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Biomedical subjects

U Pohl

Publications and source records attributed to U Pohl.

At least 73 records · Page 4Linked to original sources
PubMed1991

Effects of vasoactive agonists on the membrane potential of cultured bovine aortic and guinea-pig coronary endothelium.

1. The effects of bradykinin, ATP, adenosine, histamine and thrombin on the membrane potential of confluent monolayers of cultured bovine aortic endothelial cells (BAECs) and guinea-pig coronary endothelial cells (GCECs) were studied at 37 degrees C using the whole-cell mode of the patch-clamp technique. 2. The amplitude histogram of the resting potentials of BAEC monolayers showed a bimodal distribution with one peak around -25 mV and another peak around -85 mV. Transitions from one potential level to the other were observed. The bistable membrane potential can be explained by an N-shaped current-voltage relation of the endothelial cell membrane. 3. When BAECs with a low resting potential (-10 to -30 mV) were superfused with maximally effective concentrations of ATP (2-10 microM) an initial hyperpolarization of -80 to -90 mV was observed which decayed to a plateau of about -60 mV within 1 min. When ATP was removed after 2-3 min the membrane potential returned to control level within 1 min. This was followed by a second hyperpolarization of 10-20 mV, which decayed within 15 min. 4. In the absence of extracellular calcium, ATP produced only a brief transient hyperpolarization in aortic endothelium. The plateau and the secondary hyperpolarization were abolished. These findings are consistent with the idea that the changes in membrane potential reflect changes in intracellular free Ca2+ and that the initial peak is due to release of Ca2+ from intracellular stores, whereas the plateau and the secondary hyperpolarization depend on transmembrane Ca2+ influx. 5. Bradykinin evoked potential changes similar to ATP in BAECs, except that the secondary hyperpolarization during wash-out was absent. When the membrane potential was more negative than -80 mV, ATP and bradykinin induced only a small initial hyperpolarization followed by a depolarization of up to 20 mV. 6. In aortic endothelium, ADP (10 microM) evoked a much smaller response than ATP. Adenosine (10 microM), thrombin (2 units/ml), acetylcholine (10 microM) and histamine (10 microM) had only a very small effect on the membrane potential, if any. 7. The amplitude histogram of the membrane potential of GCECs showed only one peak around -35 mV. In coronary endothelium, application of bradykinin, ATP, histamine, thrombin, acetylcholine and adenosine all evoked a transient hyperpolarization of 10-40 mV lasting 1 min or less, which then turned into a depolarization. 8. The K+ channel openers cromakalim (BRL 34915) and lemakalim (BRL 38227) did not affect the membrane potential of GCECs or BAECs.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗
PubMed1991

Potent effects of AP3A and AP4A on coronary resistance and autacoid release of intact rabbit hearts.

We investigated effects of platelet-derived dinucleotides diadenosine 5',5"'-P1,P3-triphosphate (AP3A) and diadenosine 5',5"'-P1,P4-tetraphosphate (AP4A) on coronary vasculature. In isolated rabbit hearts, saline perfused at constant flow (36 +/- 3 ml/min), AP3A and AP4A induced dose-dependent decreases in coronary perfusion pressure. Dose-effect curves of AP3A [-log M mean effective concentration (EC50) 6.2 +/- 0.1] and AP4A (EC50 6.4 +/- 0.2) were identical and not significantly different from those of adenosine, ADP, and ATP (n = 4-8). There were, however, distinct differences between both dinucleotides: pretreatment with endothelium-derived relaxing factor (EDRF)-inhibitors oxyhemoglobin (6 microM, n = 6) and NG-nitro-L-arginine (30 microM, n = 6) significantly reduced AP4A-induced dilation by 44 and 42% but did not affect vasomotor effects of AP3A or of sodium nitroprusside, adenosine, ATP, and ADP. Concentration of the stable hydrolysis product of prostaglandin (PG)I2, 6-keto-PGF1 alpha, increased by 173 +/- 25% in coronary effluent (n = 23) during infusion of AP3A (1 microM). This increase was significantly higher than during infusion of equimolar concentrations of AP4A (38 +/- 10%), ATP (23 +/- 5%), adenosine (20 +/- 10%), or an equimolar combination of AMP and ADP (52 +/- 25%), the hydrolysis products of AP3A. Luminometric and high-performance liquid chromatography analysis showed a nearly complete (94 +/- 3%) degradation of ATP during passage through the coronary bed while significant amounts of AP3A (31 +/- 5%) and AP4A (33 +/- 6%) remained uncleaved.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1991

EDRF-mediated shear-induced dilation opposes myogenic vasoconstriction in small rabbit arteries.

In small saline-perfused rabbit mesenteric arteries (diam 221 +/- 4 microns, means +/- SE; n = 48) in situ, the interactions of endothelium-derived relaxing factor (EDRF)-mediated flow-dependent dilation and myogenic constriction were studied. When pump flow was increased two- to fivefold (2.8 +/- 0.1-fold), input perfusion pressure rose by 133 +/- 17%. Vessel diameter first increased passively by 9 +/- 1% and then decreased to or below control values reflecting the vascular myogenic activity. This was followed by a 16 +/- 3% increase in diameter, which was flow dependent, because nonperfused vessels exposed to the same intravascular pressures did not dilate. When the perfusate viscosity was increased with dextran solutions, both the basal diameters and the flow-induced dilator responses were significantly augmented, indicating that the increase in shear stress was the stimulus. The flow-dependent dilation was abolished by inhibition of EDRF with either hemoglobin (10 microM) or NG-nitro-L-arginine (0.3 mM) and also after preincubation with neuraminidase (0.2 U/ml, 30 min), which removes part of the membrane glycocalyx. Thus, myogenic responses in small mesenteric arteries can be effectively opposed by shear-induced release of EDRF. This might be a major mechanism for maintaining adequate tissue perfusion when pressure and shear stress increase simultaneously (e.g., exercise hyperemia, autoregulation) and otherwise myogenic activity would reduce vascular conductivity.

Acetylcholine↗
PubMed1990

Endothelial cells as part of a vascular oxygen-sensing system: hypoxia-induced release of autacoids.

Higher developed organisms are equipped with many central and local control mechanisms, which enable an adequate blood and oxygen supply to tissues over a wide range of demands. Global adaptive responses include changes in the circulatory and ventilatory system as well as increases in the oxygen carrying capacity of the blood. At the level of the specialized organs there exist additional control systems for the regulation of local blood flow. Most systems make use of highly specialized cells which are able to sense the oxygen partial pressure of the transport medium, blood, and within the tissues. In the past years, it has been shown that the vascular endothelium lining the entire circulatory system can actively modulate the vascular tone and platelet functions by the release of autacoids, among them prostacyclin and endothelium-derived nitric oxide (EDRF). Recent experiments demonstrate that the release of EDRF is PO2-dependent, which suggests that endothelial cells may act as functional local oxygen sensors within the vascular system.

Adenine Nucleotides↗
PubMed1990

Endothelium-dependent modulation of vascular tone and platelet function.

Endothelial cells exert potent effects on vascular tone and platelet activity by the release of autacoids. One of the functionally most important autacoids is the endothelium-derived relaxant factor (EDRF). It inhibits platelet and vascular smooth muscle activation by cGMP-dependent attenuation of the agonist-induced rise of intracellular free Ca2+. Recent experiments suggest that EDRF has a physiologic role in the control of the vascular tone of large arteries and resistance vessels. Furthermore, there is evidence that an impairment of EDRF release may be a significant pathophysiologic factor in myocardial ischaemia. Coronary vascular tone might be also affected by the endothelium-derived vasoconstrictor peptide, endothelin, but its significance for the control of coronary blood flow remains to be elucidated.

Endothelins↗
PubMed1990

[Increased plasma level of atrial natriuretic peptide in patients with stress-induced coronary insufficiency: stretch-independent release of atrial natriuretic peptide?].

Plasma levels of atrial natriuretic peptide (ANP) were determined in 34 male patients undergoing diagnostic right heart catheterization. Patients with effort angina exhibited significant higher ANP levels at rest (259 +/- 42 pg/ml; n = 7) than patients without signs of coronary heart disease (78 +/- 30 pg/ml; n = 8). Patients with effort angina also had higher ANP levels at rest than patients exhibiting impaired cardiac function on exertion without signs of ischemia (105 +/- 15 pg/ml; n = 4), patients with only minimal functional alterations due to infarction residues (95 +/- 27 pg/ml; n = 7), or patients with only borderline changes of ST-segments during exertion (61 +/- 19 pg/ml; n = 8). In contrast, mean pulmonary capillary or right atrial pressures were not significantly different between the various groups of patients. The patients with effort angina also exhibited the highest ANP levels during bicycle exercise (846 +/- 238 pg/ml). There was only a weak to moderate linear correlation between ANP levels and pulmonary or right atrial pressures in the whole group of patients (r = 0.1-0.6). The plasma levels of epinephrine and norepinephrine and of ANP were not significantly correlated, with the exception of norepinephrine levels during exercise (r = 0.54). Our observations suggest that in patients with effort angina there may exist additional stretch-independent factors stimulating the release of ANP, possibly associated with repetitive myocardial ischemia.

Angina Pectoris↗
PubMed1990

Regulation of femoral vascular resistance by adenine nucleotides via endothelial and smooth muscle receptors.

It is well established that adenosine (ADO) and adenine nucleotides are potent vasodilators, but their role in local blood flow control is still under debate. Recent findings on contribution of vascular endothelium to the vasomotor regulation pointed out this problem. In the present study the effects of adenine nucleotides were investigated in vivo on the femoral arterial flow (FAF) and femoral vascular resistance (FVR). Selective suppression of the endothelium mediated dilation was achieved by gossypol (35 mumol/l). On intact hindlimbs ADO (4 mmol/l) and ATP (0.5 mmol/l) elicited 3.5-fold increase of FAF, in average. Resistance decreased by 6.24 +/- 0.58 and 7.23 +/- 1.12 peripheral resistance units (PRU100), respectively. After gossypol, ATP-induced dilation was either significantly suppressed (resistance-decrease was 3.70 +/- 0.58 PRU100; p less than 0.02 vs control) or turned to strong constriction (FAF decreased by 50%). ADO-induced dilation remained unchanged. These results, in agreement with in vitro data, suggest that adenosine directly relaxes the vascular smooth muscle of resistance vessels via P1-purinoceptors, while ATP-induced vasomotion is composed of a dilator effect mediated by endothelial P2y-receptors, and a direct constrictor effect on the vascular smooth muscle via P2x-purinoceptors.

Adenosine↗
PubMed1989

Identification and partial characterization of an adenosine(5')tetraphospho(5')adenosine hydrolase on intact bovine aortic endothelial cells.

The biologically active dinucleotides adenosine(5')tetraphospho(5')adenosine (Ap4A) and adenosine(5')-triphospho(5')adenosine (Ap3A), which are both releasable into the circulation from storage pools in thrombocytes, are catabolized by intact bovine aortic endothelial cells. 1. Compared with extracellular ATP and ADP, which are very rapidly hydrolysed, the degradation of Ap4A and Ap3A by endothelial ectohydrolases is relatively slow, resulting in a much longer half-life on the endothelial surface of the blood vessel. The products of hydrolysis are further degraded and finally taken up as adenosine. 2. Ap4A hydrolase has high affinity for its substrate (Km 10 microM). 3. ATP as well as AMP transiently accumulates in the extracellular fluid, suggesting an asymmetric split of Ap4A by the ectoenzyme. 4. Mg2+ or Mn2+ at millimolar concentration are needed for maximal activity; Zn2+ and Ca2+ are inhibitory. 5. The hydrolysis of Ap4A is retarded by other nucleotides, such as ATP and Ap3A, which are released from platelets simultaneously with Ap4A.

Acid Anhydride Hydrolases↗
PubMed1989

LY 83583 (6-anilino-5,8-quinolinedione) blocks nitrovasodilator-induced cyclic GMP increases and inhibition of platelet activation.

We studied the effects and the mechanism of action of the cyclic GMP-lowering substance 6-anilino-5,8-quinolinedione (LY 83583) on cyclic GMP-mediated inhibition of platelet function. The activation of washed human platelets by thrombin was counteracted by 8-bromo-cyclic GMP and the direct activators of soluble guanylate cyclase, sodium nitroprusside and endothelium-derived relaxant factor (EDRF = nitric oxide). LY 83583 significantly antagonized the inhibitory effect of sodium nitroprusside and EDRF, but not that of 8-bromo-cyclic GMP, on thrombin-induced aggregation, ATP-release, adhesion to native endothelial cells and increase in concentration of free intracellular calcium ions. In accordance, increases in intracellular cyclic GMP by sodium nitroprusside and EDRF were attenuated by LY 83583. The inhibition of cyclic GMP-mediated effects on platelets by LY 83583 could be related to inhibition of platelet soluble guanylate cyclase, as the activation of the purified enzyme from platelets by sodium nitroprusside was directly inhibited by LY 83583. This effect of LY 83583 was attenuated in the presence of superoxide dismutase. Our findings support the hypothesis that sodium nitroprusside and EDRF inhibit platelet activation by stimulation of soluble guanylate cyclase via nitric oxide. Consequently, inhibition of nitric oxide-induced cyclic GMP formation by LY 83583, which may act by intracellular generation of superoxide anions, facilitates platelet activation.

Adenosine Triphosphate↗
PubMed1989

Characterization and immunolocalization of the protein contents of micronemes of Sarcocystis muris cystozoites (Protozoa, Apicomplexa).

Affinity-purified polyclonal antibodies generated against micronemes obtained by the subcellular fractionation of Sarcocystis muris contain two major proteins of 16 and 17 kDa. Antibodies cross-react with microneme antigen of S. tenella and S. cuniculi but not with the S. sp. of wild boar (Sus scrofa). Microneme antigens could be traced by immunoelectron microscopy in metrocytes as early as 47 days postinfection and in gamonts of S. muris in cell cultures up to 4 h after inoculation.

Animals↗
PubMed1989

Effect of FOY-305 (camostate) on severe acute pancreatitis in two experimental animal models.

Two models of severe acute pancreatitis were chosen and pancreatitis induced by sodium taurocholate and by a choline-deficient ethionine-supplemented diet, to evaluate the effectiveness of FOY-305 (camostate), a new synthetic trypsin inhibitor. Prophylactic administration of FOY-305 had a significantly favorable effect on the course of the sodium taurocholate-induced disease and on the survival rate of the treated group. A beneficial effect on the amylase and lipase content in serum and ascites was found, but no effect was observed on enzyme concentration in pancreatic tissue or on the degree of histologically detectable organ destruction. Therapeutic administration of FOY-305 had a significantly positive influence when infused directly, 5 and 30 min after the operation, whereas enzyme increase and organ destruction remained unaffected. FOY-305 showed a beneficial effect when given prophylactically or therapeutically at the beginning of the pancreatitis induced by a CDE diet, with no significant change in enzyme increase and degree of organ destruction. The favorable effect on survival time and rate in the early phase of these two severe experimental forms of pancreatitis may justify an evaluation of FOY-305 in a clinically controlled study.

Acute Disease↗
PubMed1989

Differential vascular sensitivity to luminally and adventitially applied endothelin-1.

When secreted into the vascular lumen, endothelin-1 (ET-1) potentially may act as a circulating pressor substance. We investigated whether luminal ET-1 can directly stimulate smooth muscle in isolated vascular segments. Rabbit femoral arteries and veins whose luminal and adventitial surfaces could be perfused separately were used. Luminally administered ET-1 (1 nM) induced a vasoconstriction (21 +/- 5% of outer resting diameter) in segments without endothelium whereas in segments with intact endothelium, no significant vasomotor response was observed. In segments without endothelium, however, the vasoconstrictor responses to luminal and abluminal ET-1 were not significantly different. Similar results were obtained in segments of femoral veins. No release of endothelium-derived relaxing factor (EDRF) could be detected (guanylate cyclase assay) in segments of rabbit aorta and vena cava following stimulation with ET-1 whereas there was a slight increase (by 20 +/- 13%) of PGI2 release. It is concluded that the endothelium forms a tight barrier to circulating ET-1 (up to 1 nM) in intact vessels that has no functionally significant effect on endothelial autacoid release.

Animals↗
PubMed1989

Modulation of the vasodilator action of SIN-1 by the endothelium.

We studied the influence of endothelium-derived relaxing factor (EDRF) on sydnonimine (SIN-1)-induced vasodilatation and the accumulation of cyclic GMP in the rabbit femoral artery. The potency of SIN-1 to elicit vasodilatation in norepinephrine-contracted femoral arteries was significantly enhanced in the absence of the endothelium or following impairment of the synthesis of EDRF with gossypol or NG-nitro-L-arginine, whether the application of SIN-1 was intra- or extraluminal. The increase in cyclic GMP in the femoral segments by a combination of SIN-1 and endothelium-derived relaxant factor (released by the endothelium of either the rabbit thoracic aorta or the femoral artery) was significantly less than the sum of the increases in cyclic GMP induced by each agent alone. In contrast, stimulation of purified soluble guanylate cyclase by submaximal concentrations of SIN-1 was additive with the effect of EDRF, released from acetylcholine-stimulated rabbit aortas. This indicates the absence of a direct interaction between the factor and SIN-1 at the level of soluble guanylate cyclase. The interaction seems to be specific for cyclic GMP-mediated responses, since cyclic AMP-induced dilatations elicited by isoproterenol were not affected by the presence of the endothelium. The results indicate that the endothelium can modulate the vascular reactivity to SIN-1. This modulation may be mediated either by EDRF or by another endothelial substance that alters the metabolism or the action of cyclic GMP in vascular smooth muscle.

Animals↗
PubMed1989

Xanthine oxidase inhibitor in acute experimental pancreatitis in rats and mice.

It has been suggested that oxygen-derived free radicals play a decisive role in the pathogenesis of acute experimental pancreatitis in a model of edematous pancreatitis. Accordingly, allopurinol, a xanthine oxidase inhibitor, was shown to mitigate the development of nonfatal acute pancreatitis in ex vivo perfusion models using dogs. For further evaluation of allopurinol, its effect was studied in two forms of fatal necrotizing acute experimental pancreatitis: sodium taurocholate-induced pancreatitis in rats and choline-deficient ethionine-supplemented diet-induced pancreatitis in mice. Allopurinol did not affect the mortality rate, pancreatic enzyme elevation in serum and ascites, the enzyme content of the pancreas, or any parameter indicating histopathological damage in the pancreas. Although these experiments did not determine the role oxygen-derived free radicals play in the development of pancreatitis, they show, none the less, the absence of any beneficial therapeutic effect of a xanthine oxidase like allopurinol on the development of the disease once it has begun.

Acute Disease↗
PubMed1989

Hypoxia stimulates release of endothelium-derived relaxant factor.

It was tested whether hypoxia stimulates the release of endothelium-derived relaxant factor (EDRF). In paired segments (with and without endothelium) of either femoral artery (n = 49) or aorta (n = 42) from rabbits, selective luminal hypoxia (Po2 = 24 +/- 8 mmHg) was induced, whereas the Po2 at the adventitial side was kept above 300 mmHg. Hypoxia induced a dilation of 11 +/- 2% in aortic segments with endothelium, whereas the paired segments without endothelium dilated by only 1.2 +/- 0.2% (P less than 0.001). Similar results were obtained in femoral segments (11.8 +/- 1.5% dilation in segments with endothelium vs. 1.4 +/- 0.2% in segments without; P less than 0.001). Likewise in 19 out of 36 bioassay experiments, perfusate from endothelium-intact rabbit aortas or cultured bovine aortic endothelial cells exposed to hypoxia elicited dilation (10.7 +/- 3.2%) in the detector. The EDRF-inhibitors, hemoglobin (5 microM) and dithiothreitol (200 microM), significantly inhibited the hypoxia-induced dilation of intact segments as well as of assay segments perfused with effluent from hypoxic donors. These results suggest that hypoxia stimulates the release of EDRF from native and cultured endothelium. Low partial pressures of oxygen, such as those that exist in small arteries and arterioles, might therefore be a physiological stimulus for continuous release of EDRF.

Acetylcholine↗