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At least 289 records · Page 16Linked to original sources
PubMed1994

Pharmacologic modulation of the cutaneous vasculature in the isolated perfused porcine skin flap.

The isolated perfused porcine skin flap (IPPSF), an ex vivo model system used in cutaneous toxicology and pharmacology, is capable of assessing the percutaneous absorption of vasoactive compounds. However, the vascular responses of the IPPSF to classical pharmacologic agents have not been calibrated. The ability of acetylcholine, nitroglycerin, tolazoline, and norepinephrine to affect vasculature resistance and glucose utilization was investigated in the IPPSF. Norepinephrine infusions between 10(-7) and 10(-5) M increased vascular resistance in a dose-dependent manner; half-maximal (EC50) and maximal responses occurred at 3.18 x 10(-6) and 10(-5) M, respectively. In non-preconstricted flaps, neither acetylcholine, nitroglycerin, nor tolazoline vasodilated the IPPSF; however, acetylcholine, nitroglycerin, and tolazoline each lowered vascular resistance in a dose-dependent manner in norepinephrine-preconstricted flaps. Maximal relaxation was induced at 10(-4), 10(-6), and 5 x 10(-5) M, by tolazoline, acetylcholine, and nitroglycerin, respectively, whereas the EC50 values were 2.88 x 10(-7), 1.35 x 10(-8), and 1.72 x 10(-7) M, respectively. In flaps pretreated with norepinephrine and methylene blue (a potential blocker of edothelium-derived relaxing factor), no concentration of acetylcholine, and only the highest concentration of nitroglycerin, lowered vascular resistance. In non-preconstricted flaps, glucose utilization decreased in norepinephrine-infused flaps, increased in nitroglycerin- and tolazoline-infused flaps, and was biphasic in acetylcholine-infused flaps. These results indicate that the IPPSF responds to pharmacologic agents in a manner similar to classic in vitro and in vivo models. Thus, the IPPSF would be a relevant model for investigating the delivery and/or toxicity of pharmacologically active compounds.

Acetylcholine↗
PubMed1993

N omega-nitro-L-arginine, an inhibitor of nitric oxide synthesis, decreases noradrenaline outflow in rat isolated perfused mesenteric vasculature.

In the isolated perfused rat mesenteric vasculature with intestine attached N omega-nitro-L-arginine (L-NNA) (30 mumol/l), an inhibitor of nitric oxide (NO) synthesis from L-arginine, did not alter spontaneous noradrenaline outflow. Transmural field stimulation (2-10 Hz) caused a frequency-dependent increase in noradrenaline outflow. The evoked overflow was reduced by L-NNA. L-Arginine (0.3 mmol/l) attenuated the inhibition of noradrenaline overflow by L-NNA. These results suggest that NO increases the release of noradrenaline in rat mesenteric vasculature.

Animals↗
PubMed1976

Dynamics of sulfonylurea-induced insulin release from the isolated perfused rat pancreas.

In the isolated perfused rat pancreas various sulfonylurea drugs were tested with a basal glucose level of 1 mg/ml in the perfusion buffer and were found to cause a biphasic insulin response. NOVOCS 476, a new and potent sulfonylurea, and glibenclamide qualitatively differed from tolbutamide, glibornuride, glipizide, and glisoxepide, which were all alike in terms of the relationship between first and second phases of insulin release.

Animals↗
PubMed1975

Effects of concanavalin A on the isolated perfused rat liver.

In the isolated perfused liver, Concanavalin A provoked a significant decrease of flow rate within 2 to 4 min. which was dose-dependent and could be partly inhibited by specific antagonists. Furthermore it was found that the lectin led to a decline of the respiration, an increase of the lactate/pyruvate ratio and a release of the transaminases into the medium. It was suggested that Concanavalin A displaced endothelial cells in the liver capillaries, which occluded the vessels and decreased the flow rate. The decreased respiration was considered to be secondary to this effect.

Animals↗
PubMed1992

Regulation of secretion by vasoactive intestinal peptide in isolated perfused rat submandibular glands.

The isolated, perfused gland was used to examine the regulation of saliva volume and protein content by vasoactive intestinal peptide (VIP). In the absence of other secretagogues, VIP produced a modest, sustained saliva flow with a biphasic dose-response curve in which saliva volume was greatest at 1 nM VIP (28.5 +/- 3.8 microliters in the first 5 min, n = 4) but reduced at lower and higher concentrations. The protein concentration in saliva released in response to VIP (0.86 +/- 0.13 micrograms/microliters) was substantially higher than with 30 nM acetylcholine (0.06 +/- 0.02 micrograms/microliters) or 1 nM substance P (0.30 +/- 0.05 micrograms/microliters). During the first 5 min of stimulation, VIP and substance P were synergistic in terms of volume and protein content whereas inclusion of VIP did not increase acetylcholine-stimulated flow in the first 5 min but produced a higher sustained flow over the next hour. After stimulation with acetylcholine, subsequent addition of VIP transiently enhanced saliva volume and protein content in a monophasic, dose-dependent manner with effects at 1 pM VIP and higher. The responses were different for VIP compared with other cAMP-mobilizing agents and the involvement of multiple VIP receptor subtypes was suggested from experiments in which a VIP antagonist blocked the VIP enhancement of saliva volume but not the increase in protein.

Acetylcholine↗
PubMed1979

Surfactant cholesterol metabolism of the isolated perfused rat lung.

1. The isolated perfused rat lung was used as the principal model to study surfactant cholesterol metabolism. 2. Cholesterol was found to represent over 50% of the neutral lipid of both the total surfactant and the lamellar body fractions. 3. De novo synthesis of cholesterol from [1-14C]acetate accounted for only 1% of the surfactant cholesterol, the remainder being derived from exogenous cholesterol supplied as serum lipoproteins. 4. Lipoprotein [1,2-3H2]cholesterol was incorporated into the lamellar body and extracellular surfactant fractions. The increase in the cholesterol specific activities of these fractions with time was consistent with a precursor-product relationship between the lamellar body cholesterol and that of the extracellular surfactant. 5. Incorporation of [methyl-14C]choline and [1,2-3H2]cholesterol indicated that the metabolism and secretion of lamellar body and extracellular surfactant cholesterol parallels that of phosphatidylcholine and suggests that most if not all extracellular surfactant cholesterol is derived from the lamellar body. 6. Comparison of the relative specific activities of incorporated [1,2-3H2]-cholesterol indicate that 59% of the total surfactant cholesterol is located extracellularly.

Animals↗
PubMed1991

Mechanistic aspects of uptake and sinusoidal efflux of dibromosulfophthalein in the isolated perfused rat liver.

Using the isolated perfused rat liver technique we examined whether the accumulation and sinusoidal efflux processes of the organic anion dibromosulfophthalein (DBSP) are dependent on the intracellular ATP content, chloride concentration in the perfusion medium as well as temperature of the medium and whether they are mediated by the same or by separate carrier mechanisms. The net sinusoidal efflux rate, being the resultant of sinusoidal efflux and re-uptake, was decreased more than 50% after lowering the medium temperature from 37 to 26 degrees indicating that the efflux process is carrier-mediated. The uptake rate was decreased only 18% after lowering the medium temperature to 26 degrees. Lowering of the hepatic ATP content for more than 80% clearly decreased the DBSP uptake rate but not the sinusoidal efflux rate. These observations indicate that these opposing transport steps probably are mediated by two separate carriers. Additional evidence for this hypothesis originated from the observation that sinusoidal efflux of DBSP was decreased about 30% whereas hepatic uptake of the substrate remained unaltered after replacing chloride in the perfusion medium with gluconate. In summary, we conclude that uptake and sinusoidal efflux of DBSP are mediated by two separate carrier systems that are influenced differently by ATP depletion, temperature lowering and presence of Cl-gradients.

Adenosine Triphosphate↗
PubMed1981

alpha 2-Adrenoceptor agonistic effect of B-HT 920 in isolated perfused hindquarters of rats.

In isolated perfused hindquarters of rats pretreated with reserpine the alpha 2-adrenoceptor selective agonist B-HT 920 decreased the flow dose-dependently. This effect was strongly antagonized by yohimbine and less by prazosin, and the reverse potency was demonstrated for methoxamine. With increasing concentrations of B-HT 920, a half maximal effect was achieved with 10(-6.64) M. This value is discussed wih respect to the antagonistic potency of B-HT 920 at alpha 1-adrenoceptors with a pA2 of 4.9.

Adrenergic alpha-Agonists↗
PubMed1992

Manipulation of dopamine receptors alters hypoxic pulmonary vasoconstriction in isolated perfused rat lungs.

Using an isolated, perfused rat lung model, we examined the hypoxic pulmonary vasoconstriction (HPV). We studied the alterations in HPV induced by the selective DA1 receptor agonist, fenoldopam, the selective DA1 antagonist, SCH 23390, as well as a combination of these agents. Fenoldopam significantly attenuated HPV. SCH 23390 had no effect on HPV, but was ableto block the effect of fenoldopam. These data confirm the presence of vasodilatory DA1 receptors in the pulmonary vascular bed. The data further suggest that ongoing DA1 activity may be important in counterbalancing some pathologic pulmonary hypertensive states.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1984

Mathematical model for cadmium kinetics in the isolated perfused rat liver system.

The isolated perfused rat liver (IPRL) preparation has previously been used to investigate cadmium kinetics. A mathematical model which has been developed to simulate cadmium kinetics in the IPRL is described. The model takes into consideration binding of cadmium to both intra- and extracellular proteins and the mechanisms of membrane transport. In addition, the competitive interaction of cadmium with endogenous zinc is incorporated into the model. Model simulations of the behavior of cadmium and zinc in the perfusion medium, liver, and bile are compared to results from IPRL experiments involving cadmium doses ranging from 0.29 to 15.6 mumol. A major contribution of this model is the identification, from a kinetic point of view, of two high-molecular-weight classes of intracellular cadmium-binding species which can be identified by two distinct peaks in Sephadex G-75 profiles of hepatic cytosol. This model can be utilized for the quantitation of kinetics based on specific mechanisms involved in cadmium hepatic kinetics.

Animals↗
PubMed1977

The influence of unsaturated fatty acids on prostaglandin-release in isolated perfused guinea-pig hearts.

Isolated perfused hearts of guinea-pig continuously release a prostaglandin-like substance into the effluent. Polyunsaturaed fatty acids, linoleic acid and arachidonic acid greater than linolenic acid, induced an increase in PG-efflux. Oleic acid was without effect. The results suggest that PG-formation is involved in the increase of contractile force and coronary flow after administration of linoleic, linolenic and arachidonic acids.

Animals↗
PubMed1979

The prostaglandins system and insulin release. Studies with the isolated perfused rat pancreas.

Using the isolated perfused rat pancreas PGE2 (1 MUM and 10 muM) had no effect on basal or glucose (10 and 20 mM)-induced insulin release (IR). PGF2 alpha stimulated basal IR at 1 muM and inhibited IR at 10 muM. The glucose-induced IR was unaffected by this PG. Furosemide (5 and 10 mM) led to a monophastic IR at low glucose (glu) and to a potentiation of IR at high glu. Only high indomethacin (Indo) (50 microgram/ml) inhibited glu-induced IR. The stimulatory effect of furosemide on IR could not be inhibited by indomethacin. However mepacrine (0.1 mM) abolished the furosemide effect. Also glu-induced IR was inhibited by mepacrine. Acetylsalicylic acid (30 mg/100 ml) had no significant influence on glu-induced IR. These findings provide evidence that phospholipase activation rather than increased PG synthesis might primarily be involved in the secretory process of insulin.

Animals↗
PubMed1984

A simple system for the investigation of protein binding effects on the renal handling of drugs in an isolated perfused rat kidney preparation.

An isolated perfused rat kidney preparation was developed that allowed drug-protein binding in the perfusate to be varied while maintaining renal function. When applied to digitoxin and frusemide, two drugs highly bound to bovine serum albumin, the fraction of drug unbound could be continuously varied over approximately a 30-fold range.

Animals↗
PubMed1985

Effects of cigarette smoke and 3-methylcholanthrene on the disposition of phencyclidine and its N-ethylamine analogue in the isolated perfused lung of rats.

The isolated perfused lung (IPL) of rats were used to examine the pulmonary disposition and metabolism of radiolabeled phencyclidine (PCP) and N-ethyl-1-phenylcyclohexylamine (PCE). The IPL removed PCP and PCE from the perfusate and converted them to free and conjugated metabolites. At the conclusion of a 1-h perfusion, the lung accumulated at least 20% of the administered radioactivity and metabolized more than 30% of the added drug. Pretreatment of rats with 3-MC or cigarette smoke enhanced significantly PCP and PCE metabolism by the IPL. The concentration of conjugated PCE metabolite in the perfusate of the IPL was increased significantly by both 3-MC and cigarette smoke pretreatments whereas the concentration of conjugated PCP metabolite was not affected by cigarette smoke exposure and increased only slightly after 3-MC pretreatment. Pretreatment of rats with 3-MC or cigarette smoke also altered the amount of radioactivity accumulated by the lung tissue at the conclusion of a 1-h perfusion. Inasmuch as PCP and PCE are often abused by humans via smoke inhalation, a significant amount of these drugs may be stored or metabolized by the lung.

Animals↗
PubMed1985

Studies on cumene hydroperoxide-induced lipid peroxidation in the isolated perfused rat heart.

In the isolated, perfused rat heart, lipid peroxidation, induced by cumene hydroperoxide (Cum OOH), is accompanied by the release of malondialdehyde (MDA). Using a modified perfusion technique resulting in the separate collection of coronary and interstitial effluent, it can be shown that upon Cum OOH (0.5 mM) perfusion there is an immediate release of MDA in the coronary effluent and a delayed release in the interstitial fluid, indicating the susceptibility and coronary vascular tissue towards free radical-induced lipid peroxidation. Perfusion with Cum OOH leads to an initial increase of the coronary flow and a depressed contractility followed by a cardiac arrest concomitantly with the onset of MDA release in the interstitial fluid. Finally, during prolonged perfusion the coronary flow diminishes and contracture of the heart muscle ('stone heart') develops. These phenomena resemble those occurring during the 'calcium paradox'. Although the contractility diminishes immediately after the perfusion with Cum OOH the tissue ATP level and energy charge (formula; see text) remain constant. From the moment of cardiac arrest the ATP and creatine phosphate levels gradually decrease and the energy charge drops simultaneously with the appearance of MDA in the interstitial fluid. In contrast to the calcium paradox there is no simultaneous increase in the myocardial AMP level. Various mitochondrial enzymes (cytochrome c oxidase, monoamine oxidase, carnitinepalmitoyltransferase I and palmitoyl CoA synthetase) were tested and not affected by Cum OOH perfusion. During the development of contracture after 20 min of Cum OOH perfusion massive contraction band necrosis of cardiac tissue occurs. However, overall protein release is lower when compared with the protein release during the calcium paradox.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenine Nucleotides↗
PubMed1998

Vasodilatation induced by nicotine in the isolated perfused rat kidney.

1. In isolated perfused rat kidney, under a constant flow of 8-10 ml/min, mean basal perfusion pressure was found to be 82.57 +/- 8.96 mm Hg (n = 70). 2. After a bolus injection of 10 micrograms/0.1 ml phenylephrine (PE) which causes maximum vasopressor response, a 93.27 +/- 0.56 mm Hg increase in basal perfusion pressure was recorded (n = 70). In control experiments, a submaximum dose of PE (3 x 10(-6) M) caused a 68.37 +/- 0.47 mm Hg (n = 5) increase in perfusion pressure. 3. Nicotine, at a dose of 100 micrograms/0.1 ml, decreased the perfusion pressure raised by submaximum dose of PE. This nicotine-induced dilatation was 24.97 +/- 3.27% of maximum PE constriction (n = 5). 4. Nicotine-induced dilatation was not affected by atropine, guanethidine, hexamethonium, tetrodotoxin, capsaicin, indomethacin, quinacrine, NG-nitro-L-arginine, methylene blue, glibenclamide, tetraethylammonium, 4-aminopyridine and ouabain (n = 5).

Animals↗
PubMed1997

Comparison of the disposition of hepatically-generated morphine-3-glucuronide and morphine-6-glucuronide in isolated perfused liver from the guinea pig.

PURPOSE: Humans and guinea pigs metabolise morphine extensively, forming the isomers morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) in relatively similar ratios. Both metabolites are formed in the liver, and their greater polarity relative to the parent aglycone may limit their permeability across hepatic membranes. This study compared the disposition of hepatically-generated M3G and M6G in perfused livers isolated from guinea pigs. METHODS: Livers were perfused at 30 ml/min in a non-recirculating manner with Krebs bicarbonate buffer containing morphine (6 to 7 microM). Perfusing medium, venous perfusate and bile were collected at regular intervals and concentrations of morphine, M3G and M6G determined by reversed-phase HPLC. RESULTS: Concentrations of morphine, M3G and M6G in perfusate and the rates of biliary excretion of M3G and M6G were consistent between 20 and 50 min of perfusion. The mean (+/-s.d.) ratio for the rate of formation of M3G relative to M6G was 3.7 +/- 1.5. A mean 33 +/- 3% of morphine extracted by the liver was recovered as summed M3G and M6G. Of the M3G and M6G formed during a single passage, 19 +/- 11% and 9 +/- 9%, respectively, was excreted into bile; the values were significantly different (P = 0.002). CONCLUSIONS: A greater fraction of hepatically-generated M3G excreted into bile compared to that for M6G reflects differences in their relative transport across sinusoidal and canalicular membranes of hepatocytes, possibly via carrier-mediated systems.

Analgesics, Opioid↗
PubMed1985

Serine synthesis by an isolated perfused rat kidney preparation.

The isolated perfused rat kidney was shown to synthesize serine from aspartate or glutamate, both of which are also precursors of glucose. The major products of aspartate metabolism were ammonia, serine, glutamate, glucose, glutamine and CO2. Perfusion of kidneys with aspartate in the presence of amino-oxyacetate resulted in a near-complete inhibition of aspartate metabolism, illustrating the essential role of aspartate aminotransferase in the metabolism of this substrate. Radioactivity from 14C-labelled aspartate and from 14C-labelled glycerol was incorporated into serine and glucose. Production of both glucose and serine from aspartate was suppressed in the presence of 3-mercaptopicolinic acid. These data provide evidence for the operation of the phosphorylated and/or non-phosphorylated pathway for serine production to the presence of 3-mercaptopicolinic acid. This is explained by simultaneous glycolysis. The rate of glucose production, but not that of serine, was greater in kidneys perfused with glutamate or with aspartate plus glycerol than the rates obtained by perfusion with aspartate alone. These data are taken to suggest that serine synthesis occurred at a near-maximal rate, and that the capacity of the kidney for serine synthesis from glucose precursors is lower than that for glucose synthesis.

Amino Acids↗