Erkki Seppälä

Effects of mild physical exercise on serum lipoproteins and metabolites of arachidonic acid: a controlled randomised trial in middle aged men.

To study the effects of physical exercise on biochemical risk factors for ischaemic heart disease 31 healthy middle aged men undertook regular physical exercise for two months and 29 served as controls in a randomised trial. In the men taking regular exercise serum cholesterol concentrations increased 26% more in the high density lipoprotein subfraction two (HDL2) and decreased 31% more in the subfraction three (HDL3) and 9% more in the low density lipoprotein fraction than in the control group. A tendency towards increased plasma 6-keto-prostaglandin F1 alpha concentration and decreased serum thromboxane B2 concentration was found during the period of regular exercise, but prostaglandin E2 concentrations remained unchanged. The increase in plasma 6-keto-prostaglandin F1 alpha concentration was associated with an increase in serum HDL2 cholesterol concentration in the group taking regular exercise. Our data suggest that mild regular physical exercise favourably influences cholesterol distribution in serum lipoproteins in healthy middle aged men and may have beneficial effects on circulating metabolites of arachidonic acid.

A modified method for extraction and purification of prostaglandins with resin XAD-2

Non-ionic resins such as XAD-2 have been widely used as part of routine procedures in the gas chromatographic-mass spectrometric determinations of prostaglandins from aqueous solutions. However, there are reports that XAD-2 cannot be used in connection with radioimmunoassay (RIA), because the column constantly leaks a polymer which almost completely inhibits the antigen-antibody binding. It seems, however, possible to overcome these difficulties by modifying the procedure. The present method can be used with RIA and in combination with further chromatographic purifications for GC-MS determinations.

Evening primrose oil and olive oil in treatment of rheumatoid arthritis

SummaryThe effects of 10 ml of evening primrose oil or olive oil, administered twice daily for 12 weeks, on clinical and laboratory signs and on plasma prostaglandins were studied in 18 patients with rheumatoid arthritis. The plasma concentration of PGE2 decreased and that of TxB2 increased in both treatment groups, but no significant improvement could be seen in either group.

Effects of antirheumatic drugs on leukotriene B4 and prostanoid synthesis in human polymorphonuclear leukocytes in vitro

The effects ofd-penicillamine, sodium aurothiomalate, indomethacin, timegadine and tolfenamic acid on the lipoxygenase and cyclo-oxygenase pathways of arachidonic acid metabolism were studied in human polymorphonuclear leukocytes (PMNs)in vitro. In short-term incubations,d-penicillamine and aurothiomalate did not affect leukotriene B4 (LTB4), prostaglandin E2 (PGE2) or thromboxane B2 (TXB2) production. Each of the three non-steroidal anti-inflammatory drugs (NSAIDs) used were potent inhibitors of prostanoid synthesis. In higher concentrations they also reduced LTB4 production; timegadine and tolfenamic acid were effective in concentrations comparable to those measured in plasma during drug therapy, whereas indomethacin was needed in ten times higher concentrations. The different effects of NSAIDs on 5-lipoxygenase activity may be of importance in their therapeutic actions as well as in the appearance of some side-effects, e.g. gastric irritation and “aspirin-induced” asthma.

Exercise-Induced Increase in Plasma Arachidonic Acid and Thromboxane B2 in Healthy Men: Effect of β-Adrenergic Blockade

We examined the effects of β-blockade with the nonselective antagonist propranolol, the cardioselective antagonist atenolol, and the cardioselective antagonist with partial agonist activity, practolol, on the levels of free arachidonic acid (AA), thromboxane B2 (TxB2), prostaglandin (PG) E2, and 6-keto-PGF1α in plasma, and TxB2 production by platelets during clotting in six normal subjects during sub-maximal dynamic exercise. The drugs were given intravenously in equipotent increasing doses before the exercise test. Exercise induced a clear increase in AA, TxB2, and 6-keto-PGF1α in plasma. During the first 60 min of exercise all three β-blockers decreased the plasma levels of AA and TxB2. Propranolol (0.19 mg/kg) was slightly more effective than atenolol (0.19 mg/kg) or practolol (0.64 mg/kg); however, at exhaustion, propranolol was markedly more effective than the other two blockers. Plasma 6-keto-PGF1α and PGE2 levels were less affected by β-blockade during exercise, and no significant effect was seen on TxB2 formation by platelets. The plasma 6-keto-PGF1α/TxB2 ratio was markedly higher after propranolol treatment than after treatment with the other two blockers during the exercise period. These results suggest that the capability of a nonselective blocker to inhibit both β1- and β2-adrenergic receptors may be of advantage because of the more effective inhibition of thromboxane formation than with a cardioselective blocker, especially when the sympathetic tone is markedly increased.

Comparison of the effects of different anti-inflammatory drugs on synovial fluid prostanoid concentrations in patients with rheumatoid arthritis

SummaryThe effects of one-day treatment with nine nonsteroidal anti-inflammatory drugs and prednisolone on human synovial fluid concentrations of prostanoids were studied. The doses were calculated so as to be approximately equipotent according to clinical experience and the recommendations of the manufacturs. Most of the drugs used reduced clearly PGE2 and TxB2 levels in synovial fluid, but only a slight diminution in 6-keto-PGF1α values was found. Carprofen, diclofenac, indomethacin, naproxen and tolfenamic acid reduced significantly the synovial fluid PGE2 concentrations. Diclofenac and indomethacin also reduced significantly the synovial TxB2 concentrations.

Divergent effects of atenolol, practolol and propranolol on the peripheral metabolic changes induced by dynamic exercise in healthy men

SummaryA study has been made of the effects of intravenous atenolol, practolol and propranolol on the changes induced by exhaustive dynamic physical exercise in blood pressure, heart rate and blood levels of lactate, glucose, insulin, free fatty acids and potassium. The mean endurance of dynamic exercise was reduced by all three beta-blockers, most markedly by propranolol. After all the beta-blockers heart rate showed a similar decrease during the first 60 min of exercise; atenolol caused the smallest reduction at exhaustion. All three beta-blockers lowered the systolic blood pressure during exercise; propranolol was the most active agent both during exercise and during recovery. The diastolic pressure was higher during exercise after treatment with the beta-blockers, especially propranolol. The beta-blockers did not markedly affect the elevation of blood glucose was abolished by atenolol. Plasma insulin was reduced by exercise after beta-blockade, most markedly after propranolol and practolol. All the beta-blockers were equipotent in reducing up to 60 min the exercise-induced increase in plasma free fatty acids, although at exhaustion propranolol had a significantly greater effect than atenolol or practolol. Serum potassium was higher after propranolol and atenolol than after practolol during exercise and recovery.

Inhibition of prostaglandin synthesis by indomethacin interacts with the antihypertensive effect of atenolol

The interaction of inhibition of prostaglandin (PG) synthesis by indomethacin (75 mg/day) with the antihypertensive effect of atenolol (50 mg b.i.d.) was studied in 11 untreated otherwise healthy men 35 to 45 years old with essential hypertension. Atenolol for 3 weeks decreased supine blood pressure (BP) from 157/109 mm Hg during placebo to 148/97 mm Hg. Indomethacin alone for 1 week slightly increased BP and antagonized the antihypertensive action of atenolol. Atenolol reduced plasma renin activity (PRA) to 40% but did not modify either the urinary excretion of vasodilatory PGs (PGE2 and prostacyclin measured as 6‐keto‐PGF1α) or plasma kininogen and urine kallikrein. Indomethacin suppressed PRA to 27% and PG excretion to approximately 70% but did not markedly change plasma kininogen and urine kallikrein excretion. The decreased excretion of 6‐keto‐PGF1α, the metabolite of the main vasodilatory prostanoid prostacyclin, correlated with the increased BP measured in standing subjects. The effects of indomethacin were practically the same when given with atenolol as when given alone. We conclude that the slight increase in BP by indomethacin in essential hypertension is associated with the reduced production of vasodilatory PGs but not with alterations in activities of the renin‐angiotensin or kallikreinkinin systems.

Adrenaline infusion evokes increased thromboxane B2 production by platelets in healthy men: the effect of beta‐adrenoceptor blockade

Abstract. The effects of direct adrenergic stimulation, achieved by 60‐min adrenaline infusion (0·1–0·2 μg kg‐1 min‐1), on thromboxane B2 (TxB2) production by platelets in whole blood ex vivo and on ADP‐induced platelet aggregation were studied in seven healthy male volunteers. The effects of two beta‐adrenergic blocking agents, pindolol and practolol, on the adrenaline‐induced changes were furthermore analyzed. Adrenaline administration resulted in an about ten‐fold elevation in plasma adrenaline, and an about threefold increase in TxB2 production by platelets at 30 min of infusion. The increased TxB2 production persisted throughout the entire adrenaline infusion, and up to 30 min of postinfusion period (recovery). Pindolol blunted markedly the effects of adrenaline on platelet TxB2 production, whereas practolol seemed to have only a weak effect. The sensitivity of platelets to ADP‐induced aggregation did not change during the 60 min of adrenaline infusion. However, at 60 min of recovery the platelets showed a significantly increased sensitivity to ADP. Correspondingly, pindolol treatment did not affect platelet sensitivity during the infusion period, but at 60 min of recovery it had caused a significantly decreased sensitivity of platelets to ADP‐stimulation. Plasma‐free fatty acids increased markedly during the adrenaline infusion. This increase was totally blocked by pindolol, but only partly by practolol. The present results demonstrate that adrenaline, at plasma levels seen for example, in complicated myocardial infarction, stimulates platelet TxB2 production and increases the sensitivity of platelets to ADP after the infusion. Pindolol, but not practolol, inhibits these adrenaline‐induced changes in platelet behaviour.

Effects of a prostacyclin analog iloprost on kidney function, renin-angiotensin and kallikrein-kinin systems, prostanoids and catecholamines in man

Iloprost (ZK 36 374), a stable analog of carbaprostacyclin, was infused for 72 h to nine patients with advanced obliterative arterial disease. Iloprost caused a marked vasodilation and a compensatory increase in cardiac output. The glomerular filtration rate increased by 45% and tubular reabsorption of sodium and water were reduced by 80% and 107%, respectively. The urine excretion rate increased by 122%. Tubular handling of potassium and calcium were not influenced by iloprost but magnesium reabsorption was stimulated. The renin-angiotensin system was not activated while serum angiotensin converting enzyme activity was decreased. Kallikrein excretion in urine was increased 4.4-fold but plasma kininogen, a substrate for kallikrein in producing vasoactive kinins, was unaffected by the drug. Plasma levels of 6-keto-PGF1 alpha and TxB2 were decreased and their excretion in urine increased. Plasma catecholamines were not changed by iloprost. Several of the changes persisted for at least the first postinfusion day. The results indicate that iloprost increases urine excretion rate by increasing glomerular blood flow and by inhibiting sodium and water reabsorptions. The kinin-forming system, but not the renin-angiotensin system or plasma catecholamines, may be activated. The decrease in plasma level of prostanoids can be, at least partly, due to their increased excretions in urine.