Platelet lipoxygenase inhibitors attenuate thrombin- and thromboxane mimetic-induced intracellular calcium mobilization and platelet aggregation.

Platelets metabolize arachidonic acid via cyclooxygenase and lipoxygenase (LO) enzymatic pathways. Although platelets produce large amounts of arachidonic acid metabolites via the LO pathway, little is known regarding the physiological significance of these products. We used three structurally dissimilar LO inhibitors, 5,8,11-eicosatriynoic acid (ETI), baicalein and phenidone, and found that LO inhibition attenuated thrombin- and U46619 (a thromboxane mimetic)-induced increases of platelet intracellular calcium ([Ca++]i) in washed human platelets. LO inhibitors also reduced platelet aggregation induced by thrombin and U46619. The effect of ETI on reducing the thrombin-induced [Ca++]i elevation persisted even when cation channels were blocked, suggesting that LO inhibitors modify release of Ca from intracellular stores. Stimulating endogenous LO product formation potentiated thrombin-induced [Ca++]i responses and aggregation, and these effects were eliminated by ETI. ETI did not alter inositol 1,4,5-trisphosphate production in stimulated platelets, but increased platelet cyclic AMP production in thrombin- or forskolin-stimulated platelets. These results suggest that LO products are regulators of platelet [Ca++]i mobilization and aggregation in response to some agonists, and that LO inhibitors may work in part by modifying platelet cyclic AMP metabolism.

Dietary NaCl restriction deteriorates oral glucose tolerance in hypertensive patients with impairment of glucose tolerance.

This study investigated whether the change of glycemic response to oral glucose loading with an increase of dietary NaCl intake is different between salt-sensitive and salt-resistant groups, or whether it is related to glucose tolerance on a low NaCl diet independent of salt sensitivity. The plasma glucose and insulin response to 75 g oral glucose intake was assessed on low (34 mmol/day) and high (342 mmol/day) NaCl diets in 31 patients with essential hypertension, and the area under the curve for both variables (AUCglu and AUCins) was calculated. The data on the high NaCl diet were corrected for change in hematocrit. The percentage change in systolic, diastolic, and mean blood pressure between the two diets was defined as the salt sensitivity index (SSI) for systolic blood pressure (SSISBP), diastolic blood pressure (SSIDBP), and mean blood pressure (SSIMBP), respectively. The mean values of both AUCglu and AUCins decreased significantly with increase of NaCl intake; however, there was no significant correlation between SSI (SSISBP, SSIDBP, or SSIMBP) and the percentage changes in AUCglu and AUCins. Meanwhile, the percentage changes in AUCglu and AUCins significantly correlated with the respective values of AUCglu and AUCins on the low NaCl diet. These results suggest that extreme NaCl restriction may deteriorate glucose metabolism in hypertensive patients, especially in those with diabetes mellitus or impaired glucose tolerance.

Timing for administration of an antihypertensive drug in the treatment of essential hypertension.

To find the best timing for administration of long-acting antihypertensive drugs, we gave nitrendipine, a calcium antagonist of the dihydropyridine group, once a day to six hospitalized and drug-free patients with essential hypertension, changing the time of administration and studying the effects on the circadian rhythm of blood pressure. After control values of 24-hour blood pressure variations were taken with patients on placebo, a 10-mg tablet of nitrendipine was given for 3 days on three occasions--at 6 AM on awakening, at 8:30 AM after breakfast, and at 6 PM after supper; 24-hour blood pressure values for each period were recorded on the third day. The 24-hour blood pressure values during the control period showed a biphasic circadian rhythm, with higher values during wakefulness and lower values during sleep. The control period was also characterized by a rapid rise in blood pressure on awakening, the so-called morning surge of blood pressure, and a gradual decline during sleep at night. Although the morning surge was not completely suppressed by nitrendipine given after breakfast, it was diminished by the drug given on awakening or after supper; the latter brought a deeper decline in blood pressure during sleep compared with other times. The average of 24-hour blood pressure values obtained by nitrendipine given on awakening was the lowest among the three occasions. Thus, administration of long-acting calcium antagonists with a rapid onset of action on awakening in the early morning seems to be a more rational and beneficial alternative than the conventional administration after breakfast.(ABSTRACT TRUNCATED AT 250 WORDS)

Endogenous erythropoietin and salt sensitivity of blood pressure in patients with essential hypertension.

To investigate a possible involvement of endogenous erythropoietin (EPO) in the salt sensitivity of blood pressure in essential hypertensive (EHT) patients, plasma EPO concentrations were measured during different salt intakes in 14 patients with EHT. All patients were given low salt (34 mmol NaCl/day) and high salt (342 mmol NaCl/day) diet of 7 days each. The plasma EPO concentrations were significantly higher on the high salt diet than those of low salt diet (23.5 +/- 1.9 v 18.7 +/- 1.8 mIU/ml, mean +/- SD, P < .05). The percentage change of plasma EPO concentration with salt loading correlated positively with hematocrit (Ht) at high salt diet (r = -0.62, P < .02) and tended to be correlated with plasma hemoglobin at high salt diet (r = 0.52, P < .10). These results suggest that the secretion of EPO is increased in response to hemodilution caused by the salt loading and the increased EPO concentration in plasma which may contribute to the increase in blood pressure through an expansion of total blood volume due to an enhanced red cell generation in combination with salt and water retentions.

12-Lipoxygenase products modulate calcium signals in vascular smooth muscle cells.

Previous studies have shown that inhibition of the lipoxygenase pathway of arachidonic acid metabolism can prevent the development of elevated blood pressure in renin-dependent models of hypertension. Agents that inhibit the lipoxygenase pathway such as phenidone and the flavonoid baicalein can selectively attenuate contractile responses to angiotensin II in vivo as well as in isolated vascular tissue. In the present study, the effects of lipoxygenase inhibitors on pressor-induced changes in cytosolic calcium were examined in cultured rat vascular smooth muscle cells using the fluorescent dye fura-2. Two structurally unrelated lipoxygenase inhibitors, baicalein and 5,8,11-eicosatriynoic acid, attenuated angiotensin II-stimulated increases in cytosolic calcium in both normal and calcium-poor buffer. The addition of 5-, 12-, or 15(S)-hydroxyeicosatetraenoic acid alone to the cells had no acute effect on intracellular calcium concentration. However, the addition of 12(S)-hydroxyeicosatetraenoic acid but not 5- or 15(S)-hydroxyeicosatetraenoic acid restored the initial calcium response to angiotensin II in vascular smooth muscle cells pretreated with both inhibitors; 5,8,11-eicosatriynoic acid also reduced [Arg8]-vasopressin and endothelin-stimulated increases in intracellular calcium. The attenuation of vasopressor-induced calcium transients by agents that inhibit lipoxygenase may explain their observed hypotensive effects in vivo. Moreover, lipoxygenase products, in particular 12(S)-hydroxyeicosatetraenoic acid, may act as mediators for the intracellular actions of angiotensin II and possibly other pressor hormones in vascular tissue by regulation of intracellular calcium metabolism.