Techniques for measuring regional blood flow.
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Biomedical subjects
Publications and source records attributed to H I Peterson.
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The effects of locally deposited fibrin and of tranexamic acid-induced antifibrinolysis on forming granulation tissue were studied in the light of a recently developed method for treatment of postoperative fistulas by occlusion with a fibrin clot. Perforated teflon cylinders, either empty or fibrin-filled, were implanted subcutaneously in rats and extracted after 2 weeks. Fibrin deposition was found to stimulate granulation tissue ingrowth into the cylinders but it did not change the fibrinolytic activity in the granulation tissue. A significantly higher fibrinolytic activity was, however, found in the tissue fluid collected from the space between the granulation tissue and the implanted fibrin clot compared to tissue fluid from cylinders implanted empty. Tranexamic acid significantly reduced the fibrinolytic activity on the granulation tissue and delayed lysis of the implanted fibrin clot. It also reduced granulation tissue ingrowth but it did not abolish the positive effects of the clot on granulation tissue formation.
Different observations on the reactivity of tumor vessels to vasoactive drugs have suggested a decreased, a similar or an increased reactivity to vasoactive stimuli in the vascular bed of tumors as compared to normal tissues. No adrenergic innervation of newly developed tumor vessels has been found, while preexisting normal vessels incorporated during tumor growth may retain some innervation. In transplantable rat tumors, contractile cells, including smooth muscle cells, have been seen in tumor vessels. From recent experimental studies, it was concluded that the tumor's vascular bed is probably in a state of maximal dilatation and therefore sensitive to vasoconstriction, but less sensitive to pharmacological dilatation. These observations may correspond to regional tumor hypoxia and progressive development of tumor necrosis during tumor growth. The results of experimental tumor studies might question the reliability of diagnostic and therapeutic procedures in clinical oncology, which are based on differences in the reactivity to vasoactive drugs between normal and malignant tissues.
The intratumor distribution of the capillary permeability surface area product (PS) correlated to the intratumor distribution of vascular space and of blood flow was studied by labeled albumin in a transplantable rat fibrosarcoma. A wide heterogeneity in intratumor distribution of PS was found. The tumor PS values were not significantly correlated to tumor vascular space or to blood flow values. This might suggest that intravascularly administered drugs could reach a comparative high intratissue concentration also in less vascularized tumor areas.
The intratumor distribution of plasma volume and of blood flow was studied simultaneously by radioisotope techniques in a transplantable rat fibrosarcoma. Intravenous administration of norepinephrine changed the distribution of both plasma volume and blood flow to produce low values in tumor and in normal muscle. Intravenous administration of papaverine was surprisingly followed by similar effects, probably due to a direct influence of papaverine on cardiac function. Intraaortal administration of papaverine into the studied tissue area did not influence tumor blood flow or plasma volume but increased normal muscle plasma volume. The results might support a previously suggested possibility that one can directly influence the tumor vascular bed with vasoconstricting drugs, while tumor vessels are more resistant to pharmacologic dilatation probably because of their normal state of close to maximal dilatation.
A recently developed method for occlusion of fistulas with a fibrin clot initiated studies of the effects of deposited fibrin on granulation tissue formation. Perforated Teflon cylinders, empty or fibrin-filled, were implanted subcutaneously in rats for 2, 3 and 4 weeks and the composition of the ingrowing granulation tissue was followed by sequential biochemical analysis. The concentration of fat and water and the cellularity, measured as DNA concentration, were the same throughout the period studied in the granulation tissue from cylinders implanted empty and fibrin filled. After 2 weeks of implantation, the collagen concentration was higher in fibrin-filled cylinders than in cylinders implanted empty. The higher collagen concentration was explained by a higher proportion of mature collagen-synthesising cells. After 3 and 4 weeks of implantation there was no difference in the collagen concentration between cylinders implanted empty and fibrin filled.
The growth rate (studied by mean tumor dry weight) and vascularization (studied by microangiography) of two transplantable rat tumors, a 20-methylcholanthrene-induced fibrosarcoma and a hepatoma, were significantly reduced by three prostaglandin synthesis inhibitors, indomethacin, diclofenac-sodium and aspirin, irrespective of whether the drugs were administered early or late during tumor growth.
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The influence of vasoactive drugs, including noradrenaline, isoprenaline and papaverine, on the local blood flow of a transplantable rat sarcoma and of normal subcutaneous tissue of the rat was studied by local [133 xenon] clearance technique. The microvascular bed of the tumour was studied by transmission electron microscopy (TEM). Vessels with one layer of contractile cells were found in the tumour vascular bed by TEM. A significant reduction of both tumour and normal subcutaneous tissue blood flow was found after administration of noradrenaline added to the injected xenon solution. In a dose-response experiment the tumour and subcutaneous vascular beds seemed to be equally sensitive to noradrenaline. Isoprenaline did not influence the blood flow in either subcutaneous tissue or tumour, while papaverine increased subcutaneous tissue blood flow significantly but did not influence tumour blood flow. The results of the present blood flow studies might suggest that the tumour vascular bed is normally in a state close to maximal dilatation.
To examine the influence of fibrin clots, perforated Teflon cylinders have been implanted subcutaneously in rats. Fibrin clots made from both species specific fibrinogen and from an non-species specific preparation, together with ingrowing granulation tissue, kept the implanted cylinder filled during the four week study period. This was valid for both concentrations investigated. Interaction between granulation tissue and fibrin clot differed between the two fibrin types.
Gastric mucosal lesions were induced in rats by pyloric ligature and intragastric instillation of hydrochloric acid. Within 4 h all rats developed focal mucosal lesions. Early regeneration was observed 72 h after release of the pyloric ligature and replacement of the hydrochloric acid by a phosphate buffer. A significantly increased gastric mucosal fibrinolytic activity was found 4 h after pylorus ligation. The submucosal vascular fibrinolysis remained unchanged. Following release of the pyloric ligature the increased mucosal fibrinolysis returned to normal values after 72 h. Intravenous administration of tranexamic acid significantly decreased the mucosal and vascular fibrinolytic activity without influencing the formation of induced gastric lesions. Increased mucosal fibrinolysis is probably not involved in the development of mucosal lesions.
The influence of tocopherol on the effect of local irradiation under induced ischaemia by temporary tourniquet of two rat tumours transplanted intramuscularly into one hindleg was evaluated. An impaired retardation of growth rate occurred in tumours irradiated under ischaemia. This effect was eliminated by pretreatment of animals with tocopherol. In separate experiments the method of inducing ischaemia was investigated by MDO-electrode measurements of tumour tissue oxygen pressure. A significant tumour hypoxia was found under tourniquet of the tumour-bearing leg of the animals. Pretreatment with tocopherol did not influence the tumour pO2.
The influence of tocopherol, administered intramuscularly in different single doses, on the effect of local irradiation of a transplanted rat sarcoma was investigated. Tocopherol in doses of 5, 25 or 50 mg/100 g body weight enhanced significantly the tumour growth retardation induced by irradiation. Tocopherol in a dose of 100 mg/100 g body weight as a placebo preparation had no similar effect. The influence of tocopherol administered intramuscularly or orally in identical doses was similar.
Administration of tranexamic acid given from tumour transplantation up to sacrifice 5 days later, inhibited the early vascularization of an intramuscularly transplanted rat sarcoma. A marked reduction of angiographically demonstrated vascular connections between tumour and normal muscle was observed. In older, larger tumours an increased frequency of small non-vascularized and probably necrotic tumour areas was suggested after administration of tranexamic acid. An inhibiting effect of tranexamic acid on tumour growth rate has been earlier reported in both experimental and clinical studies. This effect may be explained by an influence of tranexamic acid on tumour vascularization.
The vascularization of an intramuscularly transplanted rat sarcoma was studied by microangiography. Administration of tranexamic acid as well as of indomethacin reduced the vascular connections between tumour and surrounding normal muscle. These drugs also reduced tumour growth rate irrespective of whether they were administered early or late during tumour growth. An electron microscopy study of tumour specimens from animals given tranexamic acid did not reveal any degenerative vascular changes. One explanation of the inhibition of tumour growth and vascularization by tranexamic acid and by indomethacin may be reduction of a local inflammatory reaction induced by tumour transplantation and stimulating tumour vascularization.
The influence on the intratumour blood flow distribution in a transplantable rat sarcoma by a potent antifibrinolytic drug, tranexamic acid, administered intraperitoneally for 3 or 10 days was studied by the intratumour distribution of intravenously injected 86Rb. A local Xenon clearance technique was used to study the direct effect of tranexamic acid on local tumour blood flow. local tumour blood flow and the intratumour blood flow distribution after administration of tranexamic acid for 3 days were unchanged compared to controls. Prolonged administration of tranexamic acid changed the intratumour blood flow distribution significantly towards low flow values. This might be one mechanism behind the inhibiting effect of tranexamic acid in tumour growth rate, previously observed in both experimental and clinical studies.
Tissue fibrinolysis in the stomach and intestine of the rat was studied with a histochemical technique. After perfusion of blood vessels to reduce the influence of circulating plasminogen activator and inhibitor fibrinlysis was localized mainly to submucosal arteries and to the serosa of the gastrointestinal tract. This is opposite to previous observations, in which tissue fibrinolysis in the gastrointestinal tract was suggested to be mainly localized to veins. A method for semiquantitative analysis of tissue fibrolysis in the rat stomach is described.
An optimal inhibition of tissue fibrinolysis, studied by a histochemical fibrin slide technique in the rat stomach, was obtained by administration of tranexamic acid in a dose of 60 mg/100 g body weight. A significant fibrinolysis inhibition was found within 5 min, when tranexamic acid in this dose was given either intravenously or intragastrically. A prolonged duration of fibrinolysis inhibition was observed after intragastric administration. After 4 hr no inhibitory effect of tranexamic acid could be recorded, irrespective of the route of administration.