Impaired catecholamine inactivation. A prohypertensive stimulus after dietary linoleate deficiency in salt-loaded rats?

Experiments were carried out on salt-loaded rats (1.5% NaCl as drinking fluid) to further explore the mechanisms by which blood pressure increases after a linoleic acid-deficient (LAd) diet. In 4-week-old LAd rats (0.5 cal% LA, hydrogenated palm kernel fat) compared to linoleic acid-rich rats (LAr, 13.3 cal% LA, sunflower oil), we observed, from the base of a reduced content of omega-6-polyunsaturated fatty acids in the tissues, an increase in blood pressure by 12 mm Hg (p less than 0.001), a diminished formation of prostaglandin E (PGE), and an unchanged formation of PGF in the aorta as well as a reduction in the in vitro uptake of 14C-norepinephrine into cardiac, aortic, and renal tissues, and a reduced degradation rate of 14C-norepinephrine in cardiac tissue. These differences in LAr vs LAd rats were not exaggerated. With respect to aortic PGE formation, 14C-norepinephrine uptake into aortic and renal tissues and 14C-norepinephrine degradation even lessened when the diet was begun prenatally, although the reduction of omega 6-polyunsaturated fatty acids in the tissues was aggravated. Our conclusion is that a fault in catecholamine inactivation may be involved in the pathogenesis of increased sympathetic activity and blood pressure elevation in LAd-fed, salt-loaded rats, possibly via alterations of endogenous prostanoid formation.

Blockade of ADP-induced Ca2+-signal and platelet aggregation by lipoxygenase inhibitors.

Stimulation of platelets results in the liberation of arachidonic acid (AA) which is further metabolized via the cyclooxygenase or lipoxygenase (LPG) pathway. We have examined the effect of inhibition of LPG on (i) the ADP-induced increase of cytoplasmic Ca2+ concentration and (ii) platelet aggregation. Lipoxygenase inhibitors, nordigidroguaiaretic acid (NDGA) and BW-755C, both suppressed ADP-induced Ca2+-signals and aggregation in a dose-dependent manner, with an IC50 value of 1 2 microM for NDGA. Qualitatively the same effect was obtained with 4-bromophenylacyl bromide, the inhibitor of phospholipases A2 and C. By contrast, cyclooxygenase inhibitor indomethacin had only a negligible effect on Ca2+-signals and suppressed only the second phase of ADP-induced aggregation. It is concluded that the LPG pathway of AA metabolism in platelets might play a crucial role in ADP-induced Ca2+-signal generation and platelet aggregation.

The role of prostaglandins in the pathogenesis of hypertension.

1. Biosynthesis of PGE2 from [14C]arachidonic acid has been found to be lower and PGF2alpha higher in the renal medulla of spontaneously hypertensive (SH) rats than in normal Wistar (NW) rats. 2. Biosynthesis of prostacyclin (PGF1alpha) from [14C]arachidonic acid was decreased in lungs, aorta and heart of SH rats. 3. Metabolism of [3H]PGF1alpha was decreased in renal cortex and lungs and PGE2 increased in SH rats in comparison with NW rats. Thus the lungs of SH rats let more PGF and less PGE enter the systemic circulation. 4. Emotional stress decreased the metabolism of [3H]PGF1alpha in lungs of SH and NW rats, the effect being less in SH rats.

Attenuation of blood pressure increase in spontaneously hypertensive rats by diets enriched with polyunsaturated fatty acids.

We investigated the influence of dietary polyunsaturated fatty acids (PUFA) on the blood pressure of spontaneously hypertensive rats (SHR). Feeding male adult SHR a linoleic acid (LA) rich or a PUFA poor diet did not alter the systolic blood pressure during a two months regimen. Feeding young male SHR an LA rich or a PUFA deficient diet beginning in the prehypertensive phase did not influence the development of hypertension. But when the regimen was begun in the pregnant mothers during the last week of pregnancy and continued in the offspring, the male offspring showed a significantly reduced increase in blood pressure when fed with an LA rich or a linolenic acid rich diet compared with PUFA deficient fed rats. This effect was not so markedly expressed in the female offspring.

[Role of prostaglandins in the pathogenesis of bronchial asthma in children and possibilities in therapeutic treatment]. / Papel de las prostaglandinas en la patogenia del asma bronquial en los niños y posibilidades en el tratamiento terapéutico.

During the past few years, in relation to study of prostaglandins, biochemical active lipids recently identified, a large quantity of physiological and pathological processes involving these compounds have been described. Convincing data confirm the regulation of the tone of smooth trachea and bronchial muscles by these substances. In this sense and within the pathological states of the respiratory system, bronchial asthma is of special interest. Recently, a detailed description of the pathogenesis of bronchial asthma, and particularly of this atypical form, has been investigated. Classic mediators of anaphylaxis, such as histamin, SRS-A, serotonin, acetylcholin, etc., have important roles in the pathogeny. Fewer works, however, have been dedicated to the study of prostaglandins and the results obtained are often contradictory. In this study, the importance of prostaglandins E, F-2 alpha, A and B are investigated in 84 patients with a diagnosis of bronchial asthma. Their ages varies between 2 and 11 years. 51 suffered from the atypical form, 11 from infectious form and 22 the mixed form. To diagnose each case, detailed anamnesis and clinical tests were carried out as well as cutaneous tests with non bacterial and fungous allergens. The RAST technique and total levels of IgE were also used. The control group of 45 children were studied in the same way. With regard to the results obtained, during the intercrisis period a rise in PGF2-alpha and a decrease in PGE could be observed. During the crisis period, an even greater rise in the concentration of PGF2-alpha and a lesser of increase of PGE were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasoconstrictor reactions in spontaneously hypertensive rats versus Wistar Kyoto can be increased or decreased depending on the conditions of perfusion.

The reactions of resistance vessels in SHR and WKY hindquarters were compared during saline or blood perfusion. During saline constant-flow perfusion at all initial pressures (80-200 mmHg) sympathetic vasoconstrictor effects were greater in SHR than those in WKY. During perfusion at constant and equal pressure vasoconstrictor responses were greater in SHR vs. WKY only at high pressure--200 mmHg. On the other hand, under constant pressure conditions at lower pressures (80 and 120 mmHg) sympathetic stimulation induced weaker responses in SHR than in WKY, which at, for example, 80 mmHg was the case at every frequency of sympathetic stimulation used (2-20 Hz). Also, the responses to exogenous noradrenaline and vasopressin occurred during perfusion at low (80 mmHg) and for both equal constant-pressure conditions lower in SHR than in WKY. Comparison of sympathetic effects in SHR and WKY during blood hindquarter perfusion revealed similar results. Also, when SHR and WKY responses were compared at their ordinary levels of constant-pressure, sympathetic vasoconstrictor effects in SHR were lower than those in WKY.

Antihypertensive action of dietary polyunsaturated fatty acids in spontaneously hypertensive rats.

The experiments were carried out in order to clarify the mechanisms of attenuation of hypertension development by means of diets enriched with polyunsaturated fatty acids (PUFA) in spontaneously hypertensive rats (SHR). Female SHR were fed a linoleic acid rich (LAr) diet (13.3 cal % LA, sunflower oil), a linolenic acid rich (LNAr) diet (18.8 cal % LNA, 3.9 cal % LA; linseed oil) and a PUFA deficient diet (0.5 cal % LA, hydrogenated palm kernel fat), respectively, during the last week of pregnancy and during the suckling period. Corresponding diets were given to the male offspring up to an age of 16 weeks. Our results demonstrate that the attenuation of hypertension development in LAr and LNAr fed male SHR was paralleled by an increased in-vitro uptake of 14C-norepinephrine into cardiac and aortic tissues as well as an increased degradation rate of 14C-norepinephrine in cardiac tissue. Ex vivo prostaglandin (PG) formation was reduced after LNAr diet in the aorta (PGF2 alpha, PGI2-like material) and in the kidney medulla (PGE, PGF2 alpha). It is concluded that an increased catecholamine inactivation may play a role in the attenuation of hypertension development in LAr and LNAr diet fed SHR.

Na+/H+ exchange in PAF-stimulated platelets.

In experiments on human platelets, inhibition of Na+/H+ exchange was caused either by equimolar substitution of external Na+ with choline or N-methyl-D-glucamine, by decreasing the pHo to 6.8, or by an inhibitor of the antiport 5-(N-ethyl-N-isopropyl)amiloride (EIPA). In all these cases a considerable inhibition of PAF-induced platelet aggregation and as a rule a more or less marked decrease in the cytoplasmic Ca2+ signal (quin-2-loaded platelets) occurred. Stimulation by 10(-7) M PAF caused biphasic pHi changes in human platelets loaded with the pH-sensitive fluorescent probe BCECF: a small transient decrease, followed by a sustained increase of 0.02 +/- 0.006 pH units, resulted from stimulation of the Na+/H+ exchange. Thrombin (0.1 U/ml) also caused biphasic pHi changes, but the alkalinization step was more pronounced (0.15 +/- 0.03 U). Every means of Na+/H+ exchange inhibition prevented a rise in pHi in stimulated platelets. Activation of the adenylate cyclase system by carbacyclin suppressed the agonist-induced pHi increase. The inhibition of neither cyclooxygenase by 10(-5) M indomethacin nor calmodulin-dependent enzymes by 10(-5) M calmidazolium affected the agonist-induced pHi signals. A decrease in temperature from 37 to 24 degrees C caused a considerable increase in the lag phase of the pHi signal induced by tetradecanoyl phorbol acetate (TPA), but did not affect the kinetics of the pHi signal induced by PAF. An inhibitor of protein kinase C (PKC), compound H-7 (60 microM), completely abolished the TPA-induced increase in pHi but caused only a partial inhibition of the pHi signal in about 50% of the experiments with PAF. On the basis of these results the conclusion is drawn that the activation of PKC is not the only pathway for the PAF-induced stimulation of Na+/H+ exchange. The PAF-induced pHi rise depended both on the presence of extracellular Ca2+ and on the [Ca2+]i increase. On the other hand, inhibition of Na+/H+ exchange decreased the magnitude of the Ca2+i signal in PAF-induced platelets loaded with quin-2, but did not influence the Ca2+ mobilization from intracellular stores as measured by quin-2 or chlortetracycline in experiments with thrombin-stimulated platelets. We conclude that in PAF-activated platelets some initial increase of [Ca2+]i is essential for Na+/H+ exchange activation while activated antiport potentiates a full-scale Ca2+ influx into the cells.