Haemodynamic effects of 8-day octreotide and prazosin administration in portal hypertensive rats

Fifty-five novel rat microsatellite markers were isolated from libraries specific for rat chromosomes (Chrs) 1, 2, and 7. The markers were mapped in three backcross rat populations. Thirty of these markers mapped to Chrs 1, 2, or 7, while the other 25 mapped to other chromosomes. New markers for two genes, liver-specific transporter gene (Livtr) and insulin-responsive glucose transporter (Glut4), were also mapped to rat Chrs 9 and 10, respectively. Three provisionally assigned markers from previous studies were also confirmed. Detailed methodologies for the generation and enrichment of clones containing repeat sequences and for the isolation of chromosome-specific markers are presented, since they represent unique combinations and modifications of previous protocols. Such methods and the newly presented markers should be useful for both specific and general mapping studies in the rat.     

Acute hemodynamic effects of estrogen administration in postmenopausal women

The hemodynamic effects of estrogens in replacement doses have not been fully clarified; therefore, we studied the acute hemodynamic changes after 0.625 and 1.25 mg of conjugated estrogens, administered intravenously, using a thermodilution catheter, in postmenopausal women without structural heart disease. Pulmonary and systemic pressures and resistances and stroke volume did not change compared with baseline, but heart rate and cardiac output decreased significantly, which may be associated with estrogen's previously described calcium-blocking effect or with a more recently contemplated beta-blocking action.     

Drug administration in chronic liver disease

Cirrhosis encompasses a range of pathophysiological changes that may alter drug disposition. Drugs that are dependent primarily on the liver for their systemic clearance are more likely to be subject to reduced elimination and subsequent accumulation. Drug accumulation may lead to excessive plasma drug concentrations and adverse effects, if the adverse effects of the drug are concentration-dependent. The effects of hepatic insufficiency on the pharmacokinetics of drugs are not consistent or predictable. Furthermore, the influence of hepatic disease on the disposition of various drugs can vary, even though those drugs may share the same apparent metabolic pathway. Problems in forecasting drug kinetic behaviour are further enhanced by the additional impairment of kidney function (frequently encountered in patients with advanced liver disease) and by the unpredictability of the glomerular filtration rate using customary methods in patients with cirrhosis. Accordingly, dosages are generally adapted empirically, with the help of serum drug concentrations, when applicable. However, drugs eliminated predominantly by hepatic metabolism are not among those most commonly inducing adverse drug reactions or causing severe complications in patients with cirrhosis. Electrolyte disturbances and the hepatorenal syndrome produced by furosemide (frusemide)-the disposition of which is not substantially modified in liver disease-appear to be the most frequent adverse drug reactions in patients with liver disease. Furthermore, clinically significant alterations in the action of medications at concentrations generally considered to be in the normal therapeutic range are not uncommon. Tissue responsiveness to the pharmacological action of some drugs may be modified, as evidenced by the increased susceptibility of the brain in patients with cirrhosis to the action of many psychoactive agents. Another example is the greater susceptibility of such patients to the nephrotoxic potential of aminogly-cosides, which should not be used in this patient group. Drugs may also interfere with adaptive physiological processes induced by liver disease. ACE inhibitors and nonsteroidal anti-inflammatory drugs counteract the enhanced activity of the renin-angiotensin system in advanced liver disease, thereby generating a high risk of excessive hypotension or acute renal failure, respectively. These drugs are best avoided in patients with cirrhosis. Finally, there may be pharmacological effects that overlap with some pathophysiological modifications related to the process of liver disease, such as increased portal pressure produced by some calcium antagonists, or hypoprothrombinaemia related to the inhibition of synthesis of vitamin K-dependent clotting factors by some beta-lactam antibacterials (especially moxalactam and cefamandole). Accordingly, the use of these drugs should be avoided in advanced liver disease. It is noteworthy that reduced drug metabolism in patients with liver disease does not seem to have a significant impact on the frequency of hepatotoxicity. Special caution should be exercised, however, in patients with alcoholic liver disease because excessive alcohol intake may potentiate the hepatotoxic effect of paracetamol (acetaminophen).     

The hemodynamic effects of the in-vivo administration of insulin-like growth-factor I

BACKGROUND: Recent studies have demonstrated that IGF-I has several biological activities that correlate with the GH axis, by acting as a cell protecting factor and a promoting compound in different tissues and organs. Our latest findings have demonstrated a potential application of IGF-I in the treatment of postischemic renal injury, which frequently appears after a kidney transplant. The beneficial effect of the renal postoperative recovery probably correlates with the regulation of the vascular tone, in which IGF-I plays a role with other cytokines. However, this rises the question whether IGF-I has any effect on the general hemodynamic status. This study was designed to underline the intraoperative hemodynamic effect of exogenous IGF-I in an experimental setting of renal transplantation in swine. METHODS: Twelve female swine underwent a left renal autotransplantation. At the reperfusion the animals were separated in two groups. Group one served as control. Group two received 400 micrograms of IGF-I (added to the flushing solution). The animals were kept under complete hemodynamic monitoring over the operation. RESULTS: Among the different parameters studied (mean arterial pressure, mean pulmonary arterial pressure, pulmonary wedge pressure, central venous pressure, cardiac output, oxygen extraction ratio, systemic vascular resistance, oxygen delivery and oxygen consumption), any statistically significant difference between group one and two were observed. CONCLUSIONS: While the clinical administration of IGF-I requires further studies, the in vivo administration of this peptide is apparently well tolerated, and does not cause any hemodynamic instability to the operation.     

Systemic and coronary hemodynamic effects of repetitive cocaine administration in conscious dogs

The cardiovascular actions of cocaine are complex, and previous studies suggest that tachyphylaxis to the positive chronotropic and pressor effects of cocaine may develop after repetitive administration. We examined changes in systemic and coronary hemodynamics when single or multiple doses of intravenous (i.v.) cocaine were administered to conscious dogs. Dogs were chronically instrumented for measurement of aortic blood pressure (BP) and left ventricular pressure (LVP), LV dP/dtmax and dP/dt50, subendocardial segment length (%SS), diastolic coronary blood flow (CBF) velocity, and cardiac output (CO). Myocardial oxygen consumption was estimated by the pressure-work index (PWI). In one series of experiments, a single dose of cocaine (0.1, 0.2, 0.4, 0.8, or 1.6 mg/kg) was administered on 5 consecutive days in random fashion and peak changes in systemic and coronary hemodynamics were recorded. These doses were then randomly repeated in a second group of experiments with a 1-h interval between doses on the same day. Peak and steady-state changes in cardiovascular variables were recorded within and between each dose, respectively. In other experiments, higher doses of cocaine (0.8 or 1.6 mg/kg; separate groups) were administered four times at 1-h intervals in the same dogs and peak and steady-state changes in hemodynamics were determined. Cocaine caused dose-related increases in heart rate (HR), mean arterial pressure (MAP), LV systolic pressure (LVSP) and end-diastolic pressure (LVEDP), PWI, CO, and diastolic coronary vascular resistance and decreases in %SS when administered on different days. Cocaine also caused significant increases in baseline HR, MAP, LVSP, and PWI between doses given on the same day at 1-h intervals, but the absolute value of the peak response to cocaine of these hemodynamic parameters was independent of dosing regimen. These results were confirmed when we administered four doses of 0.8 mg/kg cocaine at 1-h intervals. The results indicate that baseline changes in systemic hemodynamic variables are a predominant feature of repetitive administration of lower doses of cocaine (< or = 0.8 mg/kg), but administration of higher doses of cocaine (> or = 8 mg/kg) at 1-h intervals caused tachyphylaxis to the hypertensive actions and myocardial oxygen consumption effects of cocaine.     

Early administration of ramipril in acute myocardial infarction: neurohormonal and hemodynamic effects and tolerability

Although several large studies indicate a beneficial effect of angiotensin-converting enzyme (ACE) inhibitors after myocardial infarction, the optimal timing of therapy in terms of safety and the effects on neurohormones during myocardial infarction are less well known. In order to investigate the effect of ramipril, administered within 24 h after myocardial infarction, on hemodynamics and neurohormones and its safety, 20 patients with a myocardial infarction were studied. Nine patients had an anterior, 10 an inferior, and 1 a non-Q-wave infarction. Fourteen patients received thrombolytic therapy, whereas 6 did not. The initial dose of ramipril was 1.25 mg, but was gradually increased to 5 mg during the next 4 days. Side effects did not occur. The mean arterial pressure decreased 8 h after the first dose from 84 +/- 2 mm Hg (control) to 77 +/- 2 mm Hg (p < 0.05) and remained decreased thereafter. This was accompanied by a reduction in systemic resistance of 8% after 8 h and of 12% on day 2. Heart rate, cardiac and stroke indexes, and pulmonary artery and wedge pressures did not change. The ACE activity decreased within 1 h of ramipril administration with a maximum of 71% at 4 h after the second dose and remained at this level throughout the study. Angiotensin II decreased by 34% (day 2) and by 41% (day 5). The renin activity gradually increased from 33 +/- 7.5 to 75.4 +/- 11.5 microM/ml on day 5, whereas epinephrine was reduced from day 2 onwards, with a maximal reduction of 71% on day 5. Arginine vasopressin was significantly reduced 5 h after ramipril administration until the end of the study, with a maximum of 77% on day 3. Moreover, a late but significant decrease in norepinephrine occurred on day 5. Thus, oral ramipril results in early ACE inhibition, followed by progressive attenuation of the neuroendocrine activation and a reduction in afterload during the acute phase of myocardial infarction. It is well tolerated, also in combination with nitroglycerin and thrombolytic therapy.     

Hyperthermia following MDMA administration in rats: effects of ambient temperature, water consumption, and chronic dosing

In two experiments it was found that the hyperthermia which follows MDMA ("Ecstasy") results from an interaction of direct pharmacological effect of the drug and the prevailing environmental conditions in which it is administered. In Experiment 1, rats given fixed doses of either 2.5, 5.0 or 7.5 mg/kg MDMA or saline were injected on different days at ambient temperatures (Ta's) of 11, 24, and 30 degrees C. At each Ta drinking water was freely available following dosing on one session and temporarily unavailable on a second. The hyperthermic and hyperkinetic responses were monitored using remote biotelemetry. Experiment 2 used a between-subject design in which each group of rats received a standard 7.5 mg/kg dose of MDMA administered at only one of the three levels of Ta(24 degrees C) and at only one level of the water-availability factor. Dosing in some groups was continued for a further 13 days to test for tolerance or sensitization effects. Ambient temperature significantly affected the magnitude of the hyperthermia but not the hyperkinesis. Water deprivation during the drugged period significantly augmented the hyperthermia, but only in the high Ta (30 degrees C.) condition. Chronic dosing produced sensitization of both hyperthermic and hyperkinetic responses. The findings indicate that ambient temperature, water consumption and frequency of drug use affect the hyperthermia which follows MDMA administration.     

Diversity in the renal hemodynamic effects of dihydropyridine calcium blockers in spontaneously hypertensive rats

BACKGROUND: Death rates from coronary hearts disease have exhibited remarkable declines in most industrialised countries. Cardiovascular mortality has been the subject of extensive research and we considered it important to analyse recent local population based data on hospital outcomes of acute myocardial infarction (AMI). AIM: To document the trends in in-hospital mortality from AMI in Victoria from 1987-1994. METHODS: This was a retrospective analysis of data from the Victorian Inpatient Minimum Database relating to all public acute care hospitals. All separations recording a principal diagnosis 410 (AMI) were selected. Changes in distribution of AMI separations, in-hospital mortality, and changes in length of stay were examined. RESULTS: The mean age of women admitted was 72 years compared with 64 years for men. Women comprised around a third of the overall sample but the proportion varied from 13% in those under 50 years to 57% among those aged 80 years and over. A striking decline in mortality was observed throughout the eight year period. The relative age adjusted decline was 33.5% (40% in males and 26% in females) with rates remaining higher in women. This decline occurred despite the increasing representation of those aged over 80 years. There was a significant decline in the mean length of stay (1.8 days) over the eight year period but this is likely to have had only minimal impact on mortality rates. CONCLUSION: We have documented welcome declines in in-hospital mortality from AMI that are not an artefact of declining lengths of stay. Our observations parallel those in similar overseas studies. Large changes in medical management have taken place from the mid 1980s and may be partly responsible, but a change in disease process cannot be ruled out.     

A microcholangiographic study of liver disease models in rats

RATIONALE AND OBJECTIVES: Rats develop hepatobiliary injury due to small bowel bacterial overgrowth (SBBO) that, at specimen, resembles cholangiography sclerosing cholangitis. To better visualize the smaller bile ducts, we used microcholangiography to determine the spectrum of biliary lesions in this and five other models of liver disease. METHODS: The models studied were as follows: (1) Surgically created jejunal, self-filling blind loops induce SBBO. (2) Intraperitoneal injection of a bacterial cell wall polymer, peptidoglycan-polysaccharide (PG-PS), causes granulomatous hepatitis. (3) Intraperitoneal injection of endotoxin (lipopolysaccharide) causes sinusoidal congestion and shock. (4) Bile duct ligation induces bile duct proliferation. (5) Alpha-naphthyl-isothiocyanate (ANIT) induces bile duct proliferation. (6) Carbon tetrachloride (CCl4) causes fibrosis and cirrhosis. Warmed barium sulfate, gelatin, and saline were injected in the extrahepatic bile duct. Liver slices (2 mm) underwent microradiographic techniques, and images were correlated with histology. RESULTS: Rats with SBBO had irregular and dilated extrahepatic bile ducts with thickened walls. Rats treated with endotoxin and CCl4 had normal microcholangiograms. Bile duct proliferation was identified following ANIT and bile duct ligation. Rats given PG-PS demonstrated irregular intrahepatic bile ducts. Microcholangiograms following SBBO and PG-PS showed similarities including focal ductal dilatation, narrowing, proliferation, and destruction. CONCLUSION: Various models of liver injury induce characteristic cholangiographic appearances. Microcholangiography is useful in examining biliary tract lesions and complements histology.     

Natriuretic and kaliuretic effects of central acute cadmium administration in rats

To investigate the mechanism of sugar accumulation in fruit vacuoles, a full length cDNA (CitVATP-A) encoding the vacuolar H+-ATPase 69-kDa catalytic subunit was isolated from a cDNA library constructed from citrus fruit (Citrus unshiu Marc.). A 2304-bp insert of CitVATP-A was coded for a 623 amino acid polypeptide with a predicted molecular mass of 68.68 kDa. The deduced amino acid sequence for CitVATP-A showed a 96.5% homology with the carrot homologue. Genomic Southern blot analysis suggested that CitVATP-A is a low-copy number gene. Northern blot analysis of leaves and fruits during the developing stages showed that the level of expression is high in young leaves and is low in mature leaves, and that it increased in both the edible parts and the peel, during fruit growth and maturity.     

The chronobiological aspects of the hemodynamic effects of clonidine in Wistar rats under immobilization stress

The aim of the study was estimation of the incidence rate of complications arising in the course of fractional plasmapheresis (FPA), the analysis of their causes and design of prophylactic measures. 139 courses comprising 410 FPA sessions were delivered in 118 patients with various diseases. The highest rate of complications was 4.7%. If put on FPA without previous preparation, the patient experienced marked hypotension because of fast escape from circulation of 500 ml of blood. Induction of short-term hypervolemia in patients with low arterial pressure prevents emergence of cardiovascular complications in the course of blood exfusion.     

Effects of acute and delayed effects of prior chronic cocaine administration on regional rates of cerebral protein synthesis in rats

Single or repeated treatments with cocaine (15 mg/kg, i.p.) in rats modify rates of local cerebral protein synthesis (ICPSleu) measured with the [1-14C]leucine method. A single dose of cocaine to naive rats reduced ICPSleu by about 10% throughout the brain; the most statistically significant reduction was in the nucleus accumbens, shell portion (P = .0003). A comparable dose of cocaine administered acutely after 1 wk of daily cocaine injections had no effects on ICPSleu. Delayed effects of prior chronic cocaine treatment were studied in experiments in which one rat of each pair received injections with saline for 8 days and the other cocaine, and on the 15th day ICPSleu was measured. In these experiments delayed effects of the chronic cocaine treatment were observed; in the cocaine-treated rats ICPSleu was significantly increased in selective brain regions, i.e., prefrontal and primary olfactory cortex (P < .006). These results suggest that acute effects of a single dose of cocaine and residual effects of chronic cocaine treatment on ICPSleu are distinctly different and occur in different regions of the brain.     

Long-term effects of prenatal indomethacin administration on the pulmonary circulation in rats

Mechanical properties of the adult pulmonary vasculature are affected by perinatal experience of hypoxic pulmonary hypertension. In the present study, we followed the long-term effects of perinatal pulmonary hypertension induced by means other than hypoxia in rats. Daily injections of indomethacin (1 mg.kg-1 body weight (BW)) were given to the parturient rats. Their newborn pups had significantly increased number of muscularized peripheral pulmonary vessels. Pulmonary hypertension, however, did not persist to adulthood (mean pulmonary arterial pressure (Ppa) was 17.2 +/- 1.3 torr in the experimental group and 16.4 +/- 0.8 torr in controls). Pulmonary hypertension induced in adult rats by exposure to chronic hypoxia or by acute hypoxic challenges was similar in indomethacin-treated and control rats. Normoxic perfusion pressure/flow (P/Q) plots in isolated lungs were less steep in indomethacin-treated than in control rats. Acute hypoxia increased the slope of P/Q plots in indomethacin treated rats but not in controls. The described changes in the pulmonary vasculature induced by indomethacin are similar to those found previously in adult rats born in hypoxia. We conclude that perinatal pulmonary hypertension permanently modifies the pulmonary vasculature.     

Vasoactive intestinal peptide in cirrhotic rats: hemodynamic effects and mesenteric arterial receptor characteristics

Vasoactive intestinal peptide (VIP) blood levels in cirrhosis are elevated, but its hemodynamic and receptor characteristics remain unclarified. We aimed to quantify VIP receptor characteristics in mesenteric arteries, plasma VIP concentration by radioimmunoassay (RIA), and the hemodynamic effects of VIP infusion in bile duct-ligated (BDL) cirrhotic and sham-operated control rats. Mesenteric arterial membranes were prepared by ultracentrifugation, and receptor characteristics were studied using 125I-labeled VIP as a radioligand. For the hemodynamic study, there were four groups: cirrhotic and sham-operated rats were infused with either VIP (50 ng/kg/min for 15 minutes) or equivolumic isotonic saline. Regional blood flows were measured in conscious rats with radioactive microspheres. Receptor studies showed high- and low-affinity binding sites for VIP, which had similar equilibrium dissociation constants (binding affinities) and receptor densities for both the cirrhotic and control rats. Plasma VIP concentrations were significantly elevated in the cirrhotic rats. In both cirrhotic and sham-operated rats, VIP infusion produced plasma levels approximately twofold to threefold increased over the basal levels observed in cirrhotic rats. In cirrhotic rats, VIP infusion did not affect any hemodynamic parameter, whereas in the sham-operated rats VIP infusion significantly increased the mesenteric visceral blood flow. These results show that the hyporesponsiveness to VIP in cirrhotic rats is not attributable to receptor downregulation, implying postreceptor alterations. This suggests that VIP may not play a major role in the maintenance of splanchnic hyperemia in cirrhosis.     

Painful muscle cramps in liver cirrhosis and effects of oral taurine administration

We administered 3 g of taurine orally for four weeks to 35 patients suffering from liver cirrhosis with repeated muscle cramp (MC). Improvement of MC was noted in 22 cases (62.9%). We also determined the plasma taurine concentration in eight cases of liver cirrhosis with MC. The plasma taurine concentration before ingestion was 54.1 +/- 20.7 nmol/ml, whereas that of four weeks after ingestion was 125.1 +/- 59.1 nmol/ml, which was significantly elevated by 2.3 fold. As the concentration increased, the frequency of MC decreased, suggesting the good correlation between ingestion and the decrease in frequency of MC. In liver cirrhosis without MC the plasma taurine concentration was 81.0 +/- 16.7 nmol/ml, which was significantly higher than in liver cirrhosis with MC. In a few cases with taurine ingestion, serial plasma taurine concentrations were detected. Plasma taurine reached the peak value during the first week of ingestion and plasma taurine levels were maintained 2-5 fold higher during ingestion.     

Tissue-specific effects of chronic dietary protein restriction and gastrostomy on the insulin-like growth factor-I pathway in the liver and colon of adult rats

Dietary protein restriction decreases plasma concentrations of insulin-like growth factor-I (IGF-I) and reduces IGF-I mRNA levels in the liver. In addition to the actions of systemic IGF-I, locally produced IGF-I is thought to mediate autocrine and paracrine growth effects in the colon. The objectives of the present study were to investigate the IGF-I pathway in the colon and liver of adult rats under conditions of dietary protein restriction, surgical stress, and dietary protein repletion. Two groups of rats were placed on either a 20% or 2% casein diet for 19 days. Two additional groups of rats underwent gastrostomy after a 2% casein diet for 2 weeks, and then were either kept on the 2% casein diet or changed to a 20% casein diet until day 19. Dietary protein restriction reduced plasma concentrations of IGF-I and IGF-binding proteins (IGFBPs) and hepatic IGF-I mRNA content, while increasing colonic IGF-I receptor mRNA. Gastrostomy in protein-depleted animals had no effect on hepatic IGF-I mRNA, but led to a marked increase in colonic IGF-I mRNA levels. Dietary protein repletion resulted in a decrease in colonic IGF-I receptor mRNA. The distinct effects of dietary protein depletion and operative stress on the IGF pathway in the colon as compared with the liver may serve to maintain the level of IGF-I signaling in the colon by autocrine or paracrine mechanisms under these conditions.     

Anatomical and behavioral effects of colchicine administration to rats late in utero

Offspring from pregnant rats injected with 4mg/kg body weight colchicine on Embryonic Days 18, 19, and 20 were found to have isocortical and hippocampal structures greatly reduced in mass when examined at birth. Cells with pyknotic nuclei were found in Layers 5, 4, and 3 of the cerebral isocortex, the habenula, and anterior medial nuclei of the thalamus. Brains taken at Postnatal Days 22 and 132 were reduced in overall size, and had a 20-30% reduction of cells at the vertex of the neocortex with up to 50% reduction in the thickness of the corpus callosum. A decrease in activity, an increase in fearfulness and/or decreased tendency to explore, reduced error scores on the Hebb-Williams maze, poor performance on the Maier elevated maze, and a lessened sensitivity to sound-induced seizures were correlated with these anatomical changes.     

Effects of acute and chronic dieldrin administration on liver and plasma esterases of the rat

A heritable propensity to develop malignant lesions is found in individuals with familial adenomatosis of the colon an rectum (ACR) and the Gardner's syndrome variant, an autosomal dominant trait. In the present study, the growth characteristics of cultured skin fibroblasts (SF) derived from normal-appearing flat skin biopsies of ACR families, representing all phenotypes, and appropriate controls were investigated. SF were obtained from stocks between the second and fifth passages and growth to confluency in Eagle's Minimal Essential Medium (EMEM) supplemented with 15% fetal calf serum (FCS). Following trypsinization, cells were replanted in EMEM supplemented with either 1% or 15% FCS at an initial density of 4 x 10(3) cells/cm2 and counted daily for five days. Normal SF representing several age groups (both sexes) and those obtained from non-afflicted individuals of ACR families grew only in 15% FCS. In contrast, SF from ACR subjects and from embryonal skin grew both in 1% and 15% FCS. SF from several clinically asymptomatic adults, children or ACR patients, grew in 1% FCS as well. Cell cultures from ACR individuals showed regions of criss-crossed arrays and multilayered pattern. These growth properties were not observed in normal cell cultures. The SF from ACR individuals did not grow in methocel, nor did they form tumors in athymic mice. These results suggest the occurrence of previously undetected biochemical alterations in SF taken from ACR genotypes.