Role of acetyl glyceryl ether phosphorylcholine in blood pressure regulation in rats.

The role of an endogenously occurring acetyl glyceryl ether phosphorylcholine (AGEPC) in blood pressure regulation was studied with an AGEPC antagonist in rats with hypertension of various etiologies. The hypotensive activity of an intravenously injected AGEPC was competitively suppressed by the intravenous infusion of 3-(N-n-octadecylcarbamoyloxy)-2-methoxypropyl-2-thiazolioethylphospha te (CV-3988) and was dose-dependent. The CV-3988 was infused intravenously into one- and two-kidney, one clip hypertensive, deoxycorticosterone-salt hypertensive, adrenal regeneration hypertensive, spontaneously hypertensive, and normotensive control rats. The increase in blood pressure caused by CV-3988 infusion in spontaneously hypertensive and normotensive control rats was significant (p less than 0.01 and p less than 0.001, respectively, at 60 min) compared with that caused by vehicle infusion. The increase was not seen in rats with secondary hypertension. In rats with two-kidney, one clip hypertension, the initial rapid decrease in blood pressure seen after unclipping was significantly (p less than 0.05) inhibited by CV-3988 infusion as compared with that by vehicle infusion. These results suggest that endogenous AGEPC may participate in the blood pressure regulation and pathophysiology of some forms of hypertension in rats.

Effects of ouabain on blood pressure regulation in rats.

In order to test the hypothesis that a circulating inhibitor of the sodium-potassium ATPase pump may cause a concomitant rise in blood pressure and increased sodium excretion, we studied chronic effects of continuous infusion of ouabain, an inhibitor of sodium-potassium ATPase, for up to 6 days on systolic blood pressure and urinary sodium excretion in conscious rats. We also evaluated the effect of this substance in rats with hypertension induced by chronic infusion of norepinephrine. Continuous infusion of ouabain (1.2 mg/kg per day) into the jugular vein by an osmotic minipump did not induce any changes in systolic blood pressure and urinary sodium excretion in intact rats on regular diets. Furthermore it did not cause a change in systolic blood pressure in rats drinking 1% NaCl, and in unilaterally nephrectomized rats drinking 1% NaCl, when compared with vehicle-infused animals. When the same dose of ouabain was administered simultaneously with 1.8 mg/kg per day norepinephrine infused intraperitoneally by another osmotic minipump in conscious rats, systolic blood pressure rose on day 1 to only 129.3 +/- 2.8 mmHg compared with the rist to 145.0 +/- 2.0 mmHg when norepinephrine alone was infused (P less than 0.01). The antihypertensive effect of ouabain was sustained for the entire experimental period lasting for 6 days and was not associated with any changes in urinary sodium excretion. The administration of ouabain to rats made hypertensive by a 3-day infusion of norepinephrine, returned the blood pressure to control levels, and the antihypertensive effect was sustained throughout the experimental period lasting a further 3 days and was not associated with any changes in urinary sodium excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Platelet-activating factor and anti-platelet-aggregating factor in acute reduction of blood pressure following percutaneous transluminal renal angioplasty in patients with renovascular hypertension.

The mechanism of the acute fall of BP following percutaneous transluminal renal angioplasty (PTRA) was studied in four patients with renovascular hypertension caused by fibromuscular dysplasia. One hour after PTRA, systemic blood pressure and plasma renin activity in the ipsilateral renal venous blood decreased significantly (P less than 0.05), but the plasma noradrenaline level in ipsilateral renal venous blood increased significantly (P less than 0.05). At the same time, a platelet-activating factor (PAF) and an unidentified factor that inhibited the aggregation of rabbit platelets induced by PAF, arachidonic acid or ADP were detected in the ipsilateral renal venous blood, but were not found in the contralateral renal venous blood. Plasma noradrenaline level in cubital venous blood decreased significantly (P less than 0.05) after 24 hours as compared with that before PTRA and BP also maintained the normal level. These results suggest that the reduction in plasma renin activity is associated with the acute reduction in BP following PTRA. PAF and an unidentified factor blocking the aggregation of platelets may be involved in ipsilateral renal venous blood following PTRA in patients with renovascular hypertension. The reduction in plasma noradrenaline level is an additional mechanism involved in maintaining normal BP following PTRA in the late stage.

Normalization of high plasma level of ouabain-like immunoreactivity in primary aldosteronism after removal of adenoma.

Plasma ouabain-like immunoreactivity, which has been supposed to be associated with hypertension, was significantly higher in five patients with primary aldosteronism than in age-matched normotensive subjects. High plasma levels of ouabain-like immunoreactivity decreased to normal after removal of adenoma. Extracts of adenoma tissue did not contain any apparent ouabain-like immunoreactivity. Anti-ouabain antibody used in this study did not cross-react with aldosterone, cortisol, corticosterone, arachidonic acid or lysophosphatidylcholine. Hypertension, hypokalemia, a high plasma aldosterone level and low plasma renin activity were also normalized after surgery. These results indicate that hyperaldosteronism induces the high plasma level of ouabain-like immunoreactivity and this is associated in part with high blood pressure (BP) in primary aldosteronism.

Changes in plasma lipids and uric acid with sodium loading and sodium depletion in patients with essential hypertension.

The short-term effects of manipulating dietary salt intake on plasma levels of cholesterol, lipoproteins and uric acid were studied in two groups of patient with essential hypertension. With dietary salt restriction in 8 patients (10 g to 2 g salt/day for five days), plasma total cholesterol, esterified cholesterol, beta-lipoprotein, low density lipoprotein and uric acid rose significantly. With salt repletion (2 g salt/day to 20 g/day for five days) in 17 patients, plasma total cholesterol, esterified cholesterol, beta-lipoprotein, low density lipoprotein and uric acid fell significantly. Total/HDL cholesterol ratio increased significantly with salt restriction and decreased significantly with repletion. However, very low density lipoprotein, HDL-cholesterol, triglyceride, phospholipid, chylomicron and non-esterified fatty acid were not influenced by the changes in salt intake. These results indicate that the severe restriction of dietary salt raises plasma cholesterol and uric acid levels in patients with essential hypertension in the short term.

Effect of 1-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine inhibitor on the reduction of one-kidney, one clip hypertension after unclipping in the rat.

The role of 1-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine in regulating blood pressure was studied in one-kidney, one clip hypertensive rats using 3-(N-n-octadecylcarbamoyloxy)-2-methoxypropyl-2-thiazolio ethylphosphate, which specifically inhibited the hypotensive activity of exogenously injected 1-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine. The blood pressure of rats with established hypertension produced by clipping one renal artery and contralateral nephrectomy normally decreases rapidly after unclipping the artery, but this rapid decrease was significantly inhibited by intravenous infusion of 3-(N-n-octadecylcarbamoyloxy)-2-methoxypropyl-2-thiazolio ethylphosphate. This shows that endogenous 1-alkyl-2-acetyl-sn-glycero-3-phosphorylcholine participates in the rapid decrease of blood pressure after unclipping the kidney in one-kidney, one clip hypertensive rats.

Effects of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (platelet activating factor) on cardiac function in perfused guinea-pig heart.

The direct cardiac action of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF) was studied in isolated perfused guinea-pig heart preparations. PAF produced a fall in left ventricular pressure, decreases in the rate of rise of the left ventricular pressure (dp/dt) and coronary flow, but had no effect on heart rate. These results indicate that PAF is a cardiodepressant with inotropic selectivity and this effect on heart is blocked by CV-3988, a specific PAF antagonist.

Endogenous platelet-activating factor and anti-platelet-activating factor in patients with renovascular hypertension.

Renovascular hypertension is relieved by percutaneous transluminal renal angioplasty. In four patients with renovascular hypertension, platelet-activating factor (PAF) was found to be released into the ipsilateral renal venous blood after percutaneous transluminal renal angioplasty, but was not found in the contralateral renal venous blood following this procedure. Anti-platelet-activating factor with a lipid-like property was also found, and its polarity was slightly lower than that of PAF judging by its behavior on thin layer chromatography. Anti-platelet-activating factor completely blocked the aggregation of rabbit platelets induced by PAF, ADP or arachidonic acid. These results indicate that PAF and anti-platelet-activating factor are released into renal venous blood following percutaneous transluminal renal angioplasty in patients with renovascular hypertension.

Autoimmune neutropenia with anti-neutrophil autoantibody associated with Sjögren's syndrome.

A 74-year-old man developed neutropenia in association with Sjögren's syndrome. The peripheral neutrophils in his blood decreased to 210/mm3 (total white blood cell count 2,100/mm3). Bone marrow examination showed an increase in the number of neutrophil precursors. The presence of anti-neutrophil autoantibody (ANAB) in his plasma was determined by an enzyme-linked immunosorbent assay. Prednisolone therapy resulted in an increase in the neutrophil count and a decrease in the ANAB titer. However, when the daily dose of prednisolone was decreased, the neutrophil count gradually decreased, and the ANAB titer increased again. These results suggest that neutropenia in this patient was caused by ANAB, and ANAB could be the result of autoimmune disorders associated with Sjögren's syndrome.

Studies on the role of platelet-activating factor in blood pressure regulation.

Circulating levels of 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16PAF) in human subjects were measured by gas chromatography/mass spectrometry using negative ion chemical ionization. The mean (+/- S.D.) circulating C16PAF levels in patients with essential hypertension (18.1 +/- 5.3 pg/mL, n = 16) were not significantly different from those in normotensive subjects (17.2 +/- 7.2 pg/mL, n = 14). During a salt balance study, high salt intake (20 g/day) significantly increased the circulating level of C16PAF, and changes in circulating C16PAF significantly and positively correlated with changes in mean arterial blood pressure (r = 0.47, p less than 0.05). Changes in C16PAF also correlated with changes in creatinine clearance (r = 0.55, p less than 0.05), but did not correlate with changes in plasma sodium concentration, plasma chloride concentration and plasma volume. An intravenous injection of 50 micrograms of human atrial natriuretic peptide (hANP) decreased circulating C16PAF levels from 20.0 +/- 2.7 to 13.9 +/- 2.4 pg/mL of blood (n = 10, p less than 0.01) in healthy subjects. The data appear to indicate that C16PAF levels are changed by salt intake-induced mild increase in blood pressure, and that hANP may be an endogenous factor which lowers circulating C16PAF.

High plasma levels of cortisol in patients with senile dementia of the Alzheimer's type.

Plasma cortisol levels and other factors including thyroid hormone in patients with Alzheimer's type (n = 10), vascular type (n = 10) or mixed type (n = 10) senile dementia were compared with those in non-demented senile controls (n = 10). Plasma cortisol levels at 8:00 a.m. in Alzheimer's type dementia and mixed type dementia were 17.3 +/- 4.3 micrograms/dl (mean +/- SD) and 15.6 +/- 2.3 micrograms/dl, respectively. These values were significantly higher (p less than 0.005 and p less than 0.01) than those found in the control subjects (12.0 +/- 3.1 micrograms/dl). Plasma cortisol levels in vascular-type dementia (14.4 +/- 6.3 micrograms/dl) did not differ significantly from those in the controls. Plasma ACTH in senile dementia of the Alzheimer's type was lower, but not significant as compared with that in normal controls. In three subgroups of senile dementia and normal controls, plasma cortisol levels inversely correlated significantly with the degree of cognitive function. Plasma levels in TSH-thyroid system and blood pressure did not show any significant change in three types of senile dementia. These data suggest that senile dementia of the Alzheimer's type accompanies relatively and primarily high plasma cortisol levels and this may associate with cognitive dysfunction in Alzheimer's type senile dementia.

Effect of d,l-alpha-tocopheryl esters on vitamin E-deficient rats.

The data in our previous paper demonstrated that some alpha-tocopheryl esters administered orally were absorbed in their unchanged form through the lymph, while some other esters were absorbed after being hydrolyzed individually to different degrees. The hydrolysis during absorption seems to be related to the structure of the ester group of alpha-tocopherol at the 6-position. The purpose of this work is to study the metabolism and biological effect of tocopherol esters in vitamin E-deficient rats. Three esters were used on the basis of their behavior during absorption through the lymph, as follows; alpha-tocopheryl acetate (an easily hydrolyzable ester), the nicotinate (a moderately hydrolyzable one) and the pivalate (a scarcely hydrolyzable one). The easily hydrolyzable esters will suffer the same metabolic fate through absorption as alpha-tocopherol. The moderately and scarcely hydrolyzable ones have a tendency to show different physiological effects from alpha-tocopherol due to absorption of the unchanged ester. The effect of these esters on the microsomal enzymes in the liver such as cytochrome P-450, cytochrome b5, aniline and hexobarbital difference spectra and NADPH-dependent cytochrome c reductase was determined. It was shown that the pivalate inhibited the release of NADPH-dependent cytochrome c reductase activity to supernatant in spite of low distribution in the 105,000 X g sediment. The result suggests that the pivalate as a model compound may be interesting to examine for its membrane stabilizing effect of alpha-tocopherol.

Transfer of alpha-tocopherol from plasma to erythrocytes in vitamin E-deficient rats.

The transfer of alpha-tocopherol from plasma to erythrocytes was examined using labeled alpha-tocopherol in vitamin E-deficient rats and at the same time the appearance of resistance to dialuric acid-induced hemolysis in the erythrocytes was observed. It was noticed that the transfer took place in two sequential steps. The second step seemed to correlate the appearance of resistance to dialuric acid-induced hemolysis, d-alpha and d,l-alpha-Tocopherol were compared under the same in vitro experimental conditions and no difference between them was observed in the effect on the recovery of antihemolytic activity. The difference in physiological activity between d-alpha- and d,l-alpha-tocopherol may exist other than in the transfer step. The coexistence of alpha-tocopherol and alpha-tocopherol quinone did not show any inhibiton for transfer of alpha-tocopherol from plasma to erythrocytes in vitamin E-deficient rats.

Effect of vitamin E deficiency on the level of superoxide dismutase, glutathione peroxidase, catalase and lipid peroxide in rat liver.

The activities of superoxide dismutase, glutathione peroxidase, catalase and xanthine oxidase were simultaneously studied in vitamin-E deficient and -supplemented rat liver and also measured the lipid peroxide content in liver. The lipid peroxide content of vitamin E-deficient rat liver, estimated by thiobarbituric acid, increased as compared with that of vitamin E-supplemented rat liver. No marked changes of activities of superoxide dismutase, glutathione peroxidase and catalase were observed, but the activity of xanthine oxidase which is strong superoxide generator increased in vitamin E-deficient rat liver. These results suggest that vitamin E prevents the accumulation of lipid peroxide, but not controls the level of peroxide scavenging system such as superoxide dismutase, glutathione peroxidase and catalase.

Partial purification and properties of a plasma ouabain-like inhibitor of Na+, K+-ATPase in patients with essential hypertension.

Plasma levels of an ouabain-like inhibitor of Na+,K+-ATPase were higher in patients with essential hypertension compared with normal levels. The ouabain-like inhibitor was correlated significantly with blood pressure and was increased by a high-salt diet. The substance was partially purified by high performance liquid chromatography which revealed lipid-like properties, but the elution time was different from that of free unsaturated fatty acid on silica-gel high performance liquid chromatography. Its molecular weight was 600 or less, as estimated by high performance liquid chromatography with an HSG-15H column. The ouabain-like substance inhibited Na+, K+-ATPase in competition with KCl and showed positive ouabain-like immunoreactivity, whereas lysophosphatidylcholine was a non-competitive inhibitor. The ouabain-like substance was unstable at room temperature and decomposed to smaller molecular compounds which did not inhibit Na+, K+-ATPase. The inhibitory fraction gave a positive thiobarbituric acid reaction test. The mobility of the ouabain-like inhibitor on silica-gel thin-layer chromatography was different from that of prostaglandins and arachidonic acid. These results indicate that the plasma ouabain-like inhibitor of patients with essential hypertension is a lipid which is different from free fatty acid or lysophosphatidylcholine, and may be an unstable peroxide.