Prostaglandins and medicine最新文献

Forty-eight hour old anesthetised and ventilated neonatal piglets were cannulated in order to measure pressures, blood gases and cardiac outputs (CO) from which pulmonary (PVR) and systemic (SVR) vascular resistances were calculated. After baseline measurements had been made inspired gases were altered to produce hypoxemia and hypercapnia, to raise PVR. Animals then received Prostaglandin E₁ (PGE₁), Tolazoline (TOL), and Prostacyclin (PGI₂) in varying dosages until PVR was reduced or the dosage no longer tolerated.

With “hypoxia” CO, PVR and pulmonary artery (PA) pressures rose; aortic pressure also rose although SVR tended to fall. PGE₁ (5μg/kg/min) and PGI₂ (1.0 μg/kg/min) both produced a significant fall in PVR. The decrease in PVR with TOL (1 mg/kg/10 minutes and 2 mg/kg/l hour) was less consistent and in surviving animals did not achieve statistical significance by multivariate analysis. SVR fell with all drugs although the change with TOL was again non-significant. With both PGI₂ and TOL there was a trend for CO to rise and, although this did not reach significant levels, it restricted the drop in arterial pressure to approximately control levels. The fall in arterial pressure with PGE₁ was greater. The death rate with treatment with TOL was much higher than that seen with the other two drugs.

Circulatory changes in a group of animals with normal blood gases treated with PGI₂ (1 μg/kg/min) were similar to those seen with the hypoxic group.

In this preparation PGI₂ appeared the most satisfactory drug for the treatment of elevated PVR.

Arterial perfusion of isolated cat eyes with arachidonic acid (AA) increases the inflow of aqueous humor (AH), elevates the intraocular pressure (IOP) and constricts the pupil. The effect may be due to an observed vasoconstrictive action of AA on the blood vessels of the anterior segment of the eye. Indomethacin completely prevents the increase in AH formation and the constriction of the pupil but does not block the rise in IOP.

The present study investigated the effect of PGI₂ on ouabain induced arrhythmias in cats. PGI₂ was infused at a dose of 1.0, 2.0 and 5.0 μg/kg·min. PGI₂ in a dose of 1.0 μg/kg·min was without any antiarrhythmic effect. Infusions of 2.0 and 5.0 μg/kg·min PGI₂ in 3 of 10 and 7 of 10 animals, respectively, converted the ouabain induced arrhythmias into a sinus rhythm. The duration of the antiarrhythmic effect after infusion of 2.0 μg/kg·min lasted about 21 min, whereas the higher dose (5.0 μg/kg·min) had a shorter effect (about 2 min). Under these conditions and doses the systolic blood pressure decreased between 35% and 39% and the diastolic blood pressure was reduced by about 50%. Thus PGI₂ showed, when used in the given dose range, an antiarrhythmic effect on ouabain induced arrhythmias in cats. The importance of dosage, methods and species is here discussed.

The relation between the effect of vasodilator prostaglandins on ventricular arrhythmias during myocardial infarction and infarct size was studied in conscious dogs. Two infarct-limiting drugs, nitroglycerin and ibuprofen, were also studied for comparison. Infusions were given between 20 and 380 minutes after occlusion of the left circumflex coronary artery: intravenously for saline (N = 27), ibuprofen (N = 14), and nitroglycerin (N = 14); left atrially for PGE₁ (N = 11), PGE₂ (N = 12) and PGI₂ (N = 18). Doses of prostaglandins and nitroglycerin were adjusted to decrease mean arterial pressure by 5%. Pathologic infarct size was measured 2 days post-occlusion. During the infusion period, ventricular fibrillation (VF) deaths were nil with PGI₂ (p < 0.05) and nitroglycerin (p < 0.1), ventricular premature beats (VPB's) were less (p < 0.01) with PGI₂, PGE₂ and nitroglycerin, and collateral blood flow (microspheres) increased with PGE₁, PGI₂ and nitroglycerin but did not change with saline, PGE and ibuprofen. Infarct size, as percent of left ventricle or occluded bed, was less (p < 0.05) with PGE₁, PGI₂, nitroglycerin and ibuprofen but similar with PGE₂ and saline. Thus, PGE₂ diminished VPB's despite no effect on flow or infarct size. In contrast, both PGE₁ and PGI₂ diminished VPB's, increased flow and decreased infarct size, but PGI₂ also reduced VF mortality.

To examine the possibility that prostaglandin metabolism is pathophysiologically important in Raynaud's phenomenon, peripheral venous 6-keto prostaglandin Fla (6-keto PGF₁α) and thromboxane B2 (TXB₂) concentrations were measured in 45 patients with severe Raynaud's phenomenon. Patients with Raynaud's phenomenon had a significantly higher plasma concentration of 6-keto PGF₁α compared to controls (p < .001), although their plasma TXB₂ concentration was not statistically different from control patients. Subgroup analysis revealed that only patients with progressive systemic sclerosis (PSS) had an elevated plasma 6-keto PGF₁α concentration. To gauge the functional significance of the 6-keto PGF₁α elevations, seven patients with Raynaud's phenomenon were chronically administered indomethacin (50 mg P.O. b.i.d.); six of the seven patients noted no improvement in their Raynaud's phenomenon. Three of the patients developed pedal edema shortly after starting indomethacin. This study suggests that the increased plasma 6-keto PGF₁α concentration in Raynaud's phenomenon may be due to a compensatory release of prostacyclin and that the pathophysiologic defect does not involve the thromboxane mechanism.

Potassium-depleted subjects regularly excrete dilute urine with a high free-water clearance which cannot be suppressed either by solute loading or by water deprivation. In man, as in the dog and rat, potassium depletion impairs the ability of the kidney to achieve maximal urinary solute concentration and vasopressin is unsuccessful in overcoming this defect. In man and in the dog, potassium depletion induces a rise in urinary prostaglandin E₂, an effect which can be reversed with indomethacin, a cyclo-oxygenase inhibitor. To evaluate the role of prostaglandins on the renal action of vasopressin in hypokalemia, six subjects with hypokalemia of various etiologies were studied in a control, drug-free condition and again after 3 to 6 days of indomethacin (100 mg/day). Renal clearance studies to measure the maximal free-water excretion in response to an intravenous water load (10 ml/min) and to a superimposed infusion of arginine vasopressin (40 mU/hr) were performed. The results in six patients are as follows: maximal free-water clearance (control) 8.03 ± 0.8 ml/min (mean ± S.E.), with the addition of vasopressin, .14 ± 0.8; after 3 to 6 days of indomethacin, 8.55 ± 1.33; with vasopressin 0.91 ± 1.23 ml/min. There was no statistically significant difference between the maximal free water clearance with or without indomethacin. Vasopressin exerted an equally great response in both conditions and prostaglandins did not appear to play a role in free-water formation.

Cardiovascular effects of infused prostacyclin (PGI2 )were investigated in hypertensive anesthetized pigs in the steady state and at 1,2,3,4,5,10,15,20 and 30min after the beginning of the infusion PGI2 was perfused at the rate of 2 μg/Kg/min for 4 min before and after vagosympathectomy.

We measured the mean arterial pressure, heart rate, cardiac output, stroke volume, mean pulmonary arterial pressure,mean pulmonary wedge pressure and calculated total systemic resistance and total pulmonary resistance.

Our findings suggest that prostacyclin lowers pulmonary and systemic blood pressure in hypertensive animal by vasodilatation. The decrease in mean arterial pressure does not produce any change in heart rate probably because the substance also has a vagal effect. Finally, it might reduce venous return by dilatation of capacitance vessels.

PGI₂, appears to be a powerful vasodilator agent acting both afterload and preload without influencing heart rate or stroke volume.

The myotropic activity of leukotrienes A ₄, B₄, C₄, D₄ and histamine has been evaluated on selected smooth muscle preparations. LTA₄, B₄, C₄ and D₄ were several times more potent than histamine on the guinea-pig lung parenchymal strip, while on the guinea-pig trachea, LTB₄ was less active. The guinea-pig ileum either in segments or in strips of longitudinal muscles responded well to LTC₄, LTD₄ and histamine but not to LTA₄ and LTB₄. Rat and rabbit lung parenchymal strip showed very little sensitivity for leukotrienes whereas human parenchymal strips and bronchi were nearly as sensitive as the guinea-pig lung.

A deficiency of prostaglandins (especially of group E) could be an important factor in the genesis and evolution of malignant melanoma. Compensation for such a deficit would be a logical way of medically treating this tumour. In order to test this hypothesis two groups of hamsters bearing malignant melanomas were used. The first group was treated locally with PGE2 while the other group received control injections. After 12 days tumour growth in the PG test group was sharply reduced in comparison with the controls. Tumour growth resumed when PG treatment was stopped.