [Ca 2+ L, pH,, and blood pressure may suggest a possible link between altered platelet cation status and platelet function in hypertension. (Hypertension. 1993;22:853-862 12 Cytosolic free calcium regulates many cellular processes, including tone, contractility, and reactivity in vascular smooth muscle cells and activation, aggregation, and adhesion in platelets.

Effects of Antihypertensive Treatment on Platelet Function in Essential Hypertension.

“…Physiological concentra- tions of angiotensin II (10-11 mol) were observed to enhance adrenaline-induced platelet aggregation, while a high concentration (10-7 mol) had an inhibitory effect on platelet aggregation (24). Platelet aggregation induced by thrombin was enhanced in the presence of 10_9 mol angiotensin II (25). These findings suggest that the elevation of circulating angiotensin II may induce platelet activation in vivo and ACEI may inhibit platelet activation by reducing circulating angiotensin II.…”

Angiotensin II can induce and potentiate shape change in human platelets: effect of losartan

“…For example, there is evidence of an increased effect of Ang II on platelet-free calcium concentrations and intracellular pH in untreated hypertensives. 6 Other studies showed that there was an upregulation of AT 1 receptor mRNA in platelets of patients with primary aldosteronism and renovascular hypertension. 26 The number of Ang II binding sites also differs in the platelets of pregnant women with and without hypertension.…”

“…[1][2][3][4][5] Human platelets have Ang II receptors (AT 1 ) and this hormone is known to activate platelets. 6 However, Ang II has not previously been shown to induce platelet shape change (PSC), an early phase of platelet activation, which may be associated with the release of intra-platelet growth factors. [7][8][9][10][11][12][13][14][15][16] Inhibiting PSC is important because this is an aspirin-resistant phase of platelet activation.…”

Effects of aliskiren, a renin inhibitor, on biomarkers of platelet activity, coagulation and fibrinolysis in subjects with multiple risk factors for vascular disease

“…33 Angiotensin II stimulation significantly increases intracellular platelet calcium concentrations, intracellular pH and thrombin-induced platelet aggregation in untreated hypertensive as well as normotensive individuals. 34 The release of angiotensin II following pro-aggregatory stimulation suggests that this may be one of the mechanisms through which platelets can locally modulate vascular tone and promote atherogenesis. 35 The infusion of angiotensin II increased plasma b-thromboglobulin levels, reflecting a-granule secretion and expression of P-selectin.…”