Biomedical subjects

M Wahl

Publications and source records attributed to M Wahl.

At least 91 records · Page 5Linked to original sources

PubMed1992

Growth factor phosphorylation of PLC-gamma 1.

The hydrolysis of phosphatidylinositol 4,5-bisphosphate has a central role in many signalling pathways. One of the phospholipase C (PLC) isozymes that mediates this reaction is a direct substrate for the tyrosine kinase activity of several growth factor receptors. Growth factors elicit increases in both the phosphoserine and the phosphotyrosine content of the PLC-gamma 1 isozyme. PLC-gamma 1 contains three tyrosine phosphorylation sites, which have been identified as residues 771, 783 and 1254. Phosphorylation of tyrosine residues is sufficient to increase the catalytic activity of PLC-gamma 1, though other proteins may modulate this activation. However, the role of growth factor-enhanced phosphorylation of serine residues on PLC-gamma 1 remains obscure. In vitro studies of PLC-gamma 1, recovered from growth factor-treated cells, indicate that activation by tyrosine phosphorylation is not due to increased sensitivity to Ca2+, a required co-factor, but is reflected in altered kinetic constants, i.e. V(max) and, to a lesser extent, Km.

Enzyme Activation↗

PubMed1991

Selective phospholipase C activation.

Phospholipase C is a family of cellular proteins believed to play a significant role in the intracellular signaling mechanisms utilized by diverse hormones. One class of hormones, polypeptide growth factors, elicits its influence on cellular function through stimulation of cell surface receptor tyrosine kinase activity. Certain growth factors appear to stimulate cellular phospholipase C activity by selective, receptor-mediated tyrosine phosphorylation of the phospholipase C-gamma 1 isozyme. While the role of phospholipase C activity in growth factor regulation of cell proliferation remains to be clarified, the selective growth factor-stimulated tyrosine phosphorylation and activation of phospholipase C-gamma 1 is an interesting example of enzyme-substrate interaction at the crossroads of two important intracellular signaling pathways.

Cell Division↗

PubMed1991

Analysis of cromakalim-, pinacidil-, and nicorandil-induced relaxation of the 5-hydroxytryptamine precontracted rat isolated basilar artery.

The effects of the K+ channel activators cromakalim, pinacidil, and nicorandil were investigated in endothelium intact, 5-hydroxytryptamine (5-HT) precontracted rat isolated basilar artery. Cromakalim, pinacidil, and nicorandil produced concentration-dependent relaxation of rat isolated basilar artery precontracted with 5-HT with a rank order of potency of cromakalim greater than pinacidil greater than nicorandil. All compounds produced full or nearly full relaxation. The calculated Hill coefficients for cromakalim-, pinacidil-, and nicorandil-induced relaxation of 5-HT-precontracted rat isolated basilar artery were 2.20 +/- 0.36, 1.30 +/- 0.07, and 1.00 +/- 0.01, respectively. Under conditions of increased tone produced by 50 mmol/l KCl (which inhibits cromakalim-induced relaxation) pinacidil and nicorandil produced marked reversal of spasm, with pinacidil being more potent than nicorandil. In arteries precontracted with 5-HT, preincubation with glibenclamide (0.1-1 mumol/l) produced concentration-related inhibition of relaxation with calculated mean pA2 values (and slopes of Schild regression) +/- SEM of 6.84 +/- 0.20 (1.1 +/- 0.20) against cromakalim. 6.60 +/- 0.14 (0.95 +/- 0.23) against nicorandil, and 6.57 +/- 0.26 (1.04 +/- 0.18) against pinacidil. For cromakalim, pinacidil, and nicorandil the slopes of Schild regression were not significantly different from unity. Tolbutamide 10 mumol/l was without effect against the cromakalim-, pinacidil-, or nicorandil-induced relaxation. Tetraethylammonium (TEA; 1-10 mmol/l) produced noncompetitive inhibition of the cromakalim-induced relaxation, but appeared to produce competitive inhibition of the pinacidil- and nicorandil-induced relaxations. We conclude that cromakalim, pinacidil, and nicorandil produce relaxation of the 5-HT precontracted rat basilar artery by similar mechanisms to those identified in other peripheral vascular and visceral smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Comparison of cromakalim-induced relaxation of potassium precontracted rabbit, cat, and rat isolated cerebral arteries.

The effects of cromakalim were investigated in KCl-precontracted cat, rabbit, and rat isolated cerebral arteries with intact endothelium. Potassium induced contraction of all cerebral arteries studied, but exhibited marked vessel and species variation with no spasm to 20 or 30 mmol/l KCl in the rat basilar artery or 20 mmol/l KCl in the rabbit middle cerebral artery. On sustained tension to 20 mmol/l KCl, cromakalim induced concentration-related relaxation in the rabbit basilar artery and the cat basilar and middle cerebral arteries with Hill coefficients greater than unity. Cromakalim was more potent in the rabbit basilar artery precontracted with 20 or 30 mmol/KCl than in the rabbit middle cerebral artery or the cat basilar or middle cerebral artery. Elevation of the KCl concentration to 50 mmol/l inhibited cromakalim-induced relaxation and produced a decrease in the Hill coefficient. Preincubation of cerebral arteries with glibenclamide (100 nmol/l-1 mumol/l) produced concentration-related inhibition of the cromakalim-induced relaxation in the rabbit basilar, cat basilar, and cat middle cerebral arteries precontracted with 20 mmol/l KCl. The degree of rightward shift of concentration-effect curves by glibenclamide was calculated at the EC25, EC50, and EC75 levels. A good correlation was observed between the shifts at the EC50 and EC75 levels. However, the shift in concentration-effect curves for cromakalim produced at the EC25 level was markedly less than the EC50 or EC75 levels in the presence of 1 mumol/l glibenclamide. The pA2 values for glibenclamide calculated at the EC50 level were 6.6 +/- 0.09, 7.1 +/- 0.1, and 6.5 +/- 0.5 in the rabbit basilar, cat basilar, and cat middle cerebral artery, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

A summary index for the assessment of quality of life in angina pectoris.

When exploring the effects of anti-anginal therapy on quality of life (QL), it is essential to use concise, reliable, outcome measures which focus on those aspects of the disease which are affected by the anginal pain, and which are expected to be responsive to medical intervention. Analysis based on a single comprehensive index is preferable to the use of several indexes as it avoids the potential for conflicting inferences from multiple comparisons. In this paper, we describe the development of a QL index which summarizes the three questionnaires used in the North Karelian Quality of Life (KarQuol) study. The summary index (SI) will be used to compare transdermal and oral nitrate therapy in patients with angina pectoris, and represents the first stage in the construction of a disease-specific evaluative index for future trials.

Abstracting and Indexing↗

PubMed1991

Anti-anginal therapy and quality of life. A comparison of the effects of transdermal nitroglycerin and long-acting oral nitrates.

A total of 112 male patients with severe effort-induced angina pectoris (New York Heart Association functional classes II and III) participated in a randomized open trial consisting of a 6 month phase with 3 month treatment cross-overs. The aim of the study was to compare the effect of transdermal nitroglycerin (TN) patches and long-acting oral nitrates (LAON) on quality of life (QL). During the cross-over period 30 patients (20 on TN and 10 on LAON) withdrew from the study, over half of them within the first month. Although the results should be interpreted with some caution, they showed that improvement in QL was present for both treatments but greater during the transdermal therapy (unadjusted p = 0.07, adjusted p = 0.03). Anginal attacks were associated with improved QL scores, and fewer attacks occurred on TN (p = 0.06). Improvement in QL was most pronounced in patients whose recorded duration of angina was less than 8 years.

Administration, Cutaneous↗

PubMed1991

Analysis of acetylcholine-induced relaxation of rabbit isolated middle cerebral artery: effects of inhibitors of nitric oxide synthesis, Na,K-ATPase, and ATP-sensitive K channels.

The functional importance of membrane hyperpolarization through activation of ATP-sensitive K channels, or activation of the Na,K-ATPase, was investigated for acetylcholine (ACh)-induced relaxation of the rabbit isolated middle cerebral artery (MCA) precontracted with uridine triphosphate. Incubation with glibenclamide (1 microM), a known blocker of ATP-sensitive K channels, or precontraction with a high concentration of KCl (50 mM) had no effect on ACh-induced relaxation. Similarly, inhibition of the Na,K-ATPase with ouabain (10 microM) or incubation with a potassium-free solution had either no or only a small effect on ACh-induced relaxation. In contrast, NG-nitro-L-arginine (NOLAG) (1 to 10 microM), a structural analogue of L-arginine and an inhibitor of nitric oxide synthesis, produced concentration-dependent although apparently noncompetitive inhibition of ACh-induced relaxation. This inhibition was partially reversed by application of L-arginine (100 microM), a putative precursor for nitric oxide synthesis. It is concluded that membrane hyperpolarization induced by activation of ATP-sensitive K channels or Na,K-ATPase does not play a major functional role in ACh-induced relaxation of rabbit MCA. The potent inhibitory actions of NOLAG would suggest that the major mechanism of ACh-induced relaxation is by release of nitric oxide as in other cerebral and peripheral arteries.

Acetylcholine↗

PubMed1991

The lack of transmission of NANB/C hepatitis between acute and chronically infected patients and their heterosexual partners.

In order to study the risk of heterosexual transmission of non-A, non-B/C (NANB/C) hepatitis, 34 spouses and/or sexual partners to 34 index patients (13 women, 21 men; median age 39 years) with acute NANB/C hepatitis (anti-HCV positive 13/34) were repeatedly tested for antibodies to hepatitis C virus (anti-HCV) and serum alanine aminotransferase (S-ALAT) values. Spouses and/or sexual partners to 13 patients with chronic NANB/C hepatitis (11/13 anti-HCV positive) were also studied by determining anti-HCV and S-ALAT levels. No conclusive evidence of heterosexual transmission of NANB/C hepatitis was found.

Acute Disease↗

PubMed1991

Evidence against leukotrienes as mediators of brain edema.

Leukotrienes are powerful metabolites of arachidonic acid which are known to increase the permeability of peripheral blood vessels. These substances are found in brain tissue in association with cerebral ischemia, and in brain tumors. Therefore, it has been proposed that leukotrienes have a mediator function in brain edema. This hypothesis was subjected to further experimental analysis in this study, in which the authors investigated whether: 1) superfusion of the exposed brain surface with leukotrienes increases the permeability of extraparenchymal blood vessels in vivo; 2) intraparenchymal infusion of leukotrienes induces brain edema; and 3) pharmacological inhibition of leukotriene formation by BW755C, an inhibitor of leukotriene synthesis, reduces formation of brain edema from a standardized traumatic insult. The pial vessels of the parietal cortex of cats were examined by fluorescence microscopy during cerebral superfusion with the leukotrienes C4 (LTC4), D4 (LTD4), or E4 (LTE4) by using an open cranial window preparation. Intravenous Na(+)-fluorescein served as an in vivo blood-brain barrier (BBB) indicator. Superfusion of the pia with leukotrienes (up to 2 microM) did not open the barrier to fluorescein, but was associated with a significant constriction (up to 25%) of arterial and venous vessels. In experiments with slow infusion of leukotriene B4 (LTB4) or LTC4 into the white matter of feline brain, the tissue water content was subsequently determined in serial brain slices using the specific gravity method. Tissue water profiles obtained after a 15-microM infusion of either LTB4 or LTC4 were virtually identical with those of control animals infused with mock cerebrospinal fluid. Thus, neither LTB4 nor LTC4 led to an augmentation of infusion-induced brain edema. In a final series, a cold lesion of the left parietal cortex was induced in rabbits. Twenty-four hours later, swelling of the exposed hemisphere was quantified by gravimetrical comparison of its weight with that of the contralateral nontraumatized hemisphere. Eight animals received BW755C intravenously prior to and after trauma to inhibit formation of leukotrienes. Seven rabbits were infused with an equivalent volume of saline as a control study. The resulting hemispheric swelling was 7.7% +/- 0.6% (mean +/- standard error of the mean) 24 hours later in animals receiving BW755C and 7.8% +/- 1.2% in the control group, indicating that inhibition of leukotrienes was ineffective in preventing formation of vasogenic brain edema. The findings demonstrate that leukotrienes administered to the brain in concentrations occurring under pathological conditions do not open the BBB nor do they induce brain edema.(ABSTRACT TRUNCATED AT 400 WORDS)

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

PubMed1990

Effect of L-arginine on haemoglobin-induced inhibition of endothelium-dependent relaxation of isolated cerebral arteries.

The effects of Oxy-haemoglobin were investigated in the rat isolated basilar artery and compared to Methylene blue and NG-Nitro-L-Arginine (NOLAG), as these compounds interfere with the relaxation induced by the endothelium-derived relaxing factor. Acetylcholine induced a concentration-related relaxation of serotonin-precontracted arteries which was further enhanced by the application of L-arginine. Similarly, the spasmolytic activity of L-arginine was enhanced by acetylcholine. Oxy-haemoglobin, Methylene blue and NOLAG induced an increase of resting tension and inhibited acetylcholine-induced relaxation. Furthermore, inhibition of acetylcholine-induced relaxation by Oxy-haemoglobin and NOLAG but not that by Methylene blue was partially reversed by L-arginine.

Acetylcholine↗

PubMed1990

Intracellular Ca2+ measurement with Indo-1 in substrate-attached cells: advantages and special considerations.

The dual emission, Ca2+ sensitive fluorescent dye, Indo-1, offers several potential advantages over its dual excitation analogue, Fura-2. Most notable among these advantages are increased speed of measurement using dual wavelength photometry and the absence of a requirement for special quartz optics. Despite these potential advantages, only a tiny fraction of the microscopic studies of intracellular free calcium ([Ca2+]i) on substrate-attached cells has employed Indo-1. Among the reasons for the infrequent use of Indo-1 are the fact that it exhibits somewhat different spectral properties in the cytosol than it does in extracellular buffers, and the notion that it is much more sensitive to photobleaching than Fura-2. We report here that under our experimental conditions, Indo-1 photobleaching is small and does not noticeably affect the measurement of free Ca2+, even after 30 minutes of continuous illumination. We also report a new method for creating in situ standard curves that is easy, reproducible, and yields values for [Ca2+]i that are identical to those obtained with Fura-2. In addition, we have found that Indo-1 is less subject than Fura-2 to compartmentalization within subcellular organelles. These results provide baseline data to take advantage of the significant improvement afforded by Indo-1 in the measurement of rapid [Ca2+]i responses and the avoidance of compartmentalization artifacts during experiments of long duration.

Calcium↗

PubMed1990

Factors of importance when evaluating quality of life in clinical trials.

Quality of life (QoL) has during recent years become recognized as an important outcome in clinical trials. But it is not sufficient just to incorporate QoL measures in a trial. Several factors have important repercussions on the results of clinical trials using QoL as an outcome measure. Unless more attention is directed towards factors that may be important when evaluating QoL, the value of including these measurements in clinical trials will be minimized. Important issues pertain to trial design, duration of follow-up, the role of placebo effects, side effects, and confounding variables.

Attitude to Health↗

PubMed1990

Role of leukotrienes as mediator compounds in brain edema.

Leukotrienes accumulate in brain tissue after cerebral ischemia and in brain tumors. Thus, their release might contribute to the blood-brain barrier damage observed under these conditions and, hence, brain edema. The effect of these substances on the permeability of pial vessels and whether inhibition of LT synthesis reduces cold injury brain edema were studied. The pial vasculature of cats was studied by fluorescence microscopy. The cortex was superfused with LTC4, LTD4, or LTE4 via a cranial window. Na(+)-fluorescein was intravenously administered as blood-brain barrier indicator. LT concentrations up to 2 microM did not induce any leakage of the blood-brain barrier indicator into the parenchyma. However, all LTs tested constricted pial arteries and veins. Brain edema formation was studied in rabbits with cold injury. BW755C, an inhibitor of cyclooxygenase and lipoxygenase preventing formation of LTs, was given before and after trauma. Control animals received saline only. BW755C was ineffective in attenuating cold injury edema. Hemispheric swelling in control animals was 7.8 +/- 1.1%, and 7.7 +/- 0.4% in animals with treatment. LTs, even when administered to the brain in concentrations exceeding levels occurring under pathological conditions, did not induce barrier damage, nor did inhibition of LT synthesis attenuate formation of vasogenic edema. The results provide further evidence against LTs as mediator compounds of this process.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

PubMed1989

Cerebrovascular effects of prostanoids. In-situ studies in pial arteries of the cat.

The effect of prostaglandin (PG) E2, F2 alpha, the thromboxane A2 mimetic U46619 (9,11-dideoxy-9 alpha,11 alpha-methanoepoxy-prostaglandin F2 alpha) and the prostacyclin mimetic iloprost was investigated in feline and rat pial arteries in-situ using perivascular microapplication and measurement of vascular diameter. U46619 induced a concentration-dependent vasoconstriction with a maximal response of 24% at 10(-6) mol.l-1 and an EC50 of 4.9 x 10(-8) mol.L-1. This effect was inhibited by the thromboxane receptor blocking drugs AH23848 B [[1 alpha(z),2 beta,5 alpha]-(+/-)-7-[5-[(1,1'-(biphenyl)-4- yl]methoxy]-2-(4-morpholinyl)-3-oxocyclo-pentyl]-4-heptenoic acid)] and EP092 [(+/-)-5-endo-(6'-carboxyhex-2'z-enyl)-6-exo[1'-[N- (phenylthiocarbamoyl)-hydrazano]-ethyl]-bicyclo[2,2,1]-hepta ne], indicating the involvement of thromboxane-prostanoid-receptors. PGF2 alpha produced vasodilatation in cats with an increase in vessel diameter of 30% at 10(-3) mol.l-1, but constricted rat pial arteries concentration-dependently with a maximal response of 23% at 10(-4) mol.l-1. PGE2 and iloprost induced concentration-dependent (10(-9)-10(-5) mol.l-1)) dilatations with apparent maximal responses of 39% and 34% at 10(-5) mol.l-1, respectively. The corresponding EC50 values were 2.45 x 10(-7) mol.l-1 (PGE2) and 3.5 x 10(-7) mol.l-1 (iloprost). These data demonstrate the presence of prostanoid receptors mediating constriction and dilatation under in-situ conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

The effects of pinacidil and tolbutamide in feline pial arteries in situ.

The vasomotor effect of the K+ channel opener pinacidil was investigated in feline pial arteries of the parietal cortex. Perivascular microapplication (5 microliters in 40 sex) and an image splitting method for the measurement of vascular diameter were employed. Pinacidil (10(-11) - 10(-7) M) induced concentration-dependent dilatations at 10(-9) M and higher concentrations. A maximal dilatation of about 42% was achieved at 10(-8) M, the dilatation at 10(-7) M was reduced to 22%. The sulphonylurea tolbutamide exerted per se no effect in pial arteries but it blocked concentration-dependently the pinacidil induced dilatation. This is consistent with the presence of ATP-sensitive K+ channels in pial arteries which are closed under resting conditions.

Animals↗

PubMed1989

Blood-brain barrier permeability and vascular reactivity to bradykinin after pretreatment with dexamethasone.

The role of kinins as mediator substances is increasingly recognized in cerebral ischemia and trauma. It has previously been shown that cerebral exposure to bradykinin, which causes brain edema, is associated with arteriolar dilatation and selective opening of the blood-brain barrier (BBB) to small molecular weight indicators, such as Na+-fluorescein. Since the evidence suggests that these effects results from an activation of the arachidonic acid cascade, particularly from formation of E- and I-type prostaglandins, therapeutical inhibition of the cerebral effect of bradykinin has been attempted by pretreatment of experimental animals with dexamethasone. The BBB function and changes of the pial vessel diameters were studied by fluorescence microscopy in cats in alpha-chloralose anesthesia during superfusion of the exposed cerebral cortex. After a control phase bradykinin was added to a cerebral superfusate in concentrations of 4 x 10(-8) M to 4 x 10(-3) M. Two additional groups of animals received dexamethasone in a dose of 1, or 5 mg/kg body wt., respectively, 5 h prior to the cerebral superfusion with bradykinin. Na+-fluorescein (mol wt.: 376) was infused intravenously as a BBB indicator. The BBB marker remained strictly confined to the intravascular compartment under control conditions. Pretreatment with dexamethasone did not prevent opening of the BBB by bradykinin, either at the low, or high dose. However, the low dose of dexamethasone blunted the vasodilatory response to bradykinin, whereas the high dose (5 mg/kg) was found to enhance the dilatory properties of bradykinin at concentrations of 4 x 10(-3) M.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Increased dosage of diphtheria toxoid for basic immunization of adults.

Basic immunization of adults with increased dosages of a diphtheria toxoid vaccine (2100 flocculation units (Lf)/mg) was evaluated. Three injections of 7.5 Lf or 15 Lf diphtheria toxoid were given to 243 adults who had a history of no more than one previous vaccine injection. Systemic reactions were rare in both groups. Following the first two injections, local reactions (greater than 5 cm) were observed in 6-14% of the adults. After the third injection, 35% of adults in the 15 Lf group reported a local reaction (greater than 5 cm) compared to 11% in the 7.5 Lf group (p less than 0.001). The 15 Lf dose elicited a better antitoxin response than the 7.5 Lf dose. In a seronegative subgroup including 65 vaccinees who showed no booster response to the first vaccination, 79% had a postvaccination titer of greater than or equal to 0.1 IU/ml and 28% a titer of greater than or equal to IU/ml after the third injection of 7.5 Lf. The corresponding numbers in the 15 Lf group were 94% and 44%, respectively. The study demonstrates that 7.5 Lf and 15 Lf diphtheria toxoid of high purity can safely be given to adults for basic immunization. The higher dose is more immunogenic but local reactions increase after the third injection.

Adult↗

PubMed1989

Cerebrovascular effects of prostanoids: in-vitro studies in feline middle cerebral and basilar artery.

The effect of prostaglandin (PG) E2, F2 alpha, the thromboxane-A2 mimetic U46619 (9,11-dideoxy-9 alpha,11 alpha-methanoepoxy-prostaglandin F2 alpha) and the prostacyclin mimetic iloprost was investigated in cat middle cerebral and basilar arteries in vitro precontracted with 5-hydroxytryptamine (5-HT) (50nM) in the absence and presence of the cyclooxygenase inhibitor indomethacin or the thromboxane receptor blocker AH23848B [1 alpha (z),2 beta,5 alpha]-(+)-7-[5-[1,1'-(biphenyl)-4-yl] methoxy]-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid). PGF2 alpha and U46619 both produced further concentration-related contractions of basilar and middle cerebral artery, U46619 being approximately 1,000 times more potent than PGF2 alpha. Iloprost produced concentration-related relaxations of precontracted basilar and middle cerebral artery, the mean maximum relaxations produced at a concentration of 1.3 microM being 57.3% and 80.6%, respectively of the contraction produced by 50nM 5-HT. PGE2, 100nM relaxed the basilar and middle cerebral artery, 46.7% and 38.5% respectively. However, at 1 microM, PGE2 caused contraction. Indomethacin, 2.8 microM had no effect on contractile or relaxant responses to any of the prostanoids. Oxyhaemoglobin inhibited the relaxation of both arterial preparations but had no effect on responses to PGE2 or iloprost. The thromboxane-receptor blocker AH23848B antagonised the contractile responses to U46619, PGF2 alpha and PGE2 and had no effect against relaxant responses to PGE2 or iloprost. It is concluded that both contraction- and relaxation-inducing prostanoid receptors are present in the in vitro preparation of feline basilar and middle cerebral artery. Under sustained tension conditions, endothelial factors do not appear to be involved in the responses to dilating prostanoids.

Animals↗