Coronary Collateral Microcirculation Reserve Becomes Vestigial with Aging

<b><i>Introduction:</i></b> Our previous study indicated that coronary collateral microcirculation reserve (CCMR), native collaterals, transports blood flow to an ischemic area to reduce ischemic tissue injury. This study aimed to observe the changes of CCMR in the hearts of different month-old rats. <b><i>Methods:</i></b> We selected 2-, 8-, 16-, and 24-month-old rats as the research objects to monitor the changes of CCMR in rats with aging. After acute myocardial infarction, lectin-FITC was injected into the femoral vein vessels of rats to mark CCMR vessels in the ischemic area. <b><i>Results:</i></b> Results of the lectin-FITC perfusion experiment indicated that the number and collagen IV coverage of CCMR vessels declined with aging. Moreover, data suggested a correlation between endothelial nitric oxide synthase and a decline in the number of CCMR vessels. <b><i>Conclusion:</i></b> Aging causes CCMR decline in rats.

Effects of leaf extracts of Vernonia amygdalina on the force and rate of contractility of an isolated mammalian heart

Background: Vernonia amygdalina is a common medicinal plant that is widely used by local communities and traditional herbalists in central Uganda in management of various conditions including hypertension that occurs as a result of changes in heart contractility. However, there is limited scientific information of V. amygdalina effects on the force and rate of contractility of the heart. The study evaluated the inotropic and chronotropic effect of methanol, aqueous, ether and total crude leaf extracts of V. amygdalina on isolated perfused rabbit heart.Methods: An experimental laboratory based study determined the effects of V. amygdalina extracts on the rate and force of contraction isolated perfused rabbit using the Langendorff’s heart perfusion experiment and methods. The heart rate (beats/minute) was counted per minute. The force of contraction of the heart was determined measuring the height of each peak on the kymogram.Results: The findings showed that the force and rate of heart contractility reduced with increasing doses of methanol, aqueous ether and total crude leaf extracts at doses of 0.5, 8.0, 62.0 and 250.0 mg/ml. The force and rate of heart contractility at a dose of 250.0 mg/ml for all the extracts were comparable to that of acetylcholine drug to almost causing cardiac arrest.Conclusions: The leaf extracts of V. amygdalina contain compounds that reduced the force and rate of contraction of an isolated rabbit heart.

Absorption Mechanism of Cyclosporine A Loaded pH-Sensitive Nanoparticles in Rats

CyA was prepared into CyA Eudragit S100 nanoparticles (CyA-S100 NP) and the mechanisms of CyA-S100 NP improving the CyA absorption in gastrointestinal tract (GI) were studied systematically in rats. In the GI distribution study, the emptying rates of CyA-S100 NP in duodenum, jejunum, ileum and colon were all lower than these of Neoral®, while in stomach, it was larger than that of Neoral®. In in situ recirculating intestine perfusion experiment, the largest absorption in CyA-S100 NP group occurred in ileum while that in Neoral® group arised in duodenum. The sequence of (AUC0–240 min/A for CyA-S100 NP and Neoral® group was ileum > duodenum > jejunum > colon and duodenum > jejunum > ileum > colon, respectively. CyA in nanoparticles degradated by luminal contents and subcellular fractions were more slowly than these in Neoral®, suggesting the significant protect effect of nanoparticles. Mucoadhesion study in small intestine showed that among all the parts of intestine, CyA-S100 NP exhibited larger mucoadhesive characteristics than Neoral® microemulsion. The sequence of mucoadhesion for CyA-S100 NP group was duodenum > ileum > jejunum and colon, while that for Neoral® group was duodenum > ileum, jejunum and colon, suggesting different site-specific behaves. These results illustrated that nanoparticles increased the absorption of CyA could be attributed to fast stomach empting rate, absorption site specific, small degradation rate by luminal contents, high bioadhension of nanoparticles to intestine mucosa and the use of P-Glycoprotein inhibitor if there is any. This investigation is helpful for the dosage form design for other peptide or protein drugs.

Transport Characteristics of Wheat Germ Agglutinin-Modified Insulin-Liposomes and Solid Lipid Nanoparticles in a Perfused Rat Intestinal Model

Wheat germ agglutinin (WGA) modified liposomes and solid lipid nanoparticles (SLNs) were evaluated for improving intestinal absorption of insulin. In an in situ local intestinal perfusion experiment, formulations containing 100 IU/kg insulin were administered to the duodenum, jejunum, and ileum of fasted rats. As hypothesized, ileum was the best intestinal location for the absorption of insulin-containing liposomes. Serum insulin concentrations decreased for the various formulations in different absorption sites according to the following trends: Duodenum > ileum > jejunum for WGA-modified insulin-containing liposomes; duodenum > jejunum > ileum for WGA-modified insulin-containing SLNs; ileum > jejunum > duodenum for insulin-containing liposomes; ileum > duodenum > jejunum for insulin-containing SLNs; and duodenum ≥ ileum > jejunum for aqueous solution of insulin. These results imply that the nanoparticle type and delivery site were important factors with respect to increasing the bioavailability of insulin following oral administration. The proteolytic degradation as well as the epithelial permeability were primary determinants influcing insulin mucosal absorption.

Effect of Hypothermia on the Hepatic Uptake and Biliary Excretion of Vecuronium in the Isolated Perfused Rat Liver

Background Hypothermia prolongs the time course of action of nondepolarizing muscle relaxants. It is not known whether this prolongation is caused by a reduced rate of extrahepatic distribution or elimination, liver uptake, metabolic clearance, or biliary excretion. Therefore, the authors studied the effects of hypothermia on the net hepatic uptake, metabolism, and biliary excretion of vecuronium in isolated perfused rat liver. Methods Livers of Wistar rats were perfused with Krebs Ringer solution (1% albumin, 3.3% carbon dioxide in oxygen, pH 7.36-7.42, 38 degrees C). Each perfusion experiment (recirculatory perfusion system) was divided into three phases. In phase 1, a bolus dose of vecuronium (950 microg) was followed by a continuous infusion of vecuronium (63 microg/min) throughout the perfusion experiment. In phase 2, the temperature was reduced to 28 degrees C. In phase 3, temperature was restored. In controls, the temperature was kept constant throughout the perfusion. Concentrations of vecuronium and its metabolites were measured in perfusion medium, bile, and liver homogenate. Parameters of a multicompartmental liver model were fitted to the concentration patterns in perfusion medium and in bile. Results Hypothermia increased vecuronium concentrations in the perfusion medium from 4.0 microg/ml (range, 2.5-6.6) to 15.6 microg/ml (11.5-18.4 microg/ml; P = 0.018). Hypothermia reduced the biliary excretion rate of 3-desacetyl vecuronium from 18% (range, 6-37%) to 16% (range, 4-19%) of that of vecuronium (P = 0.018). Pharmacokinetic analysis confirmed that hypothermia reduced the rate constants of hepatic uptake and metabolism from 0.219 to 0.053 and from 0.059 to 0.030, respectively. Conclusions Hypothermia significantly and reversibly reduced the net hepatic uptake of vecuronium. Hypothermia reduced the metabolism of vecuronium and the biliary excretion rate of 3-desacetyl vecuronium.

Uptake and metabolism of propionate in the liver isolated from sheep treated with glucagon

The uptake and metabolism of propionate in the isolated perfused caudal lobe of the liver and in isolated hepatocytes were examined following treatment of sheep with glucagon or saline. Glucagon or sterile saline was infused at 9·8 µg/min for 3 h into the jugular vein and then the caudal lobe of the liver was removed surgically under anaesthesia. The caudal lobe was used either to prepare hepatocytes or in a non-recirculating perfusion experiment. Uptake and metabolism of propionate were studied using [2-14C]propionate. In studies using the non-recirculation perfusion of the caudal lobe of the sheep liver it was shown that the treatment of sheep with glucagon resulted in an increased rate of gluconeogenesis from propionate and in an increased net uptake of propionate by the caudal lobe. The uptake of propionate into the hepatocytes was saturable, concentrative and exhibited a Km for propionate of 0·24 (SE 0·07) mM and a maximal rate of uptake (Vmax) of 6·7 (SE 0·6) nmol/mg dry cells per min and was unaffected by glucagon treatment of sheep. After incubation of cells in medium containing 0·5 mM-[2-14C]propionate for 10 min, the rate of gluconeogenesis from propionate was 22 % higher in the hepatocytes isolated from glucagon-treated sheep. Concentrations in the medium of 1·35 mM butyrate and 1 mM-caproate inhibited propionate uptake by about 50 % and abolished the glucagon-induced stimulation of gluconeogenesis from propionate. The results are consistent with a regulatory role for glucagon in the gluconeogenesis from propionate in the sheep liver.