Pauli Ylitalo

Hemodynamic effects of iloprost, a prostacyclin analog

Iloprost is a chemically stable derivative of carbaprostacyclin. We studied its hemodynamic effects in 10 patients in an intensive care unit. Iloprost was infused intravenously for 3 days for the treatment of advanced obliterative arterial disease of the lower extremities. Clinically significant hemodynamic responses were obtained with an infusion rate of 0.5 ng/kg/min. All subjects tolerated the dose of 4 ng/kg/min, which increased heart rate an average of 11% and cardiac index an average of 26%. This infusion rate decreased mean arterial pressure by 15%, total peripheral resistance by 31%, and pulmonary vascular resistance by 34%. Mean pulmonary arterial pressure, pulmonary capillary wedge pressure, left and right ventricular stroke work indices, and rate pressure product did not change. At higher doses of up to 8 ng/kg/min, responses were augmented only slightly, but side effects such as headache, nausea, and abdominal colics became more prominent. The data show iloprost to be a potent vasodilator that reduces both pre‐ and afterload and presumably induces a compensatory increase in cardiac output and heart rate, but does not increase the work load or oxygen demand of the heart.

Accumulation of bisphosphonates in the aorta and some other tissues of healthy and atherosclerotic rabbits

Clodronate, etidronate, and pamidronate are highly hydrophilic bisphosphonates used for the treatment of bone resorption and hypercalcemia. They also inhibit the development of experimental atherosclerosis without influencing serum cholesterol level. We studied the distribution and the accumulation of the carbon 14-labeled bisphosphonates in the aorta and some other tissues of healthy rabbits and in rabbits with diet-induced atherosclerosis. After intravenous injection, clodronate and pamidronate disappeared from circulation more slowly in atherosclerotic than in healthy rabbits, and the drug concentrations in the peripheral tissues were generally lower in atherosclerotic than in healthy animals. At 24 hours after dosing in healthy rabbits, the mean aorta to plasma ratios of clodronate, etidronate, and pamidronate were, respectively, 2.4 to 2.8, 2.4 to 4.0, and 8.6 to 10. The corresponding ratios in atherosclerotic rabbits were, respectively, 13 to 22, 1.5 to 2.2, and 13 to 24. Seven days after the injection the mean clodronate concentration in the aortas of healthy rabbits was 0.5% to 0.9% of the dose given per tissue weight, and the concentration in those of atherosclerotic animals was 3.8% to 5.2% of the dose given per tissue weight. The results indicate that hydrophilic bisphosphonates, known to inhibit the atherogenesis, concentrate markedly in the aortas of healthy and atherosclerotic rabbits.

Distribution of 2-methyl-4-chlorophenoxyacetic acid and 2,4-dichlorophenoxyacetic acid in male rats: evidence for the involvement of the central nervous system in their toxicity.

The effects of different 2-methyl-4-chlorophenoxyacetic acid (MCPA) or 2,4-dichlorophenoxyacetic acid (2,4-D) pretreatments on the distribution of labeled [14C]MCPA or [14C]2,4-D given iv were studied in male rats. Single subcutaneous MCPA or 2,4-D pretreatment increased 14C activity in the brain, cerebrospinal fluid (CSF), liver, muscle, heart, or testis and decreased that in the plasma or kidney, while in the lung 14C activity remained approximately unchanged. Changes in the distribution of 14C activity as well as toxic signs such as myotonia and lethargy appeared within 0.5–1.5 hr after subcutaneous MCPA administration and disappeared in a few days. 14C activities in the brain and CSF of both saline-treated adult and 10- or 21-day-old animals were very low as compared to the other tissues, but in the treated animals these and also absolute MCPA concentration increased to about the level in the muscle or testis. Chronic MCPA exposure had only a slight effect on the distribution of 14C activity. The decreased binding of [14C]MCPA to plasma proteins caused by MCPA pretreatments may explain the increase of 14C activity in many tissues but not the high increase in the brain and CSF during intoxication. The results indicate that at large doses either the influx of MCPA and 2,4-D into the brain is highly increased or their efflux out of the brain is decreased. A potent increase in cerebral 14C activity coincided with the appearance of MCPA intoxication, which suggests that the central nervous system (CNS) is involved in the toxicity of chlorophenoxyacetic acids.

AT1 Receptor Blockade Improves Vasorelaxation in Experimental Renal Failure

Abstract— It is not known whether angiotensin II type 1 receptor antagonists can influence the function and morphology of small arteries in renal failure. We investigated the effect of 8‐week losartan therapy (20 mg/kg per day) on isolated mesenteric resistance arteries by wire and pressure myographs in 5/6 nephrectomized rats. Plasma urea nitrogen was elevated 1.6‐fold after nephrectomy, and ventricular synthesis of atrial and B‐type natriuretic peptides was increased 2.2‐fold and 1.7‐fold, respectively, whereas blood pressure was not affected. Losartan did not influence these variables. The endothelium‐mediated relaxation to acetylcholine was impaired in nephrectomized rats in the absence and presence of nitric oxide synthase and cyclooxygenase inhibition. Blockade of calcium‐activated potassium channels by charybdotoxin and apamin reduced the remaining acetylcholine response, and this effect was less marked in nephrectomized than in sham‐operated rats. Relaxation to levcromakalim, a vasodilator acting through adenosine triphosphate‐sensitive potassium channels, was also impaired after nephrectomy. The arteries of nephrectomized rats showed eutrophic inward remodeling: Wall‐to‐lumen ratio was increased without change in wall cross‐sectional area. All changes in arterial relaxation and morphology were normalized by losartan therapy. Aortic ACE content, measured by autoradiography, directly correlated to the plasma level of urea nitrogen, suggesting that renal failure has an enhancing influence on the vascular renin‐angiotensin system. Losartan normalized relaxation and morphology of resistance arteries in experimental renal failure, independent of its influence on blood pressure, impaired kidney function, or volume overload. The mechanism of improved vasodilation by losartan may include enhanced relaxation through potassium channels.

Effect of exercise on the serum level and urinary excretion of tetracycline, doxycycline and sulphamethizole

SummaryThe serum level and urinary excretion of sulphamethizole, tetracycline and doxycycline were studied in healthy volunteers subjected to intensive exercise and bed rest in a cross-over trial. Each group consisted of 7–8 subjects. The exercise or bed rest began 15 min before oral administration of the drug and was continued for the following 4 hours. During exercise serum drug concentration and the area under the serum concentration-time curve for each agent was significantly higher (p<0.05) than the corresponding values at rest. Exercise greatly suppressed the renal excretion of tetracycline and doxycycline, but the decrease alone appeared insufficient to account for the pronounced increase in serum drug concentration. Total drug excretion in urine was unchanged. Thus, it seemed most unlikely that overall absorption from the gastrointestinal tract had been altered by exercise. However, the rate of absorption appeared to be more rapid in the exercise than in the rest period. Marked haemoconcentration was not produced by the exercise. In addition to changes in absorption and elimination rates, alteration in the volume of distribution might contribute to the higher serum drug concentration during exercise. Therefore, the level of physical activity should be considered in the interpretation of pharmacokinetic data both in clinical practice and in pharmacokinetic studies.

Distribution of [14C]clodronate (dichloromethylene bisphosphonate) disodium in mice.

The distribution of 14C-labeled clodronate (dichloromethylene bisphosphonate), a new bisphosphonate for the treatment of osteolytic bone metastases and hypercalcemia, was studied in mice by whole-body autoradiography and by measuring the 14C activities in various tissues [14C]Clodronate was administered into the tail vein, and its distribution was followed from 5 min to 90 days after the injection. The drug disappeared promptly from the plasma and accumulated intensively in the bone and moderately in the spleen. In both tissues, relatively high radioactivities were measured as late as 90 days after the [14C]clodronate administration. Small amounts of 14C activity were also detected in the liver for 90 days. The results agree well with the previous observations that bisphosphonates deposit rapidly in the bone. Our findings indicate further that clodronate accumulates in the bone and the spleen for several months.

The effect of inhibition of prostaglandin synthesis on plasnta renin activity and blood pressure in essential hypertension

The influence of oral indomethacin treatment (75 mg daily for a week) on urinary excretion of prostaglandin (PG) F2alpha, plasma renin activity (PRA), blood pressure (BP) and electrolyte excretion (Na+ and K+) was studied in 21 patients with untreated essential hypertension (9 women and 12 men, aged from 40 to 45 years). PGF2alpha excretion and PRA were markedly suppressed by indomethacin in both sexes. A close correlation was found between the decreases in PGF2alpha excretion and PRA. 13,14dihydro-15keto-PGF2alpha (a metabolite of PGF2alpha) excretion also tended to be lowered during the indomethacin treatment. BP tended to increase but urine volume and electrolyte excretion were unchanged during the indomethacin period. The results suggest that in essential hypertension inhibition of the PG synthesis causes a concomitant suppression in PRA and may slightly increase BP.

Blood-brain barrier damage by 2-methyl-4-chlorophenoxyacetic acid herbicide in rats

Abstract The integrity of blood-brain barrier (BBB) to serum proteins was studied in rats acutely intoxicated by 2-methyl-4-chlorophenoxyacetic acid (MCPA). Intoxication was produced by giving sodium salt of MCPA sc in single doses of 100, 250, and 500 mg/kg at various intervals before killing the animals. Evans blue, immunohistochemistry of serum proteins, and electron microscopy were used to study the barrier. Extravasations of Evans blue-albumin complex indicating BBB damage were observed with the 250 and 500 mg/kg doses. Lateral cerebral cortex and medulla oblongata were the tissues most consistently affected. Most severe extravasations occurred 4.5 hr after administration of 250 mg/kg MCPA. At 24.5 hr, no extravasation of Evans blue could be demonstrated, which suggests reversibility of the damage. The immunohistochemical demonstration of endogenous albumin or immunoglobulin-G verified the same localizations of the BBB damage. Electron microscopy of the damaged brain areas revealed increased amounts of vesicles in the endothelial cells and local swellings of the basal laminae of the capillaries. As indicated by the extent of extravasation of serum components into the brain, BBB damages appeared within 1.5 hr and showed a marked recovery in 24.5 hr. The damages coincided with the toxic symptoms of the herbicide. Thus the central nervous system was affected by MCPA intoxication.

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.

In the dose range of 0.5-2.0 mg/kg, acetylsalicylic acid does not affect prostacyclin production in hypertensive pregnancies

OBJECTIVE To determine the dose of acetylsalicylic acid (ASA), that inhibits the production of the vasoconstrictive, aggregatory thromboxane A2 while sparing the production of the vasodilatory antiaggregatory prostacyclin. DESIGN A controlled study comparing the effects of three doses of ASA on the production of thromboxane A2 and prostacyclin. METHODS Seven pregnant hypertensive patients and five non-pregnant healthy women received 0.5, 1.0 and 2.0 mg/kg/day of ASA, each dose for 10-12 days, the treatment periods following each other immediately. Seven normotensive pregnant women served as controls and were given no ASA. Blood and urine samples were taken at baseline and after the treatment periods to determine serum thromboxane B2 and the urinary 2.3-dinor-6-ketoprostaglandin F1alpha and 11-dehydrothromboxaneB2, the major stable metabolites of prostacyclin and thromboxane A2, respectively. RESULTS The urinary excretion of 11-dehydrothromboxaneB2 was significantly higher in both hypertensive (34.9+/-18.3 pg/micromol creatinine) and normotensive (39.3+/-14.4 pg/micromol creatinine) pregnant women than in non-pregnant women (14.8+/-6.4 pg/micromol creatinine). The urinary excretion of 2.3-dinor-6-ketoprostaglandinF1alpha was also higher in normotensive pregnant women (93.9+/-50.9 pg/micromol creatinine) than in non-pregnant women (18.2+/-11.3 pg/micromol creatinine). The excretion rate of 2.3-dinor-6-ketoprostaglandinF1alpha in hypertensive patients was lower than in normotensive pregnant women (44.7+/-24.2 pg/micromol creatinine). At baseline the urinary 2.3-dinor-6-ketoprostaglandin F1alpha/11-dehydrothromboxaneB2 ratio was almost the same in the hypertensive patients (1.6) and in the non-pregnant women (1.2). The ratio was 2.6 in normotensive pregnant women. In the hypertensive group, already the lowest dose of ASA inhibited urinary 11-dehydrothromboxaneB2 excretion significantly. Because none of the doses of ASA inhibited 2.3-dinor-6-ketoprostaglandinF1alpha production, the 2.3-dinor-6-ketoprostaglandinF1alpha/11-dehydrothromboxaneB2 ratio was shifted in the favor of prostacyclin at all dose levels. In the non-pregnant women, even the highest dose level of ASA failed to affect the ratio. CONCLUSION In the dose range of 0.5-2.0 mg/kg/day, ASA has a favorable effect on the ratio of prostacyclin to thromboxane A2 in hypertensive pregnancies.