Biomedical subjects

M Kirchengast

Publications and source records attributed to M Kirchengast.

49 records · Page 3Linked to original sources

PubMed1995

Inhibition of arterial thrombus formation in two canine models: comparison of ancrod, a fibrinogen-depleting agent, the thrombin-inhibitor r-hirudin, and the glycoprotein 11b/IIIa-receptor antagonist Ro 43-8857.

Inhibition of arterial thrombus formation by ancrod, a fibrinogen depleting agent isolated from a snake venom, r-hirudin, an inhibitor of thrombin-mediated fibrinogen cleavage, or the glycoprotein (GP)IIB/IIIa-receptor antagonist Ro 43-8857 interfering with fibrinogen binding to platelets, was evaluated in two canine models. As a marker of platelet-dependent thrombus formation, cyclic blood flow reductions (CFR) were induced in the left coronary artery (LAD) of mongrel dogs by mechanical injury of the endothelium combined with critical stenosis. In the second model CFRs were induced by thrombolysis of a copper coil-induced thrombus in the carotid artery. Blood flow rate during the reocclusion phase was used as an additional parameter of efficacy. The frequency of CFRs used a indicator of platelet aggregation and adhesion was significantly diminished by all treatments in both the carotid artery- and the LAD-model. In the LAD-model, following ancrod treatment, CFRs were correlated with plasma fibrinogen concentrations. Carotid artery blood flow after reperfusion, used as indicator of occlusive thrombus formation, rapidly declined to zero in the control group but remained at a high level after treatment with ancrod or r-hirudin. Ro 43-8857 at the selected dose improved flow rate only to a minor degree but prolonged the bleeding time from a mean value of 87.2 +/- 10.9 s (n = 24) to values > 300 s in 50% of the animals. Our results indicate that CFRs as indicator of platelet aggregation and adhesion are inhibited by either treatments. Blood flow as indicator of occlusive thrombus formation, however, is effectively improved by ancrod and r-hirudin only. Inhibition of fibrinogen binding to platelet GPIIb/IIIa receptors alone was found to be less potent antithrombotic principle in this model.

Acetates↗

PubMed1994

Effects of the combined 5-hydroxytryptamine2 receptor and Ca2+ channel antagonist LU49938 on the responsiveness of isolated porcine coronary arteries with and without endothelium.

We performed experiments to determine the effects of the combined 5-hydroxytryptamine2 (5-HT2) receptor and Ca2+ channel antagonist LU49938 ((2S)-5-[N-methyl-N-(n-hexyl)]amino-2-isopropyl-2(3.4.5-trimethoxy phenyl)-valeronitril-hydrochloride) on vascular smooth muscle (VSM) and endothelium in isolated porcine coronary arteries. Rings with and without endothelium were suspended in conventional organ chambers for measurement of isometric force. LU49938 inhibited contractions evoked by serotonin, norepinephrine (NE), and prostaglandin F2 alpha (PGF2 alpha) in a concentration-dependent and noncompetitive manner. The lower concentrations of LU49938 (10(-7) and 10(-6) M) did not affect contractions to serotonin in the presence of ketanserin. However, a higher concentration of LU49938 (10(-5) M) significantly decreased the concentration-response curve to the monoamine in the presence of ketanserin. These finding suggest that LU49938 has a dual inhibitory effect on contractions: selective inhibition of 5-HT2 receptor and nonselective inhibition of the contractile process in VSM. The mechanism of this nonselective inhibition of VSM is likely to be related to inhibition of Ca2+ entry because LU49938 inhibited responses to several agonists. The time course and degree of relaxation caused by LU49938 were comparable in rings with and without endothelium in control solution or after incubation with nitro-L-arginine and/or indomethacin. LU49938 did not affect endothelium-dependent relaxations induced by serotonin and bradykinin. These results suggest that LU49938 does not affect endothelium-dependent responses in porcine coronary artery.

Analysis of Variance↗

PubMed1993

Inhibition by the combined Ca2+ and 5-HT2 receptor antagonist nexopamil (LU 49938) of intracoronary thrombus formation in a canine model of arterial stenosis and intimal damage.

We investigated the effects of nexopamil, a combined Ca2+/5-HT2 antagonist on thrombus formation in vivo and on platelet aggregation in vitro. In anesthetized mongrel dogs, cyclic flow reductions (CFRs) in the left anterior descending coronary artery (LAD) were induced by implanting a constrictor after the endothelium was injured mechanically. The CFRs were due to intracoronary thrombus formation. After CFRs were recorded for 1 h, the test compounds were injected intravenously (i.v.) for 2 min. Measurements were made for another hour. Nexopamil (0.05 mg/kg) completely abolished CFRs during the first 30 min after application without significantly altering hemodynamics. The same effect was noted with 0.02 mg/kg ketanserin (5-HT2/alpha 1 antagonist). The Ca2+ antagonist gallopamil reduced CFRs only in the highest hemodynamically tolerable dose by 40%. Serotonin-induced platelet aggregation in dog platelet-rich plasma (PRP) in vitro was most potently inhibited by ketanserin (IC50 0.55 x 10(-8) M), followed by nexopamil (IC50) 0.81 x 10(-7) M) and gallopamil (IC50 1.76 x 10(-6) M). Because serotonin is an important pathophysiologic mediator in unstable angina, 5-HT2 receptor antagonism should be of considerable benefit by preventing platelet activation and aggregation. The combination with calcium-antagonistic activity leads to an increase in coronary blood flow (CBF) and a decrease in cardiac oxygen demand. Therefore, the effects noted with nexopamil should be of importance in treating patients with coronary artery disease.

Animals↗

PubMed1991

Reperfusion arrhythmias in closed-chest rats: the effect of myocardial noradrenaline depletion and Ca2(+)-antagonism.

1. The influence of myocardial noradrenaline depletion on the incidence and severity of reperfusion arrhythmias in closed-chest anaesthetized rats was investigated. Five-minute left coronary artery occlusion was carried out via an implanted occluder. Four groups of rats were studied: controls, rats treated with reserpine (5 mg/kg, intraperitoneally) 24 h before occlusion, and rats receiving 0.2 mg/kg gallopamil intravenously 5 min before occlusion either with or without reserpine pretreatment. 2. In the control group all animals had ventricular tachycardia (VT) and fibrillation (VF) immediately after reperfusion. Gallopamil reduced VT to 50% and VF to 25% (P less than 0.05 versus control). In the reserpine group all had VT, and 67% had VF, this being not significantly different from controls. Additional treatment with gallopamil markedly reduced VT and totally prevented VF (P less than 0.05 versus control). 3. Thus, total depletion of myocardial noradrenaline stores neither prevented the occurrence nor reduced the severity of reperfusion arrhythmia in rats, while gallopamil treatment was effective.

Animals↗

PubMed1990

Differences in ischaemic myocardial potassium leakage after treatment with the calcium antagonist anipamil or the beta-blocker atenolol.

The abilities of the new calcium antagonist anipamil as well as the beta-blocker atenolol to reduce the amount of K+ released into the extracellular space during the first minutes of acute coronary artery occlusion were investigated in anaesthetized pigs. [K+]e was continuously measured epicardially with ion selective electrodes. Immediately after starting an occlusion [K+]e rose steeply from normal plasma levels of 3.5 mmol/l to values about three times as high at the end of the 6-min occlusion. This was reproducible in a second and third occlusion in the untreated control group. In the treatment groups either anipamil (0.5; 1.0 mg/kg) or atenolol (0.3 mg/kg) were injected intravenously 10 min before the second occlusion. Anipamil inhibited K+ loss into the extracellular space dose relatedly and significantly throughout the 6-min occlusion period, whereas atenolol showed no protection. The cardioprotective effect of anipamil was also demonstrated in a third occlusion 60 min post application. This different profile cannot be explained by differences in the ability of the two drugs to lower myocardial oxygen consumption; indeed this was only achieved after atenolol. It is concluded that anipamil exerted a direct protective effect on the cardiac myocyte level during ischaemia.

Animals↗

PubMed1989

Effects of gallopamil, diltiazem and nifedipine on the loss of K+ from ischaemic pig hearts.

K+ release into the extracellular space was investigated during repeated 6-min coronary occlusions before and after the intravenous administration of cardiovascular active doses of gallopamil (0.02; 0.05 mg/kg), diltiazem (1.0; 2.0 mg/kg) or nifedipine (0.01; 0.05 mg/kg) to anaesthetized pigs. [K+]e was measured epicardially using silver valinomycin electrodes calibrated in vivo. During control occlusions [K+]e- rose steeply in all groups, from a pre-ischaemic baseline value of about 3.5 mmol/l reaching a plateau value within the ischaemic period. This response was reproducible in an untreated control group. Gallopamil reduced the ischaemic K+ efflux dose dependently and significantly 10 min after injection; the higher dose also did 60 min after injection. Diltiazem had less effect on K+ efflux 10 min after administration and an effect was no longer detectable after 60 min. Nifedipine did not significantly inhibit the ischaemic K+ loss. Besides these differences in the direct protection of the ischaemic myocardium, the Ca2+ antagonists also had the following effects on the haemodynamic profile. Diltiazem and gallopamil significantly prolonged PQ intervals whereas nifedipine caused a shortening accompanied by a significant increase in heart rate. Blood pressure and LV dP/dtmax were significantly reduced by all compounds, but to a different degree. Diltiazem reduced blood pressure to a greater extent than did nifedipine and gallopamil. LV dP/dtmax was comparably reduced by gallopamil and diltiazem, while nifedipine had less effect. Thus, gallopamil exerted pronounced protective effects on the ischaemic pig heart.

Animals↗

PubMed1989

Effects of anipamil on electrocardiogram, plasma creatine kinase, and reperfusion arrhythmias after coronary occlusion in closed-chest rats.

The effect of anipamil pretreatment on ischemic electrocardiogram changes and loss of creatine kinase (CK) after 3 h of left anterior descending coronary artery (LAD) occlusion (group I) and, in a second set of experiments, on reperfusion arrhythmias after 5 min of coronary occlusion (group II) in closed-chest rats was investigated. An LAD occluder was implanted in animals under anaesthesia 8 days before coronary occlusion. Rats in group I were orally treated for 8 days with 6.0 mg/kg anipamil once daily; LAD occlusion was performed 4 h after the last treatment. Group II animals received a single injection of 0.5 or 1.0 mg/kg anipamil intravenously 30 min before coronary occlusion. Oral anipamil significantly reduced CK loss compared with untreated controls. Three hours after occlusion, plasma CK was 99 +/- 37 U/L in the anipamil group compared with 257 +/- 47 U/L in controls. During the first 10 min after occlusion anipamil delayed the increases of the R wave and of the ST segment. In the reperfusion experiments all control rats showed polymorphous ventricular tachycardia (VT) immediately after restoration of coronary flow; 77% degenerated to ventricular fibrillation (VF). After 0.5 mg/kg anipamil i.v. VT was observed in 61% of the rats, VF only in 14%; pretreatment with 1.0 mg/kg totally prevented reperfusion arrhythmias in all animals. We conclude that pretreatment with anipamil reduces the functional and biochemical damage after acute myocardial ischemia and totally prevents reperfusion-induced arrhythmias in closed-chest rats.

Animals↗

PubMed1988

Protective effect of the new calcium antagonist anipamil against isoprenaline-induced cardionecrosis in rats.

The new calcium antagonist anipamil (1,7-bis-(3-methoxyphenyl)-3-methylaza-7-cyano-nonadecane) exhibited a pronounced protective effect against isoprenaline-induced myocardial necrosis in rats. Anipamil was administered in single doses of 10 or 20 mg/kg daily for 4 days. 30 mg/kg isoprenaline was given by subcutaneous injection on the 3rd and 4th days of the study. The protective effect of anipamil was assessed by histological investigations, and its effect on the activity of the enzymes succinate dehydrogenase, NADH-NBT reductase, acid phosphatase and glucose-6-phosphate dehydrogenase in experimentally-induced myocardial damage was assessed quantitatively by microphotometry. The protective effect of anipamil against isoprenaline-induced myocardial necrosis was definitely dose-dependent: 10 mg/kg anipamil exhibited a partial protective effect, whilst 20 mg/kg anipamil protected the heart completely.

Acid Phosphatase↗

PubMedDate not supplied

Effects of the calcium antagonist gallopamil on the increase of myocardial extracellular potassium activity during LAD occlusion in dogs.

It has been implied that the increase of myocardial extracellular potassium activity [( K+]e) in the early stage of acute myocardial ischemia is a major cause of the increased likelihood of arrhythmia after acute coronary artery occlusion. There is also experimental evidence that some calcium antagonists reduce the occurrence of ischemia-induced early ventricular arrhythmias. In order to clarify the antiarrhythmic effect of gallopamil during the early phase of acute LAD occlusion, the influence of this calcium antagonist on the time course of [K+]e during acute ischemia was measured in open-chest anesthetized dogs using a K+-selective surface multielectrode. The regional myocardial blood flow was determined with 9 micron radioactive tracer microspheres. After application of gallopamil (bolus 25 micrograms/kg and infusion 2.5 micrograms/kg.min for 30 min) the maximal and mean rate of rise of [K+]e as well as the plateau of [K+]e reached during ischemia were significantly diminished compared with the control occlusions. 90 min after gallopamil, the rate of rise of [K+]e as well as the plateau of [K+]e reached were still significantly reduced, but 180 min after the gallopamil application, no significant differences between the time course of [K+]e and that of the two control occlusions could be found. Gallopamil significantly elevated myocardial blood flow in the non-ischemic area, but did not influence blood flow in the ischemic region. While collateral perfusion remains unchanged, the slowed and reduced increase of myocardial [K+]e during acute coronary artery occlusion may be an important component of the antiarrhythmic effect of gallopamil during early ischemia.

Animals↗

PubMedDate not supplied

Endothelin-1 mediates the alcohol-induced reduction of pancreatic capillary blood flow.

Increased plasma endothelin-1 (ET-1) levels in rats after alcohol administration and increased endothelin receptor expression in the pancreas in chronic alcoholic pancreatitis have led to the hypothesis that ET-1 may play a critical role in the pathogenesis of ethanol-induced pancreatic injury through impairment of perfusion. To further test the hypothesis that ET-1 mediates an alcohol-induced reduction of pancreatic perfusion, the present study compares the effect of intravenous alcohol and ET-1 on pancreatic capillary blood flow (PCBF) and investigates whether endothelin receptor blockade prevents the alcohol-induced reduction in PCBF. Anesthetized rats were randomly assigned to receive one of the following: a 1-hour infusion of 2 g/kg alcohol or the volume equivalent of saline solution plus ET-1 (1.25 microgram/kg), a specific endothelin-A receptor antagonist (50 mg/kg), or saline solution (volume equivalent). The pancreas was exposed for intravital microscopy; PCBF was determined at the same location before the test solutions were given, after the infusion, and 1 hour thereafter. Alcohol and ET-1 significantly decreased PCBF from 2.0 nl/min/cap to 1.7 nl/min/cap. The reduction in PCBF was even more pronounced when alcohol and ET-1 were combined (1.5 nl/min/cap), whereas the ET receptor antagonist increased PCBF in saline-treated rats to 2.2 nl/min cap and maintained stable PCBF in alcohol-treated animals. The observation that PCBF is reduced by both alcohol and ET-1 and that the alcohol-induced reduction of PCBF can be aggravated by ET-1 and prevented by a specific endothelin-1 antagonist supports the hypothesis that ET-1 is the mediator of the alcohol-associated reduction of pancreatic perfusion.

Animals↗

PubMedDate not supplied

Therapy for microcirculatory disorders in severe acute pancreatitis: effectiveness of platelet-activating factor receptor blockade vs. endothelin receptor blockade.

Many of the complications of severe acute pancreatitis are the result of the amplifying effects of microcirculatory disruption. The factors causing microcirculatory disorders in acute pancreatitis involve vasoactive mediators such as platelet-activating factor (PAF) and endothelin-1 (ET) activated during the inflammatory response to pancreatic injury. To further evaluate the potential therapeutic role of specific receptor antagonists (RA) to these mediators, the present study compares the effect of PAF and ET receptor blockade on microcirculation and organ function in a well-established rodent model of severe acute pancreatitis. Six hours after acute pancreatitis induction, rats were randomized to therapy with ET-RA (50 mg/kg LU-135252), PAF-RA (82 microg/kg WEB-2170), or NaCl 0.9% (volume equivalent). After 18 hours of fluid resuscitation, animals were relaparotomized for intravital microscopic determination of capillary blood flow, leukocyte rolling, and capillary permeability in the pancreas and colon. Other measurements included cardiorespiratory parameters, hematocrit, pleural effusions, ascites, urine production, and survival. Compared to saline treatment both ET-RA and PAF-RA significantly improved capillary blood flow in the pancreas and colon, reduced leukocyte rolling, and stabilized capillary permeability. The beneficial effects of receptor antagonist treatment on microcirculation were associated with decreased fluid loss into the third space, improved renal and respiratory function, and survival. Although both receptor antagonists likewise improved capillary blood flow, ET-RA was significantly more effective in counteracting leukocyte rolling and capillary leakage, thereby further reducing fluid sequestration. The present study confirms the beneficial effects of PAf and ET receptor blockade on microcirculation inside and outside the pancreas, organ function, and survival when given at the early stage of severe pancreatitis. Because ET-RA was more effective in stabilizing capillary permeability and avoiding subsequent fluid loss into the third space, we propose that ET-RA should be tested in a clinical trial (either in comparison or in addition to PAF-RA).

Animals↗

PubMedDate not supplied

Targets for endothelin in the diseased kidney: clues for therapeutic intervention.

The endothelin system has been implicated in various renal diseases. This review focuses on the involvement of endothelin-1 in pathogenesis and pathophysiology of acute and chronic renal failure with regard to its hemodynamic and nonhemodynamic effects. Future developments concerning the use of endothelin receptor antagonists and the role of endothelin in the kidney transplantation setting are discussed.

Acute Kidney Injury↗

PubMedDate not supplied

Improved recovery following posttransplant acute renal failure in rat renal isografts with an oral endothelin-A receptor antagonist.

BACKGROUND: Delayed renal function after transplantation is a strong predictor of long-term graft survival. As an increased expression of endothelin (ET) has been demonstrated during ischemia/reperfusion injury, we hypothesized that ET-A receptor blockade could improve the recovery of acute renal failure in a rat model of isogeneic kidney transplantation. METHODS: Kidneys of Fisher (F344, RT1(1v1)) rat donors flushed with cooled University of Wisconsin solution were transplanted into bilaterally nephrectomized Fisher rats. Recipient animals were treated orally either with vehicle or the selective ET-A receptor antagonist LU135252 (30 mg/kg/day p.o.) for 14 days. Unilaterally nephrectomized Fisher rats not subjected to ischemia served as controls. No immunosuppression was given. On days 2, 6 and 14, metabolic studies were performed to evaluate endogenous creatinine clearance, fractional sodium excretion, and urinary endothelin excretion. Kidneys were harvested at the end of the experiment for determination of renal ET content and immunohistochemical assessment. RESULTS: Urinary ET excretion was increased in vehicle-treated isografts compared to uninephrectomized controls after 14 days. Treatment with LU135252 resulted in a significant improvement in creatinine clearance and fractional sodium excretion to the level of uninephrectomized rats after 14 days. Isografts treated with selective ET-A receptor blockade demonstrated a marked reduction in cell surface markers for macrophages/monocytes, T cells, MHC-II, and ICAM-1. CONCLUSION: Treatment with the selective ET-A receptor antagonist LU135252 accelerates recovery of renal function after isogeneic renal transplantation and attenuates cellular graft infiltration. This effect could have major implications for the treatment of patients undergoing renal transplantation, as an improved initial renal function may delay the onset of chronic allograft rejection.

Acute Kidney Injury↗