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Biomedical subjects

W Kübler

Publications and source records attributed to W Kübler.

At least 91 records · Page 5Linked to original sources
PubMed1999

[Cell polarity in the cardiovascular system].

The importance of cell polarity as a fundamental biological principle is increasingly recognized in the cardiovascular system. Polar cell mechanisms underlie not only the development of the heart and blood vessels, but also play a major role in the adult organism for polarized endothelial functions such as the separation of the intra- and extravascular compartment and the vectorial exchange of substances between these compartments. Endothelial cells are connected through intercellular junctions which separate the functionally and structurally distinct luminal and abluminal cell surfaces. The luminal plasma membrane is in contact with the blood and takes part in the regulation of hemostasis. The abluminal cell membrane connects the endothelial cell with the basement membrane and modulates blood flow through the release of vasoactive substances. Results from epithelial model systems have shown that the polarized cell phenotype is generated by specific protein sorting and regulated protein trafficking between the trans-Golgi network and the cell surface. The polarized distribution of cell membrane proteins is maintained by anchorage with the cytoskeleton and limitation of lateral diffusion by tight junctions. Disturbances of cell polarity may contribute to the pathogenesis of disease states, including ischemic and radiocontrast-induced acute renal failure and carcinomas. Recent results have demonstrated the importance of cholesterol for protein traffic from the trans-Golgi network to the apical cell membrane. This novel intracellular function of cholesterol could point to a connection between cell polarity and the pathogenesis of arteriosclerosis. The polarity of the endothelium also has to be taken into account when developing gene-therapeutic strategies, since therapeutic success will not only depend on the efficient expression of the desired gene product, but also on its correct cellular location or secretion into the correct extracellular compartment. These examples demonstrate the biological and potentially clinical relevance of cell polarity in the cardiovascular system.

Adult↗
PubMed1999

Transregulation of adenylyl-cyclase-coupled inhibitory receptors in heart failure enhances anti-adrenergic effects on adult rat cardiomyocytes.

OBJECTIVE: In congestive heart failure (CHF), a desensitisation of stimulatory beta-receptors and of adenylyl cyclase in the heart is associated with an increase in inhibitory Gi proteins. To investigate whether the regulation of the Gi-mediated inhibitory side of the adenylyl cyclase system may be of functional importance in the failing myocardium, the contractile response of isolated adult cardiomyocytes to stimulation of inhibitory muscarinic M2 and A1 adenosine receptors was analysed. METHODS: CHF was induced in rats by banding of the ascending aorta and was verified by doubling of lung wet weight. After four weeks, contraction amplitude (delta L) and the velocity (dL/dtmax) of isolated ventricular cardiomyocytes during electrical field stimulation in the presence of 1 mM Ca2+ were measured using video micrometry. RESULTS: Contractile responses of failing cardiomyocytes to 5 mM Ca2+ were unchanged. The response to increasing concentrations of the beta-adrenergic agonist, isoproterenol (0.1-30 nM), and to forskolin (0.1 nM-1 microM) were significantly blunted. When A1 receptors were activated with N6-(R-phenyl-isopropyl)-adenosine (PIA; 0.01-1 microM) in the presence of 3 nM isoproterenol, contractility was unchanged in cells compared with those from sham-operated rats, but delta L was reduced by up to 23% and dL/dtmax by 35% in failing cardiomyocytes (P < 0.01), demonstrating an enhanced inhibitory effect of A1 receptors. The response to the M2 receptor agonist, carbachol (0.01-3 microM), was augmented to a comparable extent (delta L, -22%, dL/dtmax, -39%; P < 0.01). CONCLUSIONS: In CHF, the inotropic responses to beta-receptor-stimulation and to direct stimulation of adenylyl cyclase, but not to Ca2+, are diminished due to desensitisation of the stimulatory side of the adenylyl cyclase signal transduction system. In parallel, the responses to inhibitory receptors are augmented, leading to a pronounced Gi-mediated negative inotropic effect on failing heart muscle cells. Those anti-adrenergic effects could contribute to the contractile dysfunction of the failing heart. Reversal of the sensitisation to inhibitory stimuli might be one of the desirable mechanisms of medical therapy in CHF.

Adenylyl Cyclases↗
PubMed1999

Expression of monocyte chemoattractant protein-1 cDNA in vascular smooth muscle cells: induction of the synthetic phenotype: a possible clue to SMC differentiation in the process of atherogenesis.

In the arterial wall, smooth muscle cells (SMC) normally exist in a quiescent, differentiated state, representing the contractile phenotype. During the development of atherosclerosis SMC change towards the synthetic phenotype going along with proliferation, chemotactic response and increased monocyte binding. Expression of monocyte chemoattractant protein-1 (MCP-1), a potent chemoattractant for monocytes, has been shown to be among the earliest events in atherogenesis. We investigated the effect of MCP-1 on differentiated and dedifferentiated SMC. Differentiation of SMC was induced using Matrigel as a matrix for cultivation. MCP-1 was expressed in SMC by means of a recombinant adenovirus. Expression of MCP-1 led to dedifferentiation of SMC as demonstrated by induction of cytokeratin 18, a marker for the synthetic phenotype. Concurrently, migration was only detectable in MCP-1 expressing cells, whereas SMC infected with a control virus, coding for the nuclear-targeted lacZ gene showed no migration. The expression of intercellular adhesion molecule-1 (ICAM-1) could be demonstrated in synthetic SMC and was induced after infection of differentiated cells with recombinant adenovirus, coding for MCP-1 (AdMCP-1). Expression of ICAM-1 was associated with a tenfold higher monocyte binding compared to lacZ infected cells. Our data suggest that MCP-1 plays an important role for SMC in the functional switch from the contractile to the synthetic phenotype in the course of atherogenesis.

Adenoviridae↗
PubMed1999

Effects of the phlebotropic drug Daflon 500 mg on postischemic microvascular disturbances in striated skin muscle: an intravital microscopic study in the hamster.

The objective of this study was to investigate the effects of the micronized purified flavonoid fraction Daflon 500 mg (90% diosmin and 10% hesperidin) on I/R-induced microvascular leukocyte-endothelium interaction and leakage of the high molecular weight plasma tracer FITC-dextran (relative molecular mass, 150 kd) as assessed in the striated skin muscle of the dorsal skin fold chamber model in the hamster. Intravital fluorescence microscopy was used for analysis of microvascular perfusion, leukocyte-endothelium interaction, and macromolecular leakage of FITC-dextran 150 kd in the striated skin muscle of the hamster. A tourniquet ischemia of 4 hours' duration was induced followed by reperfusion. Animals were treated with an oral administration of Daflon 500 mg (n = six) or its vehicle (5% Arabic gum solution, n = six) for 8 days at a daily dose of 30 mg/kg body weight. Measurements in the microcirculation were made before the 8-day feeding protocol before induction of ischemia and at 0.5, 2, and 24 hours of reperfusion. In the absence of I/R, no differences in microvascular perfusion, leukocyte-endothelium interaction, and macromolecular leakage were found in Daflon 500 mg and vehicle-treated control animals before and after administration of the drugs. Induction of ischemia and reperfusion, however, elicited a significant increase in venular leukocyte rolling and sticking in vehicle-treated animals, which was accompanied by enhancement of leakage of FITC-dextran 150 kd into the perivascular tissue. Treatment with Daflon 500 mg had no effect on postischemic leukocyte rolling and sticking, and macromolecular leakage of FITC-dextran 150 kd from arterioles and postcapillary venules was significantly reduced. These data indicate that Daflon 500 mg preserves the endothelial barrier function of striated skin muscle arterioles and venules after I/R, which appears to be independent of an action on postischemic intravascular leukocyte rolling and sticking.

Animals↗
PubMed1999

External beam radiation after stent implantation increases neointimal hyperplasia by augmenting smooth muscle cell proliferation and extracellular matrix accumulation.

OBJECTIVES: We sought to examine the effects of high volume external beam radiation (EBR) after stent implantation on neointimal hyperplasia, smooth muscle cell (SMC) proliferation, presence of inflammatory cells and expression of extracellular matrix (ECM). BACKGROUND: Endovascular irradiation has been shown to reduce restenosis rates after angioplasty in preliminary trials, but conflicting results have been reported for the effects of external beam irradiation. METHODS: Forty-three Palmaz-Schatz stents were implanted into iliac arteries of New Zealand White rabbits. The arteries were externally irradiated after stent implantation with a single dose of 8 Gy (at day 3) or 16 Gy in two fractions (8 Gy at days 3 and 4) by means of a linear accelerator. In the control rabbits, no radiation was applied after stent implantation. Smooth muscle cells, macrophages and ECM were studied by immunohistochemistry at one and 12 weeks after stent implantation. Collagen type I and biglycan messenger ribonucleic acid (mRNA) levels were assessed by Northern blot analysis at one week. Neointimal cell densities and arterial lumen stenosis were measured by histomorphometry at 12 weeks. RESULTS: At 1 week, SMC proliferation at the site of stent implantation was increased after EBR with 8 and 16 Gy (26 +/- 5%, 32 +/- 3% vs. 17 +/- 8%; p < 0.01, 16 Gy vs. control). External beam radiation with 8 and 16 Gy augmented SMC proliferation proximal and distal to the angioplasty site (11 +/- 3%, 14 +/- 3 vs. 6 +/- 1%; p < 0.01, 16 Gy vs. control). Collagen type I and biglycan mRNA levels were elevated in stented arteries after EBR with 16 Gy. At 12 weeks, a marked decrease in neointimal cell density (248 +/- 97 vs. 498 +/- 117 SMCs/0.1 mm2 neointima; p < 0.005 vs. control) was noted after EBR with 16 Gy. Irradiation with 8 and 16 Gy increased arterial lumen stenosis compared with nonirradiated control rabbits (45 +/- 7%, 55 +/- 9% vs. 33 +/- 7%; p < 0.05, 8 Gy and p < 0.001, 16 Gy vs. control). CONCLUSIONS: High volume external beam radiation at doses of 8 or 16 Gy causes restenosis by augmenting proliferative activity at and adjacent to the site of stent implantation, and by dose-dependent up-regulation of extracellular matrix expression. The study suggests that excessive matrix accumulation is an important determinant of failure of radiation therapy to prevent restenosis.

Animals↗
PubMed1999

Desensitization of the pulmonary adenylyl cyclase system: a cause of airway hyperresponsiveness in congestive heart failure?

OBJECTIVES: This study was designed to investigate whether the adrenergic signal transduction in the lung and the responsiveness of airway smooth muscle to adrenergic stimulation are modulated in congestive heart failure. BACKGROUND: Wheezing and airway hyperresponsiveness are often present in heart failure. In the failing heart, chronic adrenergic stimulation down-regulates beta-adrenergic receptors and adenylyl cyclase. We hypothesized that airway dysfunction in heart failure could be due to a similar modulation of pulmonary adrenergic signal transduction. METHODS: Heart failure was induced in rats by aortic banding, resulting in increases in plasma norepinephrine, lung wet weight indicating congestion and left ventricular end diastolic pressure after four weeks. Beta-receptor densities in pulmonary plasma membranes were measured by radioligand binding using [125I]iodocyanopindolol. The G protein levels were determined by Western blot. Adenylyl cyclase activities in lung membranes were quantified as [32P]cAMP (cyclic adenosine-5'-monophosphate) synthesis rate. To functionally assess airway smooth muscle relaxation, carbachol-precontracted isolated tracheal strips were used. RESULTS: Beta-receptor density was significantly decreased in heart failure from 771 +/- 89 to 539 +/- 44 fmol/mg protein without changes in receptor affinities. The beta1-/beta2-subtype ratio, however, remained constant. The G(i and alpha) and G(s alpha) protein expression was unchanged. Adenylyl cyclase activity stimulated directly with forskolin was decreased by 28%. Relaxation of tracheal strips in response to isoproterenol and forskolin, but not to papaverin, was diminished by 30%. CONCLUSIONS: In heart failure, the down-regulation of pulmonary beta-receptors and concomitant decrease in adenylyl cyclase activity result in a significant attenuation of cAMP-mediated airway relaxation. These mechanisms may play a pivotal role in the pathogenesis of"cardiac asthma."

Adenylyl Cyclases↗
PubMed1999

Rate and time dependent effects of D-sotalol on the monophasic action potential after sudden increase of the heart rate.

Experimental and clinical data suggests that almost all Class III antiarrhythmic agents diminish their ability to prolong cardiac repolarization at fast heart rates. However, only limited data exists about the time course of efficacy decay of Class III agents after sudden increase of the heart rate. In the present study, we assessed both rate and time dependent changes of the efficacy of d-sotalol in higher stimulation frequencies following an abrupt increase in heart rate. This might imitate the situation seen in the development of paroxysmal tachycardias. Monophasic action potentials were recorded from the right ventricular apex during sinus rhythm and constant stimulation with the paced cycle length (PCL) of 550 ms, 400 ms, and 330 ms in the baseline and 20 minutes after intravenous administration of d-sotalol (2.5 mg/kg) in seven patients with documented life-threatening ventricular tachyarrhythmias. D-sotalol significantly prolonged monophasic action potential duration at different steady-state heart rates (sinus rhythm: 21.1% +/- 3.6%; PCL 550 ms: 16.6% +/- 4.3%, 400 ms: 11.2% +/- 2.7%, 330 ms: 5.8% +/- 2.1%). The prolongation is significantly shorter in higher steady-state pacing, confirming a pronounced reverse-use dependent decrease of the efficacy of d-sotalol at faster stimulation frequencies. After the abrupt increase in heart rate, the beat-to-beat adaptation of the postdrug action potential prolongation exhibits only slight reverse-use dependent shortening. The decrease of the efficacy of d-sotalol is insignificant for the first 20 consecutive beats at the stimulation frequency of the PCL of 400 msec (from 16.6% at PCL of 550 ms to 14.6% at the 20th beat of the PCL of 400 ms), and for the first ten consecutive beats at the stimulation frequency of the PCL of 330 ms (from 16.8% at PCL of 550 ms to 12.3% at the 10th beat of the PCL of 330 ms). This slow decay of action potential prolongation after an abrupt increase in heart rate might contribute to the antiarrhythmic action of d-sotalol in cardiac tachyarrhythmias.

Action Potentials↗
PubMed1999

Aortic pressure-diameter relationship assessed by intravascular ultrasound: experimental validation in dogs.

Intravascular ultrasound (IVUS) has emerged as an important diagnostic method for evaluating vessel diameter and vessel wall motion. To evaluate the validity of IVUS in assessing changes in the pressure-diameter relationship we compared measurements of abdominal aortic diameters derived from IVUS with those simultaneously obtained at the same site using implanted sonomicrometers in five chronically instrumented conscious dogs and in seven acutely instrumented anesthetized dogs. Five hundred eighty beats were analyzed to obtain peak systolic and end-diastolic diameters and to calculate aortic compliance at different blood pressure levels induced either by an aortic pneumatic cuff or by intravenous injections of nitroglycerin or norepinephrine. IVUS agreed closely with sonomicrometer measurements at different blood pressure levels. However, IVUS slightly but significantly underestimated aortic diameters by 0.6 +/- 0.7 mm for systolic diameters (P < 0.001) and by 0.7 +/- 0.6 mm for diastolic diameters (P < 0.001) compared with the sonomicrometer measurements. We conclude that IVUS is a feasible and reliable method to measure dynamic changes in aortic dimensions and has the potential to provide ready access to assess aortic compliance in humans.

Animals↗
PubMed1999

Angiotensin induces inflammatory activation of human vascular smooth muscle cells.

Multiple data suggest that the renin-angiotensin system contributes to the pathogenesis of atherosclerosis. The atherogenic effect of the renin-angiotensin system can only in part be explained by the influence of its effector angiotensin II on blood pressure, smooth muscle cell (SMC) growth, or antifibrinolytic activity. Because chronic inflammation of the vessel wall is a hallmark of atherosclerosis, we hypothesized that angiotensin II may elicit inflammatory signals in vascular SMCs. Human vascular SMCs were stimulated with angiotensin. Inflammatory activation was assessed by determination of interleukin-6 (IL-6) release into the culture medium, detection of IL-6 mRNA by RT-PCR, and demonstration of activation of nuclear factor-kappaB in electrophoretic mobility shift assays. Angiotensin II concentration-dependently (1 nmol/L to 1 micromol/L) stimulated IL-6 production by SMCs via activation of the angiotensin II type 1 receptor (demonstrated by the inhibitory action of the receptor antagonist losartan). Angiotensin I increased IL-6 production by SMCs, too. This effect was inhibited by captopril and ramiprilat, suggesting conversion of angiotensin I to angiotensin II by angiotensin-converting enzyme in SMCs. Steady-state mRNA for IL-6 was augmented after stimulation with angiotensin II, suggesting regulation of angiotensin-induced IL-6 release at the pretranslational level. Moreover, the proinflammatory transcription factor nuclear factor-kappaB, which is necessary for transcription of most cytokine genes, was also activated by angiotensin II. Pyrrolidine dithiocarbamate suppressed angiotensin II-induced IL-6 release, a finding compatible with involvement of reactive oxygen species as second messengers in cytokine production mediated by angiotensin. The data demonstrate the ability of angiotensin to elicit an inflammatory response in human vascular SMCs by stimulation of cytokine production and activation of nuclear factor-kappaB. Inflammatory activation of the vessel wall by a dysregulated renin-angiotensin system may contribute to the pathogenesis of atherosclerosis.

Angiotensin II↗
PubMed1999

A bispecific antifibrin-antiplatelet urokinase conjugate (BAAUC) induces enhanced clot lysis and inhibits platelet aggregation.

Thrombolysis is well established in the treatment of acute myocardial infarction. However, clinical application of thrombolytic agents has limitations with respect to efficacy and specificity. To achieve highly effective and at the same time clot-selective plasminogen activation urokinase was coupled to a bispecific antibody consisting of the monovalent Fab' from the antifibrin monoclonal antibody 59D8 and the monovalent Fab' from the anti-glycoprotein GPIIb/IIIa monoclonal antibody 7E3. The bispecific antifibrin-antiplatelet urokinase conjugate (BAAUC) was synthesized and characterized. Assays with either immobilized platelets, GPIIb/IIIa or fibrin showed an increase in plasminogen activation compared to uncoupled urokinase by 10-fold, 58-fold and 13-fold, respectivley (p < 0.0001 each). In vitro clot lysis was performed on platelet-rich and fibrin-rich clots and revealed an up to 5-fold higher potency of BAAUC compared to uncoupled urokinase (p < 0.0001). In vitro platelet aggregation was effectively inhibited by the hybrid molecule, whereas urokinase had no effect. BAAUC and two monospecific urokinase-conjugates, UK-59D8-IgG and UK-7E3-(Fab')2 were compared with each other with regard to similar tests. In vitro clot assays with platelet-rich and platelet-poor clots were performed. BAAUC achieved a significantly higher plasminogen activation compared to each of the monospecific conjugates (p < 0.05, respectively). We conclude that BAAUC, a bispecific plasminogen activator with antifibrin and antiplatelet properties has the potency to lyse both fibrin-rich and platelet-rich thrombi with high efficacy and to effectively inhibit platelet aggregation.

Antibodies, Bispecific↗
PubMed1999

Plasminogen activator inhibitor type-1 (PAI-1) and its role in cardiovascular disease.

Cardiovascular disease is responsible for approximately 50% of total mortality in Europe, the USA and Japan. Established risk factors including smoking, hypercholesterolemia, and hypertension explain about half of the incidence of cardiovascular disease only. Reduced endogenous fibrinolytic activity secondary to increased plasma activity of plasminogen activator inhibitor type-1 (PAI-1) is now considered as a new cardiovascular risk factor. In this review, evidence is gathered for the notion that PAI-1 constitutes a predictor of cardiovascular disease and also contributes to the development of cardiovascular disease as a pathogenetic factor. The review will focus on experimental studies modulating PAI-1 activity and clinical studies addressing coronary heart disease, myocardial infarction, restenosis after coronary angioplasty, and graft occlusion after coronary artery bypass grafting.

Animals↗
PubMed1999

Oxidative stress and atherosclerosis: its relationship to growth factors, thrombus formation and therapeutic approaches.

The initiating event of atherogenesis is thought to be an injury to the vessel wall resulting in endothelial dysfunction. This is followed by key features of atherosclerotic plaque formation such as inflammatory responses, cell proliferation and remodeling of the vasculature, finally leading to vascular lesion formation, plaque rupture, thrombosis and tissue infarction. A causative relationship exists between these events and oxidative stress in the vessel wall. Besides leukocytes, vascular cells are a potent source of oxygen-derived free radicals. Oxidants exert mitogenic effects that are partially mediated through generation of growth factors. Mitogens, on the other hand, are potent stimulators of oxidant generation, indicating a putative self-perpetuating mechanism of atherogenesis. Oxidants influence the balance of the coagulation system towards platelet aggregation and thrombus formation. Therapeutic approaches by means of antioxidants are promising in both experimental and clinical designs. However, additional clinical trials are necessary to assess the role of antioxidants in cardiovascular disease.

Animals↗
PubMed1999

Pharmacokinetics and pharmacodynamics of lanoteplase (n-PA).

In acute myocardial infarction rapid, complete, and sustained reperfusion of the infarct-related coronary artery is the most important therapeutic principle. Lanoteplase or n-PA, a third-generation plasminogen activator consisting of a deletion and point mutant of tissue-type plasminogen activator (t-PA), is a promising agent to approach this therapeutic goal. The molecule exhibits an increased plasma half-life allowing single-bolus administration. In this article, after characterizing the n-PA molecule, the currently available pharmacokinetic and pharmacodynamic data including the results of the InTIME study are reviewed.

Animals↗
PubMed1998

Induction of fibrinogen binding and platelet aggregation as a potential intrinsic property of various glycoprotein IIb/IIIa (alphaIIbbeta3) inhibitors.

The blockade of platelet integrin glycoprotein (GP) IIb/IIIa is a promising new antiplatelet strategy. The binding of ligands or of the ligand-mimetic peptide RGD causes a conformational change of GP IIb/IIIa from the nonactivated to the activated state. Because several blocking agents/inhibitors are ligand-mimetics, the current study evaluates whether these agents have the intrinsic property to activate GP IIb/IIIa. Fibrinogen binding to GP IIb/IIIa on platelets or on CHO cells expressing recombinant GP IIb/IIIa was evaluated by flow cytometry or 125I-labeled fibrinogen. Incubation with the monoclonal antibody (MoAb) fragment c7E3 (abciximab) results in fibrinogen binding to GP IIb/IIIa and in the access of ligand-induced binding sites. At low concentrations (0.01 to 0.1 microgram/mL), this intrinsic activating property of c7E3 can result in platelet aggregation. The disintegrin flavorodin and the RGD analogue fradafiban also induce fibrinogen binding, whereas the blocking MoAbs 2G12 and P2 and the activation-specific MoAb PAC-1 do not. Aspirin and indomethacin cannot block c7E3-induced fibrinogen binding to GP IIb/IIIa, but can inhibit c7E3-induced platelet aggregation. Thus, we conclude that GP IIb/IIIa inhibitors can demonstrate an intrinsic activating property, which can result in fibrinogen binding to GP IIb/IIIa and consequently in platelet aggregation. Cyclooxygenase inhibitors can inhibit platelet aggregation caused by GP IIb/IIIa inhibitors. Further studies will have to evaluate the clinical relevance of the potential intrinsic activating property of GP IIb/IIIa inhibitors and define consequences for the future drug development and evaluation of these potent antiplatelet agents.

Abciximab↗
PubMed1998

HERG potassium channel activation is shifted by phorbol esters via protein kinase A-dependent pathways.

We investigated the effects of the phorbol ester phorbol 12-myristate 13-acetate (PMA) on the rapid component of the delayed rectifier potassium current, IKr, in guinea pig cardiomyocytes and found that the IKr current amplitude was reduced by 20% with 10 nM PMA and 44% with 100 nM PMA. The ether-a-go-go-related gene (HERG) encodes IKr in human heart. We expressed HERG heterologously in Xenopus oocytes and investigated the effects of PMA on the delayed rectifier potassium current. Upon application of PMA in a concentration of 100 nM, we found a similar reduction of HERG outward current amplitude by 59%. This reduction was due to a shift in the HERG activation curve by 37 mV. The ED50 for the PMA-induced shift was 9.0 nM. The inactive 4alpha-phorbol 12-myristate 13-acetate (4alpha-PMA) had no effect. PMA is known to act by stimulating distinct protein kinase cascades. Additional application of the specific protein kinase C inhibitors chelerythrine (10 microM) or bisindolylmaleimide (1 microM) could not attenuate the PMA-induced shift. In contrast, the shift by PMA was reduced significantly when the specific protein kinase A (PKA) inhibitors H89 (50 microM) or KT5720 (2.5 microM) were applied. Forskolin (400 microM), an activator of the adenylate cyclase that results in PKA activation, shifted the HERG activation curve by 14 mV. Moreover the specific protein kinase C activator 1-stearoyl-2-arachidonylglycerol (10 microM) showed no effect. Our data suggest that mainly PKA is mediating the shift of the HERG activation kinetics.

Alkaloids↗