A percutaneous approach to cardiac haemodynamics in anaesthetised rats

Established methods for evaluating cardiac function in small animals involve surgical manoeuvres. We describe a method for evaluating left ventricular volume (LVV) and pressure (LVP) in anaesthetised adult rats. Under fluoroscopic control a 23 G needle was inserted into the left ventricular cavity of anaesthetised normotensive WKY rats. LVV was determined by biplane angiography and LVP was measured directly. Surface electrocardiograms were recorded throughout the procedure. In 8 animals the study was repeated three times, one week apart. Animals were then sacrificed and tissues harvested for histological examination. In 8 rats, the technique was found to be reproducible and there was no evidence of functional (ECG) or pathological myocardial damage following repeated measurements. In conclusion this technique provides a reproducible method of measuring LVV and LVP, allowing longitudinal haemodynamic studies in anaesthetised rats.     

Splanchnic haemodynamics in patients with coeliac disease: effects of a gluten-free diet

BACKGROUND: Coeliac disease is characterized by structural and functional changes in the small bowel which may also result in haemodynamic changes. AIMS: To establish whether splanchnic haemodynamics can be modified by a gluten-free diet. PATIENTS: Ten coeliac patients and 10 paired healthy subjects. METHODS: Echo-Doppler measurements were made of splanchnic vessels both fasting and after a standard meal before and after 9 months of a gluten-free diet. RESULTS: In comparison to controls, coeliac patients had higher superior mesenteric artery blood velocity and flow, with lower resistance indexes and higher portal vein velocity and flow, particularly 3 h after a meal. Postprandial hyperaemia was reduced and delayed in time. Intrasplenic resistance indexes were also significantly lower both fasting and after a meal. After 9 months of a gluten-free diet, no significant differences were observed between coeliac patients and controls, both fasting and after a meal. CONCLUSIONS: Splanchnic haemodynamics is significantly changed in coeliac patients, mainly after a meal. On treatment with a gluten-free diet, both fasting and postprandial haemodynamics became normal.     

Comparative assessment of secretin and motilin responses to graded duodenal acidification in anaesthetised pigs

The effects of graded duodenal acidification on plasma concentration of immunoreactive secretin, and motilin in portal vein (PV) and carotid artery (CA) were investigated in 6 anaesthetised pigs in which the proximal duodenum was excluded and sequentially irrigated with isotonic saline (pH 7.0) and with hydrochloric acid (HCl) delivered at successive rates of 2, 8 and 40 mM H+/40 min (pH of 2.8, 1.9 and 1.0, respectively) under a constant flow of 10 ml/min. The release of secretin was first observed at pH 1.9 (from basal 4.2 +/- 0.3 to a peak of 26.6 +/- 9.8 pM in PV and from 3.4 +/- 0.3 to 6.8 +/- 0.9 pM in CA) and further increased at pH 1.0 (peaks of 60.9 +/- 16.3 in PV and 16.8 +/- 2.6 pM in CA). In contrast, only the highest HCl concentration (pH of effluent: 1.0) induced significant increases of plasma motilin (PV: peak of 25.2 +/- 4.9 for basal 13.3 +/- 1.1 pM, CA: 14.3 +/- 2.4 for basal 10.5 +/- 0.6 pM). A sharp decrease of the plasma secretin and motilin concentration was observed when the venous drainage of the duodenal segment was occluded, followed by a rapid increase when the clamp was released. In the present experimental conditions, duodenal motilin-producing sites were less sensitive to graded luminal acidification than secretin cells. Thus, the release of duodenal motilin in response to variations of luminal pH may be expected to occur primarily from the most proximal part of the duodenum in physiological conditions.     

Splanchnic haemodynamics in non-alcoholic fatty liver disease: effect of a dietary/pharmacological treatment: A pilot study

BACKGROUND: Previous studies demonstrated that in experimental animals fatty liver is associated with reduced hepatic blood flow and that metformin reverses steatosis, while no data were reported in humans. AIMS: To evaluate the clinical relevance of echo-Doppler measurements and the effects of therapy in non-alcoholic fatty liver disease. PATIENTS: Twenty patients with biopsy proven non-alcoholic fatty liver disease. METHODS: Abdominal echo-Doppler examination was performed at enrolment and, in 11 patients, after 6 months of dietary/pharmacological therapy (metformin 500 mg three times a day). RESULTS: Non-alcoholic fatty liver disease was characterised by hepatomegaly, bright echotexture and posterior attenuation. Mean portal blood velocity and flow were low-normal. Brightness and posterior attenuation significantly correlated with fat score in liver biopsies as well as with the hepatic veins spectrum. After therapy, echotexture improved and liver volume significantly decreased. Portal blood velocity and flow significantly increased, intrahepatic arterial indexes decreased and the spectrum of hepatic veins improved. CONCLUSIONS: Fatty liver is associated with an impaired hepatic blood flow characterised by increased intrahepatic resistances. Vascular changes are reversed by treatment and can be measured by echo-Doppler which may be useful to evaluate the natural course of non-alcoholic fatty liver disease, and to monitor the putative beneficial effects of therapy.     

Effect of the calcium sensitizer levosimendan on the performance of ischaemic myocardium in anaesthetised pigs

The calcium sensitizer levosimendan (LEV) improves the function of stunned myocardium, cardiac performance in heart failure, and possibly the efficiency of myocardial work. The present experiments investigated the effect of LEV on myocardial contraction and metabolism of acutely ischaemic myocardium distal to a functionally effective coronary artery stenosis. Anaesthetised open chest pigs (n = 14) were instrumented to assess heart rate (HR), aortic pressure (AoP), cardiac output (CO), blood flow in the left descending (QLAD) and circumflex (QLCX) coronary artery, myocardial end-diastolic segment length and systolic shortening (edL, MSS by sonomicrometry) in the LAD- and LCX-territory. Systemic vascular resistance (SVR), and a myocardial power index (PowI) for the LAD- and LCX-region were calculated. Following obstruction of QLAD by an external snare proximal to the first diagonal branch LEV was given intravenously (10 + 20 + 30 g/kg 15 min apart, n = 8) or the vehicle of LEV (n = 6). Following LEV haemodynamics and regional myocardial performance changed significantly: HR +22 min^–1, AoP –6 mmHg, CO +17%, SVR –21%; intact myocardium: QLCX +15%, RLCX –24%, PowILCX + 39%; ischaemic myocardium: QLAD –7%, MSSLAD –42%, PowILAD –27%. The data confirm the pharmacological profile of LEV: positive chronotropy, positive inotropy, and vasodilatation. The pump function of acutely ischaemic myocardium worsened following LEV. The efficiency of myocardial performance did not improve. A beneficial effect of LEV on the function of ischaemic myocardium was possibly outmanoeuvred by the increase in heart rate.     

Significant improvement of portopulmonary hypertension after 1-week terlipressin treatment

Cirrhosis associated with moderate and severe portopulmonary hypertension carries a poor prognosis. Optimal management has not yet been defined. Current treatment options, such as prostacyclin analogues, endothelin antagonists, and phosphodiesterase-5 inhibitors, are characterized by slow onset of action and various adverse effects, particularly in patients with advanced cirrhosis. Here, we report the significant reduction of pulmonary arterial pressure after 1-week terlipressin treatment in a patient with concomitant hepato-renal syndrome. Terlipressin could be a novel and safe treatment for portopulmonary hypertension.     

A case of peripheral ischemic complication after terlipressin therapy]

Hepatorenal syndrome is a severe complication of cirrhosis, leading to death in more than 90% of cases in the absence of liver transplantation. Several treatments have been attempted as a bridge to liver transplantation. Among such treatments, terlipressin is a nonselective V1 vasopressin agonist. When comparing with ornipressin, it is known to have a similar vasoconstricting potency, but much less ischemic complication. We report a case of gangrene on toes and necrosis on the infusion site of left hand which developed after the use of terlipressin due to hepatorenal syndrome in a 41-year-old-man with liver cirrhosis. Ischemic complication of terlipressin is rare and there has been no case report in Korea. Although it is rare, we must pay attention to the peripheral ischemic complication of terlipressin.     

Pharmacokinetics and effects of recombinant human erythropoietin after intravenous and subcutaneous injections in healthy volunteers

A double-blind, placebo-controlled study of the pharmacokinetics and safety of multiple doses of recombinant human erythropoietin [rHuEPO 150 or 300 U/kg either by intravenous (IV) bolus or subcutaneously (SC)] in normal male subjects demonstrated that rHuEPO had a dose-related effect on the hematocrit independent of the route of administration and that multiple doses of rHuEPO had no direct pressor effects. When rHuEPO was injected IV, a monoexponential decrease in serum EPO level was evident for 18 to 24 hours postdose. Absorption of SC injected rHuEPO occurred more slowly, with relatively low serum EPO levels being maintained for 48 hours. All rHuEPO antibody titer determinations were negative. With the exception of significant increases in hemoglobin and hematocrit, no clinically significant changes occurred. No hypertensive, convulsive, or thrombotic events were observed. Of the adverse experiences observed in 10 subjects, none was considered clinically significant, and none of the subjects dropped out because of adverse experiences.     

Beneficial effects of intravenous nitroglycerin on haemodynamics and enzymatically estimated infarct size

The effects of intravenous nitroglycerin (TNG) were evaluated in 39 patients with a first acute myocardial infarction, subdivided according to Killip into those with left ventricular failure (N = 24) and those without (N = 15). A group of 38 randomly selected patients treated in a conventional, but unstandardized manner, served as a control (C). TNG caused a statistically significant reduction in pulmonary artery diastolic pressure, regardless of its initial value, by about 30%. Neither cardiac index nor total peripheral resistance was significantly changed. Infarct size, measured in gEq of isoenzyme MB creatine kinase (CK-MB), was smaller by about 40% in both subgroups of patients treated with TNG, when compared with the controls. A significant difference was found in peak CK-MB blood levels only in the group of patients with left ventricular failure (Killip classes II and III) treated with TNG. The best results were obtained when TNG was given not later than 4 h after the onset of the symptoms of infarction.     

Splanchnic metabolism of amino acids in healthy subjects: effect of 60 hours of fasting

Brief starvation is accompanied by decreased circulating levels of most amino acids, which has been attributed to an increased splanchnic uptake of amino acids, primarily alanine, for gluconeogenesis. However, quantitative data on splanchnic exchange of amino acids and gluconeogenic precursors is lacking. Consequently, arterial concentrations and splanchnic exchange of whole blood amino acids, ketone bodies, glucose, and gluconeogenic precursors were measured in 16 prolonged fasted (60 to 64 hours) and 15 overnight fasted (12 to 14 hours) healthy, nonobese subjects. After the 60-hour fast net splanchnic glucose production decreased by 41% to 0.31 +/- 0.02 mumol/L (P less than .001), whereas the splanchnic uptake of gluconeogenic precursors increased and could account for the total glucose output. Net splanchnic uptake of taurine, threonine, serine, glycine, lysine, histidine, and arginine rose significantly in response to fasting (P less than .05 to .01) due to increased splanchnic fractional extraction. Although the splanchnic fractional extraction of alanine was augmented by 40% (P less than .001), net splanchnic uptake was not influenced by fasting. Total net splanchnic uptake of amino acids increased by 68%, from 231 +/- 44 mumol/min in the postabsorptive state to 388 +/- 63 mumol/min (mean +/- SEM) (P less than .05) in the 60-hour fasted state. However, only one half of this rise was accounted for by gluconeogenic amino acids.     

High-sensitivity C-reactive protein affects central haemodynamics and augmentation index in apparently healthy persons

OBJECTIVE: Among apparently healthy women and men, elevated levels of high-sensitivity C-reactive protein (hsCRP) predict the risk of cardiovascular events and may be useful for detecting subclinical atherosclerosis. The aim of this study was to investigate the associations between inflammatory markers, augmentation index (AIx), central pulse pressure and central systolic blood pressure in apparently healthy subjects. DESIGN AND SETTINGS: An observational study conducted at a university teaching hospital. METHODS AND RESULTS: Apparently healthy subjects (n = 158; 75 males, 83 females) passed a complete history and physical examination, blood tests and pulse wave analysis.AIx was significantly higher in patients with hsCRP levels above 1 mg/l (24.5 +/-9.9 versus 18.1+/-12.6%, P < 0.001). Central pulse pressure and central systolic blood pressure were significantly higher in the group with hsCRP levels above 1 mg/l. No differences between groups were shown for peripheral pulse pressure, peripheral blood pressures and estimated aortic pulse wave velocity. In multiple regression analysis, AIx correlated positively with age, female gender, short stature, mean arterial pressure, hsCRP (P = 0.026) and white blood cell count (P = 0.01), and negatively with heart rate. CONCLUSIONS: This study shows that plasma levels of hsCRP are positively correlated with AIx, central pulse pressure and central systolic blood pressure. Apparently healthy subjects with increased inflammatory markers have increased systemic arterial stiffness, which might reflect early atherosclerotic changes. Our results suggest that hsCRP and non-invasively measured arterial stiffness could serve as additional tools, beside conventional cardiovascular risk factors, for assessment of global arterial risk and preclinical atherosclerotic changes in arteries.     

Age-dependent effects of milrinone and levosimendan on ventricular function and haemodynamics in newborn and mature pigs

Inodilators are used in the treatment of low cardiac output, mainly after cardiac surgery. At present, there is little knowledge of the effect of inodilators in the newborn heart. Immediately after birth and in the neonatal period, the metabolism and physiology of the heart undergo major changes. We hypothesised that effects of the inodilators milrinone and levosimendan on myocardial contractility and haemodynamics under normal physiological conditions were age dependent. Animal studies were conducted on 48 pigs using a closed-chest biventricular conductance catheter method. Pigs in two age groups, that is, 5-6 days and 5-6 weeks, were assigned to milrinone, levosimendan, or a control group. We observed that both milrinone - 19.2% with a p value of 0.05 - and levosimendan - 25.7% with a p value of 0.03 compared with the control group increased cardiac output, as well as myocardial contractility with a maximum pressure development over time: milrinone 28.2%, p = 0.01 and levosimendan 19.4%, p = 0.05. Milrinone improved diastolic performance (p < 0.05) in the left ventricle in the 5-6-week-old animals. In the newborn animals, neither of the inodilators increased ventricular contractility or cardiac output; however, we observed a significant decrease in the mean arterial pressure: milrinone 34.6%, p < 0.01 and levosimendan 30.1%, p = 0.02. Both inodilators demonstrated age-dependent haemodynamic effects, and it is noteworthy that neither milrinone nor levosimendan was able to increase cardiac output in the newborn heart.     

Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs

Aims/hypothesis The insulinotropic hormone, glucagon-like peptide-1 (GLP-1), is rapidly degraded in vivo as a result of the combination of extensive enzymatic degradation and renal extraction. The GLP-1 receptor agonist, exendin-4, has a longer duration of action, and has recently been approved as a new agent for the treatment of type 2 diabetes mellitus. Exendin-4 is less prone to enzymatic degradation, but it is still unclear what other factors contribute to the increased metabolic stability. Materials and methods The overall metabolism of GLP-1 and exendin-4 was directly compared in anaesthetised pigs (n=9). Results Metabolism of GLP-1 (C-terminal RIA; t _1/2 2.0±0.2 min, metabolic clearance rate [MCR] 23.2±2.8 ml min⁻¹ kg⁻¹; N-terminal RIA; t _1/2 1.5±0.2 min, MCR 88.1±10.6 ml min⁻¹ kg⁻¹) was significantly faster than the metabolism of exendin-4 (t _1/2 22.0±2.1 min, p<0.0001; MCR 1.7±0.3 ml min⁻¹ kg⁻¹, p<0.01). Differences in arteriovenous concentrations revealed organ extraction of GLP-1 by the kidneys (C-terminal 56.6±2.6%; N-terminal 48.3±5.9%), liver (N-terminal 41.4±3.8%), and peripheral tissues (C-terminal 42.3±6.0%; N-terminal 33.0±7.8%), whereas organ extraction of exendin-4 was limited to the kidneys (21.3±4.9%). While the renal extraction of exendin-4 (6.9±2.5 pmol/min) did not differ significantly from the amount undergoing glomerular filtration (8.4±2.0 pmol/min), the renal extraction of C-terminal GLP-1 (9.0±1.1 pmol/min), exceeded the amount which could be accounted for by glomerular filtration (4.2±0.5 pmol/min, p<0.0005). Conclusions/interpretation In addition to an increased resistance to enzymatic degradation, the increased stability of exendin-4 is the result of reduced differential organ extraction compared to GLP-1. The data suggest that in the anaesthetised pig, extraction occurs only in the kidney and can be fully accounted for by glomerular filtration.     

Amnestic effects of intravenous diazepam in healthy young men

Changes in a test of memory performance were evaluated in 103 healthy young men after challenges with placebo and two different doses of intravenous diazepam (0.12 and 0.20 mg/kg). Both diazepam doses significantly impaired free recall in a dose-dependent manner. Within each dose challenge there was no significant correlation between the average serum diazepam or desmethyldiazepam levels and the average number of words recalled across the time points. The data expand our current understanding of the amnestic effects of benzodiazepines and suggest that patients abusing these drugs in large doses may develop profound degrees of memory impairment.     

Effects of sustained intravenous diltiazem infusion in healthy persons

A 3-stage infusion of diltiazem was tested in 8 subjects for up to 48 hours: a bolus injection (10 mg over 3 minutes), a rapid loading infusion (20 mg over 30 minutes) and a maintenance infusion (10 mg/hour to the end of the study). This regimen produced stable median plasma diltiazem concentrations of approximately 150 ng/ml. The median half-life of elimination for diltiazem was 206 minutes (range 144 to 452) and median total clearance was 980 ml/min (range 665 to 1,907). The PR interval lengthened 10 to 18% during the maintenance infusion in 7 subjects; in 1 subject atrioventricular nodal Wenckebach conduction was recorded during the rapid loading infusion. Systolic blood pressure decreased from 124 +/- 7 mm Hg (mean +/- standard deviation) during the control period to 121 +/- 8 mm Hg during the rapid loading infusion (p = 0.03 compared with control) and to 117 +/- 7 mm Hg (p = 0.04 compared with control) during the maintenance infusion. Heart rate did not change. PR interval and blood pressure returned to control levels within 4 hours after the infusion was stopped. Loading and maintenance infusion may be an attractive method of administering diltiazem when stable drug concentrations are required for prolonged periods.