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Biomedical subjects

B Ljung

Publications and source records attributed to B Ljung.

At least 19 recordsLinked to original sources
PubMed2001

Detection of breast cancer cells in ductal lavage fluid by methylation-specific PCR.

If detected early, breast cancer is curable. We tested cells collected from the breast ducts by methylation-specific PCR (MSP). Methylated alleles of Cyclin D2, RAR-beta, and Twist genes were frequently detected in fluid from mammary ducts containing endoscopically visualised carcinomas (17 cases of 20), and ductal carcinoma in situ (two of seven), but rarely in ductal lavage fluid from healthy ducts (five of 45). Two of the women with healthy mammograms whose ductal lavage fluid contained methylated markers and cytologically abnormal cells were subsequently diagnosed with breast cancer. Carrying out MSP in these fluid samples may provide a sensitive and powerful addition to mammographic screening for early detection of breast cancer.

Breast↗
PubMed2001

Thiazolidinediones increase plasma-adipose tissue FFA exchange capacity and enhance insulin-mediated control of systemic FFA availability.

We studied the effects of thiazolidinedione treatment (rosiglitazone 1 or 10 micromol.kg(-1).day(-1) or darglitazone 1.3 micromol.kg(-1).day(-1) for 3 weeks) on lipid metabolism in obese Zucker rats. In the basal 7-h fasted state, rosiglitazone (10 micromol.kg(-1).day(-1)) and darglitazone corrected the hypertriglyceridemia by increasing plasma triglyceride (TG) clearance and decreasing hepatic TG production, as assessed using Triton WR 1339. Free fatty acid (FFA) metabolism was assessed using 3H-palmitate tracer by estimating rates of plasma FFA appearance (Ra), whole-body FFA oxidation (Rox), and tissue-specific nonoxidative FFA disposal (Rfs). Basal Ra, plasma FFA levels, and clearance were increased by both thiazolidinediones. Detailed studies were conducted with darglitazone, which under basal conditions increased Ra (+114%), Rox (+51%), and Rfs in adipose tissues. During euglycemic clamps performed at insulin levels corresponding to those observed postprandially, darglitazone increased the glucose infusion rate from 4.7 to 13.3 mg.min(-1) and, in contrast to the basal state, it decreased Ra (-67%), Rox (-84%), and Rfs in adipose tissue, muscle, and liver. We concluded that thiazolidinediones 1) ameliorate hypertriglyceridemia by lowered hepatic TG production and augmented TG clearance (two separate kinetic effects), 2) enhance insulin-mediated suppression of systemic FFA mobilization while increasing the capacity to mobilize FFA during fasting, 3) increase FFA trafficking into adipose tissue by increasing the ability of adipose tissue to take up and store FFA, and 4) enhance metabolic flexibility by improving glucoregulation under hyperinsulinemic conditions (possibly involving reduced skeletal muscle and liver exposure to fatty acids) and augmenting the capacity to utilize FFAs during fasting.

Adipose Tissue↗
PubMed2001

Pharmacological treatment of insulin resistance in obesity.

AIM: To discuss new pharmacological possibilities for acting on the lipid metabolism abnormalities relating obesity, insulin resistance and arterial disease. DATA SYNTHESIS: Obesity is frequently associated with excess caloric fat dietary intake, especially in the form of fatty acids. An increased flux of fatty acids into muscle, liver and pancreas is probably a major cause of insulin resistance and possibly of pancreatic secretory disturbances. Liver exposure to fatty acid overload may also be the main reason for the atherogenic lipoprotein profile of insulin resistance and type 2 diabetes, which is characterised by prolonged post-prandial hypertriglyceridemia, high levels of large very low-density lipoproteins (VLDL) and small, dense low-density lipoproteins (LDL), and a reduced number of apoAl-containing high-density lipoproteins (HDL). This lipoprotein profile may be the main contributor to the high prevalence of arterial disease in patients with type 2 diabetes. The treatment of type 2 diabetes and insulin resistance in obese or non-obese subjects should therefore aim at normalising fatty acid fluxes because this can be expected to enhance insulin action and ameliorate the atherogenic lipoprotein abnormalities. The discovery of peroxisome proliferator-activated receptors (PPARs) and the elucidation of their function as master controllers of the genes involved in fatty acid metabolism have facilitated the development of potent modulating substances. Promising results have been obtained with the current generation of PPAR gamma ligands, but undesirable effects have also been reported. CONCLUSIONS: New knowledge concerning the structure and function of PPAR gamma and PPAR alpha is being used to develop non-TZD modulators with combined PPAR alpha and gamma actions in animal studies. This new generation of substances may offer a more balanced spectrum of activity that may be better suited for the treatment of the insulin resistance and type 2 diabetes frequently associated with obesity.

Animals↗
PubMed1999

Development and initial evaluation of a novel method for assessing tissue-specific plasma free fatty acid utilization in vivo using (R)-2-bromopalmitate tracer.

We describe a method for assessing tissue-specific plasma free fatty acid (FFA) utilization in vivo using a non-beta-oxidizable FFA analog, [9,10-3H]-(R)-2-bromopalmitate (3H-R-BrP). Ideally 3H-R-BrP would be transported in plasma, taken up by tissues and activated by the enzyme acyl-CoA synthetase (ACS) like native FFA, but then 3H-labeled metabolites would be trapped. In vitro we found that 2-bromopalmitate and palmitate compete equivalently for the same ligand binding sites on albumin and intestinal fatty acid binding protein, and activation by ACS was stereoselective for the R-isomer. In vivo, oxidative and non-oxidative FFA metabolism was assessed in anesthetized Wistar rats by infusing, over 4 min, a mixture of 3H-R-BrP and [U-14C] palmitate (14C-palmitate). Indices of total FFA utilization (R*f) and incorporation into storage products (Rfs') were defined, based on tissue concentrations of 3H and 14C, respectively, 16 min after the start of tracer infusion. R*f, but not Rfs', was substantially increased in contracting (sciatic nerve stimulated) hindlimb muscles compared with contralateral non-contracting muscles. The contraction-induced increases in R*f were completely prevented by blockade of beta-oxidation with etomoxir. These results verify that 3H-R-BrP traces local total FFA utilization, including oxidative and non-oxidative metabolism. Separate estimates of the rates of loss of 3H activity indicated effective 3H metabolite retention in most tissues over a 16-min period, but appeared less effective in liver and heart. In conclusion, simultaneous use of 3H-R-BrP and [14C]palmitate tracers provides a new useful tool for in vivo studies of tissue-specific FFA transport, utilization and metabolic fate, especially in skeletal muscle and adipose tissue.

Adipose Tissue↗
PubMed1999

Rosiglitazone (BRL49653), a PPARgamma-selective agonist, causes peroxisome proliferator-like liver effects in obese mice.

The PPAR (peroxisome proliferator activated receptor) transcription factors are ligand-activated nuclear receptors that regulate genes involved in lipid metabolism and homeostasis. PPARalpha is preferentially expressed in liver and PPARgamma preferentially in adipose tissue. Activation of PPARalpha leads to peroxisome proliferation and increased beta-oxidation of fatty acids in rodents. PPARgamma-activation leads to adipocyte differentiation and improved insulin signaling of mature adipocytes. Both PPAR receptors are believed to be functional targets for treatment of hyperlipidemia in man. We have treated obese diabetic mice (ob/ob), which have highly elevated levels of plasma triglycerides, glucose and insulin, for 1 week with WY14,643 (180 micromol/kg/day), a selective PPARalpha agonist, or rosiglitazone (BRL49653; 2.5 micromol/kg/day), a selective PPARgamma agonist. The doses used produce a similar therapeutic effect in both treatment groups (lowering of triglycerides and glucose). High resolution two-dimensional gel electrophoresis of livers showed that WY14,643 and rosiglitazone both produced changes in expression pattern of many proteins involved in peroxisomal fatty acid beta-oxidation. However, similar experiments performed in lean mice showed significant up-regulation of these proteins only with WY14,643 treatment. Furthermore, the proteins up-regulated by the drugs in obese mice had a higher basal expression in obese controls compared to the lean littermates. Liver PPARgamma mRNA levels were determined and we observed that PPARgamma2 mRNA levels were elevated in obese mice compared to lean littermates. As PPARalpha and PPARgamma recognize similar DNA response elements, it is likely that the effects of rosiglitazone on PPARalpha responsive genes in livers of the ob/ob mice are mediated by PPARgamma2.

Animals↗
PubMed1994

Induction of rhythm abnormalities in the fetal rat heart. A tentative mechanism for the embryotoxic effect of the class III antiarrhythmic agent almokalant.

OBJECTIVES: The aim was to test the hypothesis that the recently reported embryotoxic effect of class III antiarrhythmic agents may be a result of electrophysiological disturbances induced by these agents. METHODS: Comparative studies of drug effects in the adult and fetal rat were performed using three experimental models: (1) effects of almokalant upon pregnancy and fetal mortality in rats given daily doses of 0, 10, 50, 100, or 400 mumol.kg-1 orally in the diet on days 6-15 of pregnancy; (2) effects of d-sotalol (1-1000 microM), almokalant (0.1-100 microM) and dofetilide (0.01-10 microM) on the adult and fetal cardiac action potential in vitro; (3) voltage clamp recordings in single fetal and adult ventricular myocytes superfused with almokalant (0.5 microM). RESULTS: In the groups of rats treated with 100 and 400 mumol.kg-1, respectively, the body weight gain was decreased from day 12 of gestation, and there were no viable fetuses at termination of pregnancy. In atrial as well as ventricular tissue, the class III agents induced a concentration dependent prolongation of the fetal action potential duration, accompanied by a reduction in heart rate and eventually the appearance of rhythm abnormalities and/or early afterdepolarisations. The adult action potential duration remained unaffected. An almokalant sensitive current (probably the delayed rectifier, IK) could be evoked both in the fetal and in the adult ventricular cells. CONCLUSIONS: Class III antiarrhythmic agents were shown to induce fetal mortality and rhythm abnormalities in the rat heart. Although they do not prove a causal relationship between these effects, our observations may have implications for the clinical use of class III antiarrhythmic agents in women of childbearing potential.

Action Potentials↗
PubMed1991

Acute haemodynamic effects of felodipine, verapamil and hydralazine in the anaesthetized dog.

Felodipine, a potent dihydropyridine calcium antagonist with a pronounced vascular selectivity, was given intravenously (0.006-0.025 mumol kg-1) to anaesthetized, open-chest dogs with denervated hearts. The result was a dose-dependent decrease in mean arterial pressure (MAP) and total peripheral resistance (TPR), while heart rate (HR), stroke volume (SV) and left ventricular end-diastolic pressure remained relatively unchanged. Cardiac tension work (TTI) and oxygen consumption (MVO2) were reduced, probably due to the decrease in afterload. The relative reduction of the coronary vascular resistance (CVR) was greater than that of TPR. The hypotensive effect of verapamil (0.05-0.20 mumol kg-1) was small and MAP decreased mainly via a decrease in HR and SV. Higher doses of verapamil which induced vasodilatation could not be given without the development of complete atrio-ventricular dissociation. Hydralazine (11-45 mumol kg-1) decreased TPR and CVR in parallel but the decrease in MAP was partly counteracted by a powerful increase in HR, SV and cardiac inotropy which was associated with elevated catecholamine levels in plasma. When MAP and HR were maintained constant by means of aortic balloon inflation and atrial pacing, felodipine markedly increased coronary blood flow and coronary sinus oxygen saturation while SV, TTI, inotropy and MVO2 remained relatively unchanged. It is concluded that felodipine markedly dilates peripheral resistance vessels, and in particular those in the coronary vascular bed, without any cardiodepressant effects.

Animals↗
PubMed1990

Vascular selectivity of felodipine: experimental pharmacology.

This article presents an overview of experimental studies that illustrate the vascular vs. myocardial selectivity of felodipine. The aim of our project was to develop a calcium antagonist that would selectively inhibit the activity of the myogenically active smooth muscle of the arterial resistance vessels without causing negative inotropic effects. In vitro, selectivity was tested as the concentration ratio at 50% inhibition of the peak force of paced papillary muscle and of the spontaneous myogenic activity of rat portal vein. The latter preparation has consistently been used as an in vitro model of myogenically active vascular (arterial) smooth muscle. It was found that dihydropyridines display different quantitative structure-activity relationships with regard to vascular and myocardial effects. Felodipine was the first compound synthetized that showed 100-fold vascular selectivity. In the same test system, Ca2+ chelators, La3+, and verapamil lacked selectivity. The high vascular selectivity of felodipine has been verified in vivo in various hemodynamic experiments. Thus, felodipine lowers arterial blood pressure due to reduced peripheral resistance without altering cardiac contractility. This is the case in various animal models and applies over a wide range of plasma concentrations whether autonomic nervous control is blocked or not. In contrast, nonselective compounds such as verapamil attenuate myocardial contractility in parallel with a reduction in peripheral resistance.

Animals↗
PubMed1987

Vascular versus myocardial selectivity of calcium antagonists studied by concentration-time-effect relations.

The vascular versus myocardial selectivity of three structurally different calcium antagonists, felodipine, diltiazem, and verapamil, was studied in vitro. The model used was an isolated portal vein preparation and a paced (3 Hz) papillary muscle of the left ventricle of the rat, examined in the same organ bath. In previous experiments with the same tissues, used for screening and eventual selection of felodipine, it was found that the selectivity factors ranged as follows: felodipine much greater than nifedipine greater than diltiazem greater than verapamil = La3+. Since the effect of organic calcium antagonists is slow in onset, the present experiments were designed to determine the inhibitory potencies and the selectivity factor at equilibrium. This was possible by a computer-assisted collection of contractile force measurements and subsequent analysis of the results. In each experiment, one concentration only of one of the three calcium antagonists was given. The time-effect relation was determined for both tissues. After all experiments with a particular drug, when several concentrations had been administered, the hyperbolic concentration-effect relation was determined at various times of exposure. The ensuing pIC50 values, as related to time, for the vascular and the myocardial preparations, described by monoexponential curves and the corresponding potency values (pIC50), could be determined at equilibrium (t = infinity). It was concluded that the vascular over myocardial inhibitory selectivity was marked for felodipine (103), low for diltiazem (8.9), and none for verapamil (0.92).

Animals↗
PubMed1987

Functional antagonism of noradrenaline responses by felodipine and other calcium antagonists in vascular smooth muscles.

Calcium antagonists inhibit vascular smooth muscle activity in a way that depends on the properties of the inhibitory agent, the type of effector tissue studied, and the applied means of activation. In the experiments described here, the phasically active portal vein of the rat and the essentially tonic aortae of the rat and the rabbit were examined. They were exposed to reduced external calcium ion concentration (from 2.5 mM to 0.6 and 0.2 mM) and to the structurally different calcium antagonists felodipine, verapamil, and diltiazem in "therapeutic" and 1,000-fold higher concentrations. The tissues were pretreated for 1 h with the intended [Ca2+]0 or the calcium antagonist concentration under study. Cumulative concentration-effect curves to noradrenaline (NA) were obtained in the control situation at reduced [Ca2+]0 and at two concentrations of a calcium antagonist. In the rat portal vein, low doses of all calcium antagonists suppressed all NA responses but caused no rightward shift of the concentration-effect curve. High doses of the calcium antagonist abolished portal vein spontaneous activity and reduced the maximum NA response to some 10% of control. In the rat portal vein, reduced [Ca2+] caused rightward shifts of the NA concentration-effect curve without (0.6 mM) or with (0.2 mM) reduced maximum NA responses. In the rat aorta, reduced [Ca2+]0 and the calcium antagonists caused progressive rightward shifts of the curves with progressive reductions in the maximum NA responses. In the rabbit aorta, there was no effect on NA responses with reduced [Ca2+]0 or of the calcium antagonists in "therapeutic" concentrations: verapamil and diltiazem, but not felodipine, caused significant effects in the 1,000-fold higher concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Felodipine sensitivity in vivo and in vitro of activation pathways in vascular smooth muscles.

Felodipine is a dihydropyridine calcium antagonist that exerts a markedly selective inhibition of the smooth muscle of arterial resistance vessels. In this paper, we report on the effects of felodipine on vascular smooth muscle in vivo and in vitro. Contractions in these effector cells are categorized according to means of activation, membrane events, and sensitivity to felodipine and are discussed in terms of four schematic "activation pathways." Stimulation of aortic smooth muscle by K+ or noradrenaline may be accounted for by separate pathways (I and IV) that might involve potential-operated and receptor-operated Ca2+ channels with high and low sensitivity to calcium antagonists. In the spike-generating vascular smooth muscle of the portal vein, both spontaneous myogenic activity and responses to adrenergic stimuli of physiological intensity are more adequately described in terms of an action potential-mediated pathway (II). This pathway is sensitive to felodipine in nanomolar concentrations irrespective of the primary means of stimulation. Basal tone and adrenergic responses of resistance vessels in vivo show similar sensitivity to felodipine, suggesting that they are also mediated by II or by a closely related pathway (III) involving graded changes in membrane potential rather than in action potentials. The latter activation pathways (II and III) are the ones relevant to the pharmacodynamic effects of felodipine for therapeutic purposes.

Action Potentials↗
PubMed1987

Pharmacodynamic properties of felodipine.

This overview presents the pharmacodynamic properties of felodipine as studied in animal experiments with emphasis on results from our laboratory. Felodipine is 100-fold more potent in causing inhibition of spontaneously active vascular smooth muscle than myocardium in vitro. This vascular selectivity is significantly greater than that of nifedipine (potency ratio 15). Verapamil, D-600, La3+ and reduction of [Ca2+]o lack selectivity. The cellular mechanisms underlying this variable selectivity are not clear at present. In conscious spontaneously hypertensive rats (SHR), the plasma concentration required for 20% reduction of mean arterial pressure is approximately 10 nmol. Mean arterial pressure is lowered dose-dependently as a result of reduced peripheral vascular resistance accompanied by increased cardiac output due to transient tachycardia and increased stroke volume. There was rapid resetting of the baroreflex set point but unaltered sensitivity after felodipine and hydralazine in SHR. Therefore, the reflexogenic increase in heart rate and plasma renin activity subsided within 3 to 5 hours of continuous felodipine administration in SHR. In addition, there was a uniform dilatation of the peripheral vascular beds after felodipine administration. During long term treatment of SHR with felodipine, progression of left ventricular and vascular wall hypertrophy was prevented. Within the 'therapeutic dose range', the only primary effect observed in addition to arterial vasodilation is diuresis/natriuresis caused by a renal tubular action.

Antihypertensive Agents↗
PubMed1985

Renal and cardiovascular effects of acute and chronic administration of felodipine to SHR.

Renal function and salt and water turnover were studied in SHR during acute and chronic administration of felodipine, which is an efficient antihypertensive vasodilating Ca2+ antagonist. In conscious SHR acute administration of felodipine in hypotensive doses increased renal sympathetic nerve activity but caused renal vasodilation, increases in GFR and a 2-3 fold increase in urinary flow rate and sodium excretion. The fraction of filtered sodium excreted (FENa) was approximately doubled. The diuretic and natriuretic effects of felodipine are therefore suggested to be due to a direct inhibitory action on the renal tubular cells, resulting in reduced sodium reabsorption. Nifedipine also induced diuresis and natriuresis in this system, while minoxidil reduced water and sodium excretion. Throughout 6 months of felodipine treatment, the mean arterial pressure (MAP), remained 25-20 per cent reduced. Felodipine in combination with metoprolol reduced MAP 25-30 per cent and also caused regression of left ventricular hypertrophy, while felodipine alone prevented its further progression. Also during chronic administration, felodipine induced diuresis but had no effect on plasma volume and on sodium or potassium excretion in SHR. It is concluded that in SHR felodipine induces diuresis; on acute treatment this is secondary to reduced tubular sodium reabsorption, although during chronic treatment the sodium loss is compensated for while the diuresis remains. Thus, the cardiovascular and renal effects of Ca2+ antagonists like felodipine differ substantially from those of other potent antihypertensive vasodilators e.g. minoxidil.

Animals↗
PubMed1985

The influence of the sympathetic impulse pattern on contractile responses of rat mesenteric arteries and veins.

Contractile responses to electrical field stimulation of excised small mesenteric arteries and veins of the rat were compared when stimuli were delivered in irregular bursts or at regular intervals. Spontaneously occurring skin vasoconstrictor impulses in a few-unit median nerve recording in man were stored on tape and used to trigger a stimulator. Two irregular stimulation sequences at average frequencies of 1.6 and 1.8 Hz, respectively, were used. In the arteries, average contractile responses were significantly greater at an irregular than at an even stimulation frequency, but in the veins, similar degrees of contraction were obtained with the two modes of stimulation. The frequency-response relationships to continuous regular stimulation showed the artery to respond less than the vein at low frequencies. This apparently explains the differences in behaviour between the vessels to irregular stimulation. The results show that not only the number of impulses, but also their pattern of occurrence, may influence the degree of vasoconstriction. Thus, the normal irregular sympathetic discharge pattern in itself has a bearing on the physiology of neuro-effector control mechanisms.

Animals↗
PubMed1985

Vascular selectivity of felodipine.

Felodipine, a new antihypertensive 'calcium antagonist', was tested in animal experiments which specifically demonstrated its vascular selectivity. In vitro inorganic and organic calcium antagonists were added cumulatively to the spontaneously active rat portal vein, and the paced papillary muscle of the rat, residing in the same organ bath. Felodipine was the first compound tested to display a 100-fold vascular selectivity in this test system. In the portal vein the spontaneous activity and noradrenaline (norepinephrine)-induced responses are reduced by the drug in therapeutic concentrations in an insurmountable way, indicating that felodipine prevents activation of the vascular effector cells or interferes with the contractile process, possibly due to an intracellular action on Ca2+-binding proteins. The negative myocardial effect of felodipine, attainable only in vitro, is characterised by surmountable antagonism of the inotropic response to added adrenergic agonists or Ca2+ and is compatible with calcium influx inhibition. In vivo, felodipine was given to conscious dogs with indwelling arterial and venous catheters. The animals were studied in the horizontal position and at 45 degrees tilt. Felodipine (1 mumol/kg) and minoxidil (4 mumol/kg) lowered mean arterial blood pressure by 20 to 25%, due to reduced peripheral resistance with a reflex rise in cardiac output. Following head-up tilt (2 min) there was no orthostatic hypotension, and stroke volume was well maintained. This strongly indicates that arterial resistance vessels, but not venous capacitance vessels or myocardium, were directly affected by felodipine.

Animals↗
PubMed1985

Effect of felodipine on renal hemodynamics and excretion in the dog.

The effects of felodipine on renal hemodynamics and excretion were evaluated in the anesthetized dog. Unilateral renal arterial infusion of felodipine produced ipsilateral increases in the absolute and fractional excretion of sodium and water which were greater than those of potassium; these effects occurred in the absence of changes in mean arterial pressure, renal blood flow, or glomerular filtration rate. There were no significant effects on renal hemodynamic or excretory function in the contralateral kidney. The unilateral renal arterial infusion of isotonic saline or vehicle produced no significant effects on renal hemodynamic or excretory function in either ipsilateral or contralateral kidney. Felodipine, a calcium antagonist with vasodilator antihypertensive properties, in doses which do not affect systemic or renal hemodynamics in the dog, increased urinary flow rate and sodium excretion by decreasing renal tubular water and sodium reabsorption. As a vasodilator antihypertensive agent, felodipine possesses potentially advantageous diuretic and natriuretic properties.

Animals↗