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In genetically hypercholesterolaemic rats (RICO) the intimal plasminogen activator activity (PAA) at the nonbranching regions of the aorta, but not at the branching regions, was markedly lower than in controls.In alloxan-induced diabetes in rats, the pattern of changes in tissue PAA was different in different tissues.The anabolic steroid stanozolol induced in male rats a dose and time dependent increase in the tissue PAA; this increase was varying from one tissue to another.The antibiotic streptozotocin, at a diabetogenic dose, induced a200% increase in the intimal PAA of the aorta in RICO rats and by100% in controls(normal rats) ten weeks after a single injection. Administration of dexamethasone in normal rates24 hours and3 hours before streptozotocin injection prevented the enhancement of PAA. However, administration of dexamethasone simultaneously with streptozotocin did not affect the enhancement of the intimal PAA.The hypophysectomy induced in rats significantly increased PAA in the intima of the aorta.

The effect of aspirin or endotoxin or aspirin plus endotoxin on the circadian variations of plasminogen activator activity (PAA), tissue-type plasminogen activator (t-PA) antigen level, plasminogen activator inhibition (PAI) and plasmin inhibition (PI) in aorta, heart and brain of the rat was studied. In aorta the circadian variations of PAA, t-PA antigen and tissue-type PAI (t-PAI) were blunted by endotoxin, while the circadian variation of PI was reversed; t-PAI variation was blunted by aspirin plus endotoxin, while PI variation was reversed. Various disturbances of the circadian variations of PAA, t-PA antigen, PAI or PI in heart and brain were also observed. In conclusion, the circadian variations of fibrinolytic parameters in key organs are influenced by aspirin or endotoxin or aspirin plus endotoxin in a varying way or degree depending on the treatment, the parameter studied or the organ.

The effect of unilateral and bilateral adrenalectomy, unilateral and bilateral demedullation or unilateral adrenalectomy/unilateral demedullation on tissue plasminogen activator activity (PAA), plasminogen activator inhibition (PAI) and plasmin inhibition (PI) was studied in the rat. All the above treatments induced an increase of PAA in lungs. Increased PAA was also noted in brain after bilateral adrenalectomy or demedullation, as well as unilateral adrenalectomy/unilateral demedullation. In kidneys the PAA was decreased after bilateral adrenalectomy or demedullation and unilateral adrenalectomy/unilateral demedullation. In aorta only after bilateral adrenalectomy a decreased PAA was induced. In heart and liver no changes in PAA were noted. A decreased PAI expressed against tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) was found in lungs of all treated rats compared to controls. However, an increased PAI was noted in heart, liver and aorta against t-PA or u-PA after bilateral adrenalectomy and in liver after bilateral demedullation as well as after unilateral adrenalectomy/unilateral demedullation (rats with only one adrenal cortex). A dissociation between anti-t-PA and anti-u-PA response was seen in heart, liver and aorta. A variable change in PI was induced in kidneys, aorta, lungs and brain in all treatments except unilateral demedullation or unilateral adrenalectomy. Therefore, the effect of adrenalectomy or demedullation on tissue PAA, PAI and PI was variable and dependent on the extent of the treatment (unilateral or bilateral), the organ as well as the time after the treatment.

Histochemical studies of the distribution of fibrinolytic activity in the vagus and sciatic nerves of rat, guinea pig, and rabbit showed large areas of diffuse lysis related to the fascicles of the nerve. Foci of lysis were also located in the perineurium, in the peripheral epineurium, and particularly in the epineurium between the fascicles of the nerve. The fibrinolytic activity was caused by a plasminogen activator. The activity was highest in the rat, lowest in the rabbit and intermediate in the guinea pig. Plasmin inhibitors were located histochemically by the fibrin slide ‘sandwich’ technique. In all three species plasmin inhibition was most pronounced in relation to the nerve fascicles, with the highest degree of inhibition in the guinea pig and less in the rat and rabbit. The discrete localization of plasminogen activator and plasmin inhibitor might be of importance in the control of fibrin deposition and tissue repair following nerve injury or in inflammatory demyelinating diseases.

In a strain of genetically hypercholesterolemic rats (RICO), developed from an albino mutant of Rattus norvegicus(Sprague-Dawley, Tif: RAIf, SPF) by selective breeding, the intimal plasminogen activator activity (PAA) at the nonbranching regions of the aorta was markedly lower than at the nonbranching regions of the aorta in the control strain (Sprague-Dawley). At the branching regions of the aorta the intimal PAA showed no difference between the two strains of rats. In another strain of rats (HBC; hyper-beta-cholesterolemic) with a slightly elevated level of total cholesterol in the blood, a high concentration of LDL-cholesterol and a low concentration of triglycerides, the intimal PAA showed no difference from that in the control strain (Sprague-Dawley) at the branching and nonbranching regions of the aorta. 6 weeks after a single injection of streptozotocin at a diabetogenic dose (45 mg/kg) into RICO rats and the control strain, the intimal PAA was found to be increased by 280% in RICO rats, but only by 140% in controls, compared to that in the corresponding nontreated rats.

Plasminogen activator activity (PAA), plasminogen activator inhibition (PAI) and plasmin inhibition (PI) have been studied with spectrophotometric methods in extracts of human, bovine, ovine and rat kidneys of both sexes. In all species studied, renal PAA (cortex or medulla) was higher in females than in males. The PAA was also higher in the medulla than in the cortex in all species and both sexes. The PAA was due to both types of plasminogen activator; tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). In the human kidney (cortex or medulla) the measurement of t-PA antigen showed that t-PA is higher in females than in males; t-PA is also higher in the medulla than in the cortex in both sexes. The PAI showed the opposite pattern in all species studied; it was lower in females than in males. It was also lower in the medulla than in the cortex. PAI-1 was identified in the human kidney. Sex-related differences in renal PAA or PAI almost disappeared after bilateral orchidectomy in rats. PI showed no sex or regional differences in the species studied. Sex-related differences in renal PAA and PAI in man and various animal species might be of physiological or pathophysiological importance.

Histochemically studied, the heart, spleen, liver, kidney cortex, lung, sciatic nerve, gastrocnemius muscle, skin and tongue showed a higher fibrinolytic activity (plasminogen activator activity) in the newborn than in the adult rat. In the medulla of the kidney the activity was slightly lower in the newborn than in the adult. The plasmin inhibition was lower in the newborn than in the adult rat in all organs studied.

Rabbit skin, normally of low fibrinolytic activity, and guinea-pig skin, of medium activity, after crush injury or after the intradermal or subcutaneous injection of aluminum hydroxide, show a remarkable increase in fibrinolytic activity. The activity is caused by a plasminogen activator and is related to blood vessels. Occasionally, intense fibrinolytic activity was also observed in some specimens collected from various other organs normally low in activity. Thus two specimens of rabbit aorta, one specimen of rabbit trachea and one specimen of rabbit stomach showed increased activity related to pathological processes. One specimen of guinea-pig rectum showed intense fibrinolytic activity along the serosa.

Histochemical studies of the aorta in newborn, young, and adult rats showed that the intima in the branching regions and at the beginning of the branches has a constantly increased plasminogen activator activity in comparison with the nonbranching regions. The aortic valve also shows constantly increased activator activity. The intimal activator activity is variable in the nonbranching regions, depending on the age and the anatomical area of the aorta. In young rats (20–30 days), the overall plasminogen activator activity in the aortic intima is higher than in adult rats (2–4 months), while the activity is variable in newborn ratsi The intimal activator activity is generally higher in the thoracic aorta than in the abdominal aorta (in the nonbranching regions). The aortic wall has a low plasmin inhibitor capacity. The pattern of the endothelial plasminogen activator activity at different ages and anatomical areas of the aorta, in combination with the corresponding pattern of the aortic endothelial cell turnover, gives valuable information about the mechanism(s) of the production and normal (nonstressed) release of the endothelial plasminogen activator.

The transplacental effect of lead compounds (lead acetate and tetraethyl lead) on the tissue plasminogen activator activity (PAA), plasminogen activator inhibition (PAI) and plasmin inhibition (PI) was studied in the rat. The concentration of lead in organs of the newborn showed a great variation; the distribution of lead in the organs studied depended on the dose and the stage of gestation at injection. In each organ the concentration of lead was dose-dependent. In control specimens no lead could be detected. The tissue response of PAA, PAI and PI to the lead compounds also showed a great variation; however, there was no correlation between lead concentrations and PAA, PAI or PI responses. Changes of one or more of the parameters studied (PAA, PAI or PI) were noticed in lungs, liver, heart, brain and kidneys. The PAA was due to the tissue type plasminogen activator in all organs studied; in kidneys and lungs the urokinase type of plasminogen activator was also detected. Therefore, fetal tissue PAA, PAI and PI can be affected transplacentally by lead compounds.

Marked changes of the plasminogen activator activity, plasmin inhibition, and plasminogen activator inhibition were found in fatty streaks and fibrous plaques compared to the normal intima of the human aorta. Plasminogen activator activity and plasmin inhibition showed the following pattern: fibrous plaques > fatty streaks > normal intima. Plasminogen activator inhibition showed the opposite pattern: normal intima > fatty streaks > fibrous plaques. The tissue-type, but not the urokinase-type, plasminogen activator was detected immunologically.

The response of the fibrinolytic system to hypophysectomy in the rat was studied. 4 and 6 weeks after hypophysectomy the tissue plasminogen activator activity (PAA) was significantly increased in the intima of the aorta, slightly but significantly increased in the renal medulla, and significantly decreased in the vessels of the testis. No change in the PAA of the caudal vena cava, heart, lung and renal cortex was noted. Also, the tissue plasmin inhibition remained unchanged. No effect on the PAA in plasma euglobulin fractions was observed, whereas F VIII was slightly but not significantly decreased 6 weeks after hypophysectomy.

Determined by the histochemical fibrin slide technique, the fibrinolytic activity of lungs decreased in the following order of species: rat, mouse, pig, guinea pig, rabbit, cattle. Examined by the fibrin slide ‘sandwich’ technique, inhibition of plasmin showed the opposite mode of decrease. The possible role of these differences in the pathogenesis of various disorders of the lungs in the different species is discussed.

Blood vessels isolated from the liver of the rat, guinea-pig, rabbit, dog and pig showed histochemically a more or less high plasminogen activator activity. In whole liver sections, the abundant release and diffusion of inhibitors of fibrinolysis from the liver parenchyma during the histochemical procedure, partially or totally mask this high vascular activity.

The anabolic steroid stanozolol administered orally in male Sprague-Dawley rats induced a dose- and time-dependent increase in tissue plasminogen activator activity. The increase was highest in lung, lowest in heart, and intermediate in aorta and kidney. A slight increase in plasmin inhibition was noted only in the heart.

Histochemical study of many organs of male and female adult Wistar rats of the same age showed no difference in fibrinolytic activity (plasminogen activator activity) between the sexes.