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Biomedical subjects

A Hof

Publications and source records attributed to A Hof.

At least 19 recordsLinked to original sources
PubMed2001

Combined FTY720/cyclosporine treatment promotes graft survival and lowers the peripheral lymphocyte count in a murine cardiac allotransplantation model.

BACKGROUND: FTY720 lowers the peripheral lymphocyte count (PLC) by accelerating the migration of circulating lymphocytes to secondary lymphoid organs. We investigated the efficacy of combined FTY720+cyclosporine (CsA) treatment versus monotherapy on prolonging graft survival and on lowering the PLC. METHODS: BALB/c hearts were heterotopically grafted in C3H mice. FTY720 was administered alone or in combination with CsA. PLC and body weight were determined on day 7, day 28, or the day of rejection. RESULTS: Combining FTY720 with CsA prolonged, dose-dependently and significantly, the allograft survival. FTY720, but not CsA, lowered the PLC dose-dependently. The granulocyte count was not reduced in any group. FTY720 concentrations were not influenced by the CsA co-administration. CONCLUSIONS: Combined FTY720 and CsA treatment was well tolerated, promoted graft survival, and suppressed the inflammatory allo-response. The PLC lowering correlated well with the antirejection effects in the two-drug regimens, suggesting that the PLC might guide FTY720 therapy at low doses.

Animals↗
PubMed2001

Combined FTY720/cyclosporine A treatment promotes graft survival and lowers the peripheral lymphocyte count in DA to lewis heart and skin transplantation models.

OBJECTIVE: The immunomodulator, FTY720, lowers the peripheral lymphocyte count (PLC) by inducing migration of circulating lymphocytes to secondary lymphoid organs. We investigated the efficacy of mono- vs. combined-FTY720/CsA therapy on graft survival (GS) and on lowering the PLC in a solid organ and a skin graft model, using strains with strong MHC disparity. METHODS: Heterotopic cardiac or tail skin grafting was performed using the DA (RT1a) to Lewis (RT1(1)) rat strain combination. FTY720 was administered as a single daily dose by gavage alone or in combination with subcutaneously delivered CsA. PLC, body weight and drug concentrations were determined on day 7, 28, or the day of rejection. MAIN FINDINGS: In placebo-treated animals the heart and skin allografts rejected after 6 and 8 days. FTY720 delayed rejection of both the solid organ and skin grafts. The maximal effect was achieved at 1 mg x kg(-l) x day(-1) FTY720, resulting in a median survival time (MST) of 14 days for both allotransplants comparable to the effect achieved by 1 mg x kg x day(-1) CsA in both models. In the cardiac graft experiment with CsA co-administration, doses of 0.3 and 1 mg/kg were used. Under these conditions very small doses of FTY720 were effective in maintaining grafts throughout the treatment period. Adding higher FTY720 doses to the 1 mg x kg(-1) x day(-1) CsA was needed to effectively extend the skin GS, e.g. 0.3 mg x kg(-l) x day(-1) FTY720 prolonged GS from 13 to 47.5 days MST, i.e. well beyond the 28 day-treatment period. CsA did not influence the PLC at clinically relevant doses. FTY720 lowered the PLC significantly and dose-dependently, at doses lower than those needed for the prolongation of both cardiac and skin GS with FTY720 monotherapy. In rats with skin grafts the PLC was markedly lowered up to 1 mg x kg(-1) x day(-1) FTY720, whereas, in the heart model, it was lowered up to 0.1 mg x kg(-1) x day(-1). Independently of the graft type, within the combination regimens 0.3 mg x kg(-1) x day(-1) FTY720 achieved a maximal PLC depletion. CONCLUSIONS: Combining FTY720 and CsA was very well tolerated with respect to weight gain and lack of any clinically detectable infections. In the strain combination used FTY720 monotherapy was less effective than previously reported in maintaining grafts. The two-drug regimens extended strikingly the GS for both models. However, the prolongation of the heart GS was smoothly dose-related with FTY720 doses ranging from 0.01 to 1 mg x kg(-1) x day(-1) , whereas, the skin graft prolongation was modest at doses up to 0.1 mg x kg(-1) x day(-1) and remarkably enhanced at 0.3 and 1 mg x kg(-1) x day(-1) FTY720.

Adjuvants, Immunologic↗
PubMed2001

Efficacy of SDZ RAD compared with CsA monotherapyand combined Rad/FTY720 treatment in a murine cardiac allotransplantation model.

OBJECTIVE: The macrolide immunosuppressant RAD and the immunomodulator FTY720 have distinct mechanisms ofaction. We investigated the efficacy of RAD (everolimus, certican) alone or in combination with FTY720 on graft survival (GS)and histology in comparison with CsA, using mouse strains with strong MHC disparity. METHODS: Heterotopic cardiac grafting was performed using the C57B1/6 to C3H strain combination. Osmotic mini-pumps filled with CsA or RAD were implanted subcutaneously. IFTY720 was administered as a single daily dose by gavage. Peripheral lymphocyte count (PLC) was determined at 1, 4 and 8 weeks or on the day of sacrifice. Body weight was recorded on the day of surgery and weekly. Grafts were histologically evaluated. MAIN FINDINGS: In placebo-treated mice the allografts were rejected after 7 days. Monotherapy with 10 and 30 mg/kg/day CsA achieved 10 and 22.5 days median survival time (MST), while 0.1, 0.3, 1 and 3 mg/kg/day RAD resulted in 10.5, 20, > 56 and > 56 days MST, respectively. FTY720 lowered the PLC significantly, while the lower CsA dose and RAD did not influence the PLC. Adding FTY720 to the 0.6 mg/kg/day dose of RAD extended GS modestly but reduced significantly the perivascular infiltration and endothelialitis in the grafts compared with RAD monotherapy. CONCLUSIONS: Underthe conditions of the present experiment RAD was more potent than CsA in extending the GS. Combining FTY720 and RADwas well tolerated with respect to weight gain and lack of clinically detectable infections in the mice. The 2-drug regimens suppressed the inflammatory allo-response better than RAD monotherapy.

Animals↗
PubMed2000

Prevention of graft vessel disease by combined FTY720/cyclosporine. A treatment in a rat carotid artery transplantation model.

BACKGROUND: Graft vessel disease (GVD) is an important problem often responsible for late graft loss. The effects of FTY720, an immunomodulator with a novel mechanism of action were investigated in combination with cyclosporine A (CsA) in a carotid artery allograft model. METHODS: A segment of the carotid artery of Lewis rats was replaced by a DA allograft. Seven groups of eight rats were treated for 8 weeks with vehicle (P), CsA 0.3 (C0.3), 1 (C1) or 3 (C3) mg x kg(-1).day(-1) or a combination of CsA 1 with FTY 0.01 (C1F0.01), 0.03 (C1F0.03), and 0.1 (C1F0.1) mg x kg(-1).day(-1). Lumen area was estimated by magnetic resonance imaging, peripheral lymphocyte count and drug concentrations were determined at 1 and 8 weeks. Neointima, media, and lumen area were measured morphometrically. Intimal and adventitial infiltration of mononuclear cells, and medial smooth muscle cells number was assessed using a score. RESULTS: FTY720 did not influence CsA blood concentrations. FTY720 but not CsA decreased the PLC dose dependently. Magnetic resonance imaging revealed that treatment groups have larger lumen size than group P. Histological and morphometric evaluation showed that all aspects of GVD were dose dependently suppressed by treatment and lumen narrowing was prevented. CONCLUSIONS: CsA, at clinically relevant blood levels, suppressed GVD only partly. The addition of FTY720 was well tolerated and completely suppressed GVD development. In vivo lumen size did not correlate with the histologically estimated neointimal thickness.

Animals↗
PubMed2000

The peripheral lymphocyte count predicts graft survival in DA to Lewis heterotopic heart transplantation treated with FTY720 and SDZ RAD.

OBJECTIVE: The new immunomodulator 2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol hydrochloride (FTY720) lowers the peripheral lymphocyte count (PLC) by inducing migration of circulating lymphocytes to secondary lymphoid organs. This effect is dose-dependent at low (up to 0.1 mg/kg per day) doses in rats. We investigated the correlation between PLC and the later rejection, when FTY720 was combined with RAD. METHODS: Heterotopic cardiac grafting was performed using the DA-Lewis strain combination. FTY720 and RAD were administered as single daily doses by gavage alone and in combination starting 3 days before to 28 days after transplantation. Graft survival was monitored daily by palpation. PLC was determined at 1 and 4 weeks, body weight (BW) weekly. Histologic evaluation of grafted hearts was performed after rejection. MAIN FINDINGS: FTY720 at doses of 0.03, 0.1 and 0.3 mg/kg per day prolonged graft survival dose-dependently from 6 (placebo) to 7, 9.5 and 15 days median survival time (MST). RAD at doses of 0.3, 1 and 3 mg/kg per day delayed rejection to 8.5, 18 and 37.5 days MST. Very small FTY720 doses added to the lower RAD doses were effective in maintaining grafts throughout the treatment period and with normal weight gain, as opposed to regimens with 1 mg/kg or more per day RAD, which resulted in delayed weight gain. FTY720 lowered the PLC significantly and dose-dependently. The PLC correlated well with graft survival [Spearman rank correlation (n = 30, rs = -0.75)]. CONCLUSIONS: Fully effective FTY720 + RAD combination regimens caused no side effects with respect to the rats' general well-being or weight gain and were better tolerated than equiactive RAD monotherapy, suggesting a broader therapeutic window for the combinations. Under the experimental conditions, the PLC decrease showed an interesting correlation with the anti-rejection effects in these two-drug regimens. Thus, in rats the PLC is helpful for monitoring the biological activity of FTY720 at low doses (< 0.1 mg/kg per day), i.e. in the range of the steep part of its dose-response relationship.

Animals↗
PubMed2000

Serum lipids and their relationships with hostility and angry affect and behaviors in men.

Research into the relationship between the Type A behavior pattern and coronary heart disease suggests that the anger-hostility-aggression (AHA!) syndrome is directly related to total serum cholesterol and low-density lipoproteins. The present study involved an investigation of the specific components of the AHA! syndrome related to blood lipid levels in 98 healthy men. The disposition to experience and express anger when frustrated, criticized, or treated unfairly (angry reaction, a component of trait anger) was related to total serum cholesterol and to low-density lipoprotein levels. Age and diet also predicted levels of these lipids, but each was unrelated to angry reaction. These results suggest that in healthy men, the experience of strong angry affect in reaction to perceived rejection, criticism, or unfair treatment may be health-toxic because of its relationship to elevated unfavorable serum lipids.

Adult↗
PubMed1997

Allo- and autotransplantation of carotid artery--a new model of chronic graft vessel disease: evaluation by magnetic resonance imaging and histology.

BACKGROUND: Graft vessel disease is a special form of accelerated arteriosclerosis. Because immunological and nonimmunological factors can contribute to graft vessel disease, we developed a model that enables the study of both factors simultaneously. METHODS: A carotid artery was allografted from DA to Lewis rats, with the excised native artery autografted on the contralateral side. Five groups of six to seven rats were treated for 8 weeks with vehicle (placebo) or cyclosporine (CsA) (0.3, 1, 3, and 10 mg x kg(-1) x day(-1)), which was administered using subcutaneous osmotic minipumps. The carotid lumen area was estimated in vivo at 2, 4, and 8 weeks by magnetic resonance imaging (MRI); CsA blood levels were determined twice. Carotid neointimal thickening and medial and luminal area were measured with histological techniques. RESULTS: MRI showed bulging of the allografts but not autografts. Bulging disappeared over time with narrowing of the allograft lumina estimated by both MRI and histology. Histologically, vehicle-treated animals developed a massive neointima, which was inhibited in a dose-dependent manner by CsA. Autografts remained normal except for minimal subintimal thickening of two of four arteries in the group given the highest dose of CsA. Cellular rejection was detected in the allografts of all but the highest-dose group. The CsA blood levels were similar to those used in man at the two lower doses and about 10-fold higher at the highest dose. CONCLUSIONS: Subintimal thickening did not correlate with in vivo lumen size, a phenomenon that we have previously described for balloon catheter-induced lesions. CsA blood concentrations similar to those used in patients suppressed neointima formation in part, and 10-fold higher concentrations almost completely suppressed neointima formation.

Animals↗
PubMed1995

Further development for testing the effects of pesticides on wolf spiders.

Based on preliminary guidelines of the "Biologische Bundesanstalt für Land- und Forstwirtschaft" (BBA, Germany) for testing the effects of pesticides on wolf spiders (genus Pardosa, Lycosidae, Araneae), two test series were carried out with the pesticides Karate (a.i. lambda-cyhalothrin) and a noname product. At start of the test the pesticides were applied onto spiders and a sand substrate with an application apparatus. Thereafter, the mortality, the behavior, and the feeding rate were observed up to 14 days. Ninety-eight percent of the tested individuals belonged to the species Pardosa amentata. The results of the Karate experiments indicated a considerably higher reaction for males than for females. The aggression of the spiders proved to be a stress factor when the vessel was inhabited by more than one spider and caused higher mortality in individuals treated with pesticides. Spiders raised from cocoons in the laboratory were in general less sensitive than animals collected in the field and accustomed to laboratory conditions. Experiments performed with the noname pesticide in different seasons revealed that the sensitivity of the animals was influenced by their age. The parameters of mortality, behavior, and feeding rate proved to provide data adequate for evaluating the lethal and sublethal effects of the substances examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1993

Proarrhythmic effects of DPI 201-106 elicited with programmed electrical stimulation: a comparison with sotalol.

Among antiarrhythmic agents, those belonging to class III are considered most promising. Class III drugs act by prolonging the action potential duration (APD), which increases the effective refractory period (ERP). This effect can be achieved by several different cellular mechanisms. We hypothesized that among other variables the mechanism of action could be important for the propensity of class III agents to have proarrhythmic effects. We investigated the effects of sotalol (a potassium channel blocker) and DPI 201-106 (DPI, an activator of sodium channels) at doses causing the same increase in ERP, using programmed electrical stimulation (PES) in open-chest rabbits. After baseline measurements, three cumulative doses of DPI (0.3, 1, and 3 mg/kg) or sotalol (0.1, 0.3, and 1 mg/kg) or vehicle (placebo) were infused. Before drug administration, PES elicited arrhythmias in 11 of 21 animals. These arrhythmias remained unchanged in the placebo group and decreased dose dependently with sotalol. DPI, however, increased the inducibility of arrhythmias in all animals at the third dose. The two agents differed with respect to their effect on ERP2, measured with a second extrastimulus. In contrast to ERP1, which was prolonged to the same extent by both drugs, ERP2 was prolonged more by sotalol than by DPI. Proarrhythmic effects of sotalol could not be shown in this model. Our results suggest that the cellular mechanism that causes the class III effect is an important factor with respect to the occurrence of proarrhythmic activity.

Animals↗
PubMed1993

Antiarrhythmic and hemodynamic effects of tropisetron in anesthetized rabbits.

Tropisetron (ICS 205-930) is a novel drug that blocks serotonin (5-HT3) receptors and, at higher concentrations, potassium channels. Programmed electrical stimulation (PES) and tracer microspheres were used to investigate antiarrhythmic, systemic, and regional hemodynamic effects in anesthetized rabbits. Tropisetron (0.3, 1, and 3 mg/kg intravenously, i.v.) dose-dependently increased the effective refractory period (ERP) to a first and similarly to a second extrastimulus. The arrhythmias elicited by PES with one and two extrastimuli were suppressed dose dependently. The same doses and a higher dose (6 mg/kg i.v.) were tested for systemic, especially cardiodepressant, and regional hemodynamic activity in a second series of experiments. Doses < or = 3 mg/kg were almost devoid of systemic hemodynamic activity and did not alter the ECG. At the highest dose used (6 mg/kg), cardiodepression caused a decrease in blood pressure (BP), cardiac output (CO), and heart rate (HR) and an increase in central venous pressure (CVP). A selective increase in gastric blood flow was observed, starting at the lowest dose used. The highest cardiodepressant dose reversed this increase and decreased regional myocardial blood flow, especially to the subendocardial layer of the left ventricle, probably by lowering myocardial oxygen consumption. Antiarrhythmic effects thus start at 0.3 mg/kg, and doses < or = 3 mg/kg i.v. did not elicit hemodynamic side effects.

Animals↗
PubMed1992

Assessment of right ventricle dimensions with microsonometry in anesthetized rabbits.

Dimension measurements of the right ventricle are difficult to obtain because of its complex geometry, thus we evaluated a method of right ventricular dimension measurements. Crystals were placed on the ventral and dorsal side of the right ventricular free wall, approximately one-fourth of the right ventricular semicircle away from the septum, in the middle of a cranio-caudal axis of the ventricles. The effects of an increased (infusion of 20 mL/kg of 5% glucose for 3 min into seven rabbits), as well as decreased preload (nitroglycerin, 5 micrograms/kg/min i.v. n = 6) were measured and compared with changes during a placebo infusion (n = 6). The change in shortening of the right ventricle wall segment correlated with changes in both atrial natriuretic factor (ANF) plasma concentration (r = 0.89, p < 0.05) and central venous pressure (CVP) (r = 0.94, p < 0.05), respectively. Both these variables are influenced by right ventricular function and dimensions in healthy animals. Dimension measurements obtained across the free wall of the right ventricle appear to reflect right ventricular function well and should be useful in assessing the effects of drugs intended for the treatment of angina pectoris or heart failure.

Animals↗
PubMed1992

Effects of isradipine on plasma renin activity in sodium-loaded and -depleted conscious rabbits.

The antihypertensive effect of calcium antagonists is altered little by high salt intake or concomitant diuretic treatment. We therefore investigated whether modest changes in the salt balance might alter the acute response of the renin-angiotensin system to the calcium antagonist isradipine in conscious rabbits. Mongrel rabbits with indwelling arterial and venous catheters were pretreated with either a single subcutaneous injection of 20 mg/kg furosemide 24 h before the experiment [sodium depletion (SD)] or the addition of 0.45% NaCl to the drinking water, which was available ad libitum for 24 h [sodium loading (SL)]. Compared with SL, SD pretreatment modestly increased plasma renin activity and lowered body weight; mean arterial pressure and heart rate were unchanged. Isradipine (10, 30, and 100 micrograms/kg) infused into the femoral vein catheter decreased blood pressure and increased heart rate similarly in both groups. Increases in plasma renin activity plotted as a function of the decreases in blood pressure showed a significantly steeper slope in SD than in SL animals. When blood pressure started to recover 15 min after the end of drug infusion, plasma renin activity decreased in SL animals only. Therefore, SL or SD strongly influences the responsiveness of the renin-angiotensin system to calcium antagonists, and this may be one reason why high salt intake does not diminish the antihypertensive effect of calcium antagonists and a calcium antagonist/diuretic combination may not yield optimal therapeutic results.

Analysis of Variance↗
PubMed1992

Autonomic nervous system dysfunction alters drug effects: implications for testing drugs for the treatment of heart failure.

Blunted cardiac responses to sympathetic and vagal activation are key features of heart failure. Since the modulation of drug effects by a selective autonomic dysfunction is little known, we developed an acute rabbit model imitating these defects. Anesthetized rabbits were subject to cervical vagotomy and propranolol (1 mg/kg i.v.) pretreatment, thus eliminating vagally and sympathetically mediated cardiac responses, while maintaining the responsiveness of the peripheral circulation to these reflexes ("V-B" animals). Responses to drugs were altered in V-B compared with normal animals: Ouabain (5-50 micrograms/kg) increased myocardial contractile force more and milrinone (30-300 micrograms/kg) less, yet it increased the heart rate more; the reflex tachycardia to nitroprusside (1-10 micrograms/kg/min) was blunted and spirapril (0.1 and 1 mg/kg, all i.v.) decreased the central venous pressure only in V-B animals. Several drug effects were thus strongly modulated by autonomic dysfunction and responses of V-B animals were closer to those of heart failure patients than the responses of the normal animals, especially for milrinone.

Animals↗
PubMed1991

Baroreflex and atrial natriuretic factor concentration correlate with myocardial infarct size and predict early death in rabbits: implications for drug studies.

The severity of myocardial infarction (MI) and its functional consequences are difficult to assess in small animals. We searched for criteria to achieve such an assessment in rabbits 1 week after MI. Thirteen large mongrel rabbits (3-4 kg) were anesthetized with pentobarbitone for ligating a branch of the circumflex coronary artery and 7 rabbits were subject to a sham operation without ligation. All sham-operated rabbits and 12 MI animals survived for 1 week, when blood was obtained for biochemical analyses and the baroreflex was tested. Six animals survived to the third week (survivors) and six died earlier (nonsurvivors). The MI size, measured immediately after death, was 42 +/- 3% of the left ventricular mass in nonsurvivors and 20 +/- 7% in survivors. The plasma atrial natriuretic factor (ANF) concentration was correlated linearly with MI size (r = 0.77) over the whole range of infarct sizes and, like the MI size itself, was associated with the risk of early death (critical limit: 80 pM). Plasma renin activity and catecholamines yielded less prognostic information. The baroreflex control of the heart rate (tested using phenylephrine and nitroprusside) of nonsurvivors was severely impaired and the slopes correlated with MI size (r = 0.90 for phenylephrine and r = 0.67 for nitroprusside). The plasma ANF concentration and the baroreflex both accurately reflected MI size and also correctly classified 11/12 rabbits into survivors and nonsurvivors. An ANF- and baroreflex-based stratification of animals for future studies on therapeutic interventions after MI will reduce the number of animals required by at least 65%, making such studies far more feasible than in the past.

Animals↗
PubMed1990

The Doppler method for measuring cardiac output in conscious rabbits: validation studies, uses, and limitations.

The velocity of blood in the rabbit aorta is very fast, approaching the limits of some pulsed directional Doppler flow meters. Therefore, we thoroughly evaluated a 20- and a 10-MHz device for measuring cardiac output in rabbits. Flow probes were implanted around the ascending aorta and catheters were implanted into the left atrium (for microsphere injection), femoral artery, and vein. About 2 weeks later, cardiac output was determined with the Doppler method and simultaneously with tracer microspheres. Cardiac output was manipulated with isoproterenol, dihydralazine, guanfacine, or alinidine, intravenously. With the 20-MHz device, only normal and decreased cardiac output could be measured accurately, even with a 60 degrees implantation angle of the crystals. The 10-MHz device yielded accurate measurements also at very high flow. Surprisingly, at high aortic flow rates, both the 10- and the 20-MHz devices were unable to measure correctly diastolic flow, which is close to zero. It was necessary to adjust the position of the late diastolic Doppler signal manually to the electrical zero line. With this precaution, the 10-MHz device yielded an excellent correlation between mean Doppler signal and cardiac output. Cardiac output can be measured in absolute flow units if the flow-probe can be calibrated in vivo with an independent, accurate method about 2 wk after implantation. The baroreflex was not affected by the implanted flow probes. Within these limits, Doppler flow meters are good tools to assess drug effects on cardiac output in conscious rabbits.

Animals↗
PubMed1990

Comparative hemodynamic studies of isradipine and dihydralazine in atherosclerotic and normal rabbits.

The hemodynamic effects of the calcium antagonist isradipine (code name PN 200-110) and the arteriolar vasodilator dihydralazine were compared in atherosclerotic (cholesterol-fed) and normal conscious rabbits with implanted catheters. Regional blood flows were measured using the microsphere technique. Cardiac output and blood flow to several organs, especially to the gastrointestinal system, but not to the heart and brain, were lower in atherosclerotic rabbits than in normal ones. Intravenous isradipine (10 and 30 micrograms/kg) increased heart rate less in atherosclerotic than in normal rabbits. Isradipine had no effect on the surface electrocardiogram (ECG). In contrast, 0.4 mg/kg dihydralazine caused depression of the ST segment while decreasing blood pressure similarly. This was explained partly by an intramyocardial maldistribution of coronary blood flow (using microspheres). Isradipine increased and dihydralazine decreased flow to the brain. Isradipine redistributed cardiac output in atherosclerotic and normal animals in favor of the heart, brain, and skeletal muscle. However, in atherosclerotic animals, the high dose was less effective than the low dose in some vascular beds. Thus, isradipine is not a general vasodilator in either atherosclerotic or in normal animals, but favors the vital organs. This redistribution of cardiac output contrasts favorably with that induced by dihydralazine.

Animals↗
PubMed1990

Attenuation of endothelin-induced regional vasoconstriction by isradipine: a nonspecific antivasoconstrictor effect.

The modification of endothelin effects by the calcium antagonist isradipine was investigated by infusion of 1.0 nM/kg endothelin, a dose known to cause profound vasoconstriction, into eight anesthetized rabbits, followed by an infusion of 10 micrograms/kg isradipine or its vehicle into four rabbits each. In a second series of experiments, only isradipine (same dose) or its vehicle was infused into six rabbits each. Endothelin increased blood pressure and caused systemic vasoconstriction, marked bradycardia, and cardiodepression (measured with a strain guage), yet decreased central venous pressure. The regional vascular effects (measured with microspheres) encompassed widespread vasoconstriction (especially to the kidneys, adrenals, stomach, cecum, and heart), but also a tendency for vasodilatation (hepatic artery). Isradipine decreased blood pressure in endothelin-treated and normal animals. It increased cardiac output more in the endothelin group. The interaction between endothelin and isradipine in the peripheral circulation was generally additive. Isradipine blunts many, but not all, endothelin effects, thus resembling the antivasoconstrictor effects of calcium antagonists against a variety of vasoconstrictor agents such as angiotensin II (Ang II) or vasopressin. Similar to these, endothelin appears to cause vasoconstriction by several mechanisms, one of which apparently involves L-channel activation. A specific interaction of endothelin with the L-channel appears unlikely.

Animals↗