Regular review: somatostatin.
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Biomedical subjects
Publications and source records attributed to J N Baxter.
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The hepatic perfusion index (HPI) is an indicator of the relative hepatic arterial to total liver blood flow as measured by dynamic flow scintigraphy. Hitherto, accurate assessment of the HPI in small animals has not been possible because of methodological difficulties. A reproducible method for measuring the HPI by dynamic scintigraphy in rats is described using a rapid intraventricular bolus administration of 0.04 ml 99Tcm sulphur colloid. There was no significant difference between the HPI determined by dynamic scintigraphy and and that calculated from absolute measurements of hepatic arterial and total liver blood flow. These results indicate that the HPI derived by dynamic scintigraphy in the rat is a true estimate of the ratio of the hepatic arterial to total liver blood flow.
Micrometastases were induced in Fisher rats using an intraportal inoculation of 0.2 ml of 8 x 10(7) Walker carcinosarcoma cells. A control group received normal saline. The hepatic perfusion index (HPI) was measured during the growth and development of micrometastases. The HPI at 4 days (0.51 +/- 0.008) and at 6 days (0.65 +/- 0.16) was significantly raised when compared to controls (0.31 +/- 0.07) and at 2 days after inoculation (0.31 +/- 0.06). Hepatic artery flow did not change throughout the study period. However, portal venous inflow was decreased significantly at 4 and 6 days (0.57 +/- 0.16 and 0.55 +/- 0.11) when compared to controls (0.96 +/- 0.34). These results indicate that the change in the hepatic perfusion index is related to a decrease in portal venous inflow. The decrease in portal venous inflow could be a mechanical effect of the micrometastases on intrahepatic blood flow or to increased arteriovenous shunting.
Degradable starch microspheres (DSM, Spherex) have been shown to cause intermittent blockage of hepatic arterial flow and to increase the concentration of regionally injected cytotoxics. The Spherex monitoring system has been developed by Pharmacia, Sweden to establish the correct dose of DSM to optimize hepatic arterial blockade. Groups of normal rats received varying dosages of DSM and co-injected methylene diphosphonate (MDP) in order to reproduce the effect of reduction of passing fraction and marker flow rate as determined by the Spherex monitoring system. A flow reduction and significant decrease in passing fraction was achieved on injection of 4 mg of DSM via the hepatic artery.
Biliary excretion scintigraphy with a cholagogic test meal may be used to assess patients with suspected disorders of gall bladder motility. The interpretation of results is frustrated, however, by the lack of information about the range of normal responses in a form suitable for comparative analysis. We present the results of 41 gall bladder emptying studies on 32 normal healthy subjects (14 men, 18 women) 30 minutes after intravenous injection of 74 MBq 99Tcm-EHIDA. Gall bladder emptying was provoked by the ingestion of 300 ml milk. Gamma camera scintigraphy was used to plot gall bladder activity against time. Gall bladder emptying occurred within 10 minutes in all men and 12/18 women (p = 0.02). Gall bladder ejection fractions were significantly greater in women (p less than 0.05). Duplicate studies in nine subjects showed good reproducibility (r = 0.959). A plot of mean and (m + 2 SD) values of gall bladder activity against time has been derived. The data provide an estimate of normal gall bladder emptying response, which may be used to aid interpretation of clinical studies.
Little is known of the temporal and quantitative relationships between emptying of the stomach and of the gall bladder in patients with duodenal ulcer before and after vagotomy. A non-invasive double isotope technique was used to investigate these relationships in 27 patients with a duodenal ulcer, before and after operation-truncal vagotomy and pyloroplasty (TV + P; n = 15) and highly selective vagotomy (HSV; n = 12). A further 25 patients were studied after operation (TV + P, n = 20: HSV, n = 5). 99Tcm-EHIDA was used as the biliary tracer and 113Inm bran as the gastric content tracer. In patients with a duodenal ulcer before surgery and in 16 of the 17 patients studied after HSV, the patterns of gall bladder emptying were similar to those previously found in normal subjects. In 60% of patients after TV + P, patterns of gall bladder emptying were altered and the onset of gall bladder emptying was significantly delayed (p less than 0.001) compared with unoperated patients and patients with a HSV. The rate of gall bladder emptying did not correlate with the rate of gastric emptying in any of the patients studied. These observations suggest that TV + P, but not HSV, causes considerable alteration in coordination of gall bladder and gastric emptying.
Osmoreceptors in the upper small bowel may delay gastric emptying by inhibiting fundal tone and/or by increasing outflow resistances. In this study we examined the contribution of postpyloric resistances to this braking system. Seven dogs had gastric emptying of 250 ml 15% dextrose, labelled with 99mTc-DTPA, measured by gamma camera imaging (preoperative studies: n = 21). A proximal duodenal cannula was inserted and studies repeated in four modes: with the cannula closed (n = 14); with total diversion of gastric effluent through the cannula (n = 7); with diversion and downstream reinstillation of effluent at a constant rate (n = 14) equivalent to emptying calculated from studies without diversion; and with diversion and total reinstillation of effluent (n = 14). Gastric emptying at 90 minutes was similar in preoperative studies (48 +/- 5% - mean +/- SEM) and in those with the cannula closed (50 +/- 3%). By comparison 'total diversion' produced rapid emptying over 90 minutes (97 +/- 1%; p less than 0.001). Reinstillation of effluent at a constant rate reduced the 90 minute emptying to 59 +/- 6%, and total reinstillation slowed emptying further to 37 +/- 4% (p less than 0.05). Neither reinstillation protocol yielded gastric emptying rates that were significantly different from those in studies without diversion. With total reinstillation, emptying and hence reinstillation rates were more variable, proceeding in a step and plateau fashion. We conclude that canine jejunal osmoreceptor activity is mediated through the stomach, with postpyloric resistances playing little or no role. Gastric emptying curve analysis suggested that increments of rapid small bowel filling provoke exaggerated braking responses.
Sandostatin (SMS 201-995) was evaluated in the treatment of variceal bleeding in 9 patients with liver cirrhosis and portal hypertension who were undergoing injection sclerotherapy following a variceal haemorrhage. SMS 201-995 reduced directly recorded intravariceal pressure by 38%, whereas reductions in the wedged hepatic venous pressure were around 17%. These observations suggest that SMS 201-995 may prove useful in treating bleeding oesophageal varices in the acute situation. Preliminary, promising data are shown in the results of a randomized controlled clinical trial in which SMS 201-995 plus injection sclerotherapy vs injection sclerotherapy are compared in patients with bleeding oesophageal varices. Furthermore, in experimental work associated stimulating effects of SMS 201-995 are shown on the function of the reticulo-endothelial system both in the liver and peripherally. These effects may prove useful by reducing the effects of endotoxaemia and possibly result in arresting further liver damage.
Functional liver blood flow and hepatic artery flow were measured before and after either end-to-side portacaval or side-to-side mesocaval shunting in dogs. Functional liver blood fell by approximately 50% following both portacaval and mesocaval shunting. The hepatic artery response was variable after both portacaval and mesocaval shunts. It is concluded that side-to-side mesocaval shunts do not preserve hepatic blood flow or produce a greater compensatory increase in hepatic artery flow than conventional portacaval shunts.
The effects of total and selective portasystemic shunting on hepatic haemodynamics and some aspects of liver function were studied in rats with dimethylnitrosamine-induced cirrhosis. Immediately following end-to-side portacaval shunting there were significant reductions in wedged hepatic venous pressure (WHVP) and liver blood flow. After side-to-side mesocaval shunting liver blood flow and wedged hepatic venous flow fell by approximately the same magnitude. Selective shunting (mesocaval 'H'-grafts and splenopancreaticocaval) preserved liver blood flow to a greater extent than total portasystemic shunting but had a less marked effect on WHVP. Furthermore, selective portasystemic shunting prevented liver atrophy and deterioration in liver function which was observed in rats following total portasystemic shunting. These results suggest that in the cirrhotic rat, selective portasystemic shunts which preserve functional liver blood flow and prevent liver atrophy and a deterioration in liver function do not produce such a marked decrease in WHVP as total shunts. Further studies in man are required to evaluate the relative advantages of total and selective portasystemic shunts.
Liver blood flow (xenon-133 clearance method) and wedged hepatic venous pressure were studied in cirrhotic rats immediately after and 3 weeks following portacaval shunting (PCS), PCS and arterialisation of the portal stump with the left gastric artery (PCS-ART) or sham operation. Liver weight and function were compared 3 weeks after operation. Liver blood flow and wedged hepatic venous pressure were significantly reduced immediately after and 3 weeks following PCS. PCS-ART maintained liver blood flow and wedged hepatic venous pressure within the pre-operative range and prevented the liver atrophy and deterioration in liver function observed in rats with PCS. The results suggest that arterialisation of the portal vein with an artery which does not significantly increase sinusoidal pressure may be of benefit in preventing the early undersirable sequelae of PCS in man.
Reports on the effects of somatostatin on hepatic haemodynamics in the cirrhotic patient have provided conflicting results. Therefore, we studied the effects of different modes and rates of somatostatin administration on hepatic haemodynamics in the cirrhotic rat. Portal pressure (PP), wedged hepatic venous pressure (WHVP), portal venous flow (PVF), liver blood flow (LBF) and systemic blood pressure were measured in rats with dimethylnitrosamine-induced cirrhosis. Somatostatin was administered as a rapid injection, a continuous infusion or as a bolus dose followed by a constant infusion. One group of rats with a previously constructed portacaval shunt received a bolus dose of somatostatin followed by a constant infusion. A rapid injection of somatostatin was attended by a rapid and significant fall in all the haemodynamic parameters measured (p less than 0.01). Continuous infusion of somatostatin [4 or 8 micrograms/kg body weight (BW) h] resulted in a gradual but significant reduction in PP, WHVP, PVF and LBF (p less than 0.05), but had no effect on systemic blood pressure. A bolus dose of somatostatin (2, 4 or 8 micrograms/kg BW over 2 min) resulted in a rapid decrease in PP, WHVP, PVF and LBF (p less than 0.01), the decreases being maintained by continuous infusion. In rats with a portacaval shunt a bolus dose of somatostatin (8 micrograms/kg BW) resulted in a rapid fall in WHVP and LBF, the decrease being maintained by a continuous infusion (8 micrograms/kg BW/h).(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of varying rates of alcohol infusion (0.015-0.12 mg/g body weight/min) on hepatic haemodynamics were studied in male Wistar rats. An infusion of 0.015 mg/g body weight/min alcohol had no significant effect on portal pressure (PP) or wedged hepatic venous pressure (WHVP). However, increasing rates of infusion of alcohol (0.03-0.12 mg/g body weight/min) progressively increased PP and WHVP, the maximum increase in PP occurring following an infusion of 0.12 mg/g body weight/min (6.5 +/- 0.5 - 10.3 +/- 0.6 mm Hg). The effect of varying rates of alcohol infusion on portal venous flow and liver blood flow was biphasic. Thus following an infusion of 0.03 mg/g body weight/min alcohol, liver blood flow (40.6 +/- 4.9 - 54.3 +/- 5.8 ml/100 g/min) and portal venous flow (28.6 +/- 2.9 - 41.3 +/- 4.1 ml/min) were increased. However, following infusions of 0.06 and 0.12 mg/g body weight/min alcohol, liver blood flow and portal venous flow were decreased. The results suggest that previous conflicting reports on the effects of alcohol on hepatic haemodynamics may be related to the dose of alcohol administered.
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Twenty two patients were entered into a randomised controlled clinical trial comparing the efficacy of somatostatin and vasopressin in controlling acute variceal haemorrhage. Somatostatin was significantly more successful in controlling acute variceal haemorrhage than vasopressin (p = 0.003). Furthermore, no complications were observed during treatment with somatostatin.
The effects of systemic and intraportal administration of propranolol on hepatic haemodynamics were studied in cirrhotic and non-cirrhotic rats. In the non-cirrhotic rat systemic infusion of 4 micrograms (kg body wt)-1 min-1 propranolol significantly decreased portal pressure, wedged hepatic venous pressure, portal venous flow and liver blood flow without affecting heart rate. Similar changes were observed in the cirrhotic rat following an infusion of 2 micrograms (kg body wt)-1 min-1 propranolol. Higher rates of propranolol infusion produced greater reductions in portal pressure, wedged hepatic venous pressure, portal venous flow and liver blood flow in cirrhotic and non-cirrhotic rats but these changes were accompanied by a bradycardia. The reduction in portal pressure effected by propranolol was accompanied by an increased splanchnic vascular resistance. Intraportal injection of propranolol resulted in a rapid but transient fall in portal pressure. The decrease in portal pressure was sustained if propranolol was infused intraportally. The results indicate that propranolol effects a reduction in portal pressure via a combination of increased splanchnic vascular resistance, increased hepatic arterial resistance and reduced cardiac output. The observation that propranolol can significantly reduce portal pressure without affecting heart rate may be clinically important in the long-term management of portal hypertension. Furthermore, the rapid reduction in portal pressure following intravenous administration suggests that propranolol may be of value in the acute control of variceal haemorrhage.