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Biomedical subjects

M Kirchengast

Publications and source records attributed to M Kirchengast.

At least 37 records · Page 2Linked to original sources
PubMed1998

Endothelin-1 and unstable angina: effect of either endothelin ET(A) or ET(B) receptor antagonism in a locally injured canine coronary artery.

The role of endogenous endothelin-1 in variant angina was investigated using two endothelin receptor antagonists: LU 135252 (ET(A)) and BQ 788 (ET(B)). Cyclic flow reductions were induced in a coronary artery of mongrel dogs by combining critical stenosis with endothelial injury. One hour after induction of cyclic coronary flow reductions the dogs were randomized to intravenous treatment with either saline, or LU 135252 (10 mg kg(-1)), or BQ 788 (0.1 mg kg(-1)). Cyclic coronary flow reductions were monitored for two hours after drug and remained constant in controls as well as after BQ 788. LU 135252 reduced the number of cyclic coronary flow reductions significantly (about 50%) without effects on hemodynamics or hemostasis.

Angina, Unstable↗
PubMed1998

Beneficial effects of long-term selective endothelin type A receptor blockade in canine experimental heart failure.

OBJECTIVES: We examined the effects of chronic type A endothelin receptor (ETA) blockade in a dog model of pacing-induced cardiomyopathy. METHODS: Eight dogs received an ETA antagonist, LU 135252 (50 mg/kg orally daily) and nine dogs received a matching placebo starting at day three of pacing and continued for the remainder of the three weeks of pacing. RESULTS: In the placebo group, the mean pulmonary artery pressure and left ventricular end diastolic pressure increased from 16 +/- 3 and 8 +/- 2 mmHg, respectively, at baseline to 40 +/- 11 and 34 +/- 7 mmHg, respectively, at two weeks (both p < 0.001 versus baseline). Cardiac output declined from 3.5 +/- 0.7 to 1.9 +/- 0.6 l/min (p < 0.001). In the treatment group, LU 135252 attenuated the increase in mean pulmonary artery and left ventricular end diastolic pressure (16 +/- 3 and 9 +/- 1 mmHg at baseline to 29 +/- 3 and 27 +/- 3 mmHg, respectively, at two weeks (p < 0.001), and the decline in cardiac output (3.2 +/- 0.3 to 2.6 +/- 0.8 l/min, p < 0.01; p < 0.05 versus placebo for the three parameters). Systemic and pulmonary vascular resistance increased only in the placebo group. Left ventricular end-diastolic volume increased to a similar degree. However, LU 135252 attenuated the increase in plasma norepinephrine level (placebo, 1.2 +/- 0.5 to 3.7 +/- 1.9 pmol/l; treatment, 0.8 +/- 0.3 to 2.4 +/- 0.6 pmol/l; both p < 0.001 versus baseline; p < 0.05 versus placebo). CONCLUSION: Our results suggest that endothelin-1 plays a role in the hemodynamic perturbations in canine pacing-induced cardiomyopathy. The favourable hemodynamic effects without concomitant aggravation of neurohormonal activation suggests that ETA receptor blockade may be beneficial in the treatment of heart failure.

Administration, Oral↗
PubMed1998

Endothelin receptor blockade improves fluid sequestration, pancreatic capillary blood flow, and survival in severe experimental pancreatitis.

OBJECTIVE: To evaluate the effect of a new endothelin receptor antagonist (ET-RA) on the course of severe experimental pancreatitis. BACKGROUND: Endothelin-1 has been shown to reduce regional blood flow in various organs, including the pancreas, and to aggravate cerulein-induced mild pancreatitis. METHODS: Acute necrotizing pancreatitis (ANP) was induced in rats by standardized intraductal bile acid infusion and cerulein hyperstimulation. Serum trypsinogen activation peptides (TAP) were measured to verify comparable disease severity. Starting 6 hours after the onset of ANP, animals randomly received either saline or the new ET-RA LU-135252. Monitoring included cardiorespiratory parameters, urine output, hematocrit, and TAP levels. After 24 hours, animals were relaparotomized to determine pancreatic capillary blood flow and to assess the amount of free intraabdominal fluid and acinar cell necrosis. Survival was determined in a second set of experiments on 24 animals observed for 48 hours after pancreatitis induction and treatment with either normal saline or ET-RA. RESULTS: Comparable TAP increases confirmed equally severe ANP in both groups before treatment. Treatment with ET-RA significantly reduced the mortality rate, from 50% in untreated animals to 8%. Improved survival was associated with significantly decreased hematocrit, improved urinary output, decreased ascites, and increased pancreatic capillary blood flow. There were no significant differences in plasma TAP and acinar cell injury in the surviving animals of the two treatment groups. CONCLUSION: Therapy with the new ET-RA reduces the early mortality rate in experimental ANP, probably by reducing fluid sequestration and improving microcirculation.

Acute Disease↗
PubMed1998

Enhanced endothelin-converting enzyme immunoreactivity in early atherosclerosis.

Endothelin-1 (ET-1) is a 21-amino-acid local and circulating factor whose plasma concentrations are increased in advanced atherosclerosis. ET-1 is cleaved from a prohormone (big ET-1) by endothelin-converting enzymes (ECEs) into the biologically active mature form which mediates vasoconstriction and cell proliferation. This study was designed to test by immunohistochemistry the hypothesis that ECE is present locally in the neointima of atherosclerotic vessels. Two groups of rabbits, control (n = 6) and cholesterol-fed (1% cholesterol diet for 8 weeks; n = 6) were sacrificed. Aortas were excised and divided for determination of tissue ET-1 concentration by RIA and immunohistochemical analysis of ECE. Vascular wall ET-1 was increased in the atherosclerotic aorta (6.1 +/- 0.8 vs. 9.8 +/- 0.9 pg/mg protein; p < 0.05), whereas circulating ET-1 concentrations were similar in the two groups (3.8 +/- 0.4 vs. 2.4 +/- 1.4 pg/ml). Immunostaining revealed the presence of ECE in endothelial and vascular smooth-muscle cells of the control group. Enhanced ECE immunoreactivity was present in atherosclerotic aortas, particularly in the neointimal macrophages and smooth-muscle cells. We conclude that local vascular wall, but not circulating ET-1, is increased in early atherosclerosis. In addition, ECE immunoreactivity is increased in early atherosclerosis and may therefore contribute to the generation of local ET-1 in early experimental atherosclerosis. These studies provide important insights into the regulation of ET-1 in early atherosclerosis, which may contribute to the elucidation of factors involved in the progression of atherosclerosis.

Animals↗
PubMed1998

Endothelin-A receptor antagonist combined with hydralazine improves survival and renal function in hypertensive rats.

To investigate the role of endothelin (ET) in severe hypertension, endothelial dysfunction hypercholesterolemic stroke-prone spontaneously hypertensive rats (SHRSP on a 5% cholesterol diet) were additionally fed with 1% NaCl and 0.023% nitro-L-arginine. Under these conditions, all untreated rats died within 30 days (median 17 days). A significant prolongation of survival (median 33 days) was achieved by combination treatment with hydralazine and the ETA receptor antagonist LU 135252. Monotherapy was less effective (LU 135252 18 days; hydralazine 28 days). Likewise, only treatment with the combination completely prevented the increase in systolic arterial pressure (SAP) seen in the control group during the first 10 days and delayed development of hypertension during the subsequent observation period. The superior efficacy of the combination was also reflected by improved kidney function. After 20 days of treatment, proteinuria had only increased to 1,272 +/- 135 mg/kg/day, a reduction of 45% compared to the untreated control group (2,300 +/- 346 mg/kg/day; p < 0.05). In this animal model of aggravated hypertension and endothelial dysfunction, the combination of LU 135252 with hydralazine was superior compared to either monotherapy. Therefore, the combination of an ETA receptor antagonist with vasodilators may be a potent therapy to improve blood pressure, renal function, and survival in severe hypertension with concomitant metabolic disease.

Animals↗
PubMed1998

Improvement of postischemic acute renal failure with the novel orally active endothelin-A receptor antagonist LU 135252 in the rat.

The endothelin (ET) system may play an important role in the pathogenesis of acute renal failure (ARF). We hypothesize that the course of ARF in an ischemia-reperfusion model will be markedly attenuated by the orally active ET(A)-receptor antagonist LU 135252 (LU) because of an improvement of renal perfusion. ARF was induced in rats by clamping both renal arteries for 60 min. The study was divided into two parts. In part 1, Rats received LU orally (100 mg/kg/day) starting 1 h after induction of ARF for 14 days. Cr(s), Cl(cr) and FE(na) were measured on days 1, 6, 9, and 14 after ARF. Cr(s) was lower in the treatment group on days 1 [1.3 +/- 0.31 mg/dl (n = 9) vs. 2.7 +/- 0.46 mg/dl (n = 10); p < 0.05] and 6 [0.5 +/- 0.1 mg/dl (n = 9) vs. 1.0 +/- 0.2 mg/dl (n = 9); p < 0.05], and Cl(cr) was higher on day 1 [0.9 +/- 0.17 ml/min (n = 9) vs. 0.2 +/- 0.1 ml/min (n = 8); p < 0.05] and 6 [1.8 +/- 0.29 ml/min (n = 9) vs. 1.0 +/- 0.21 ml/min (n = 9); p < 0.05] compared with vehicle. Additionally, FE(na) was lower in treated rats on day 1 [1 +/- 0.4% (n = 9) vs. 8 +/- 3% (n = 8); p < 0.051 compared with vehicle. In part 2, ARF was induced as described. Treated animals received 10 mg/kg LU on days 0, 1, 3, 6, 9, and 14 after ARF as an i.v. bolus injection. RBF, cortex blood flow (CBF), and medulla blood flow (MBF) were measured after application of LU on the same days: LU induced an increase in RBF (day 1: 14 +/- 5.3%, n = 6, p = 0.04; day 3: 15 +/- 2.8%, n = 8; p = 0.0008; day 6: 21 +/- 5.8%, n = 6, p = 0.02; day 9: 13 +/- 4%, n = 6; p = 0.03) and CBF (day 1: 8 +/- 2.2%, n = 7, p = 0.03; day 3: 7 +/- 2.5%, n = 7; p = 0.05; day 6: 18 +/- 4.8%, n = 6, p = 0.04; day 9: 10 +/- 2.5%, n = 6; p = 0.008) up to the first 9 days. MBF did increase on days 1 (9 +/- 3.1%, n = 6; p = 0.04) and 6 (13 +/- 3.6%, n = 6; p = 0.03). Our data confirm the hypothesis that ET plays a major role in the genesis of ARF associated with ischemia-reperfusion.

Acute Kidney Injury↗
PubMed1998

Thrombin inhibition and intracoronary thrombus formation: effect of polyethylene glycol-coupled hirudin in the stenosed, locally injured canine coronary artery.

BACKGROUND: Adhesion and aggregation of platelets at sites of intimal injury are accompanied by local thrombin generation and conversion of fibrinogen to insoluble fibrin. As the long-acting thrombin inhibitor, polyethylene glycol-coupled hirudin (PEG-hirudin), would be expected to interrupt this process by inhibiting the action of thrombin on platelets and fibrinogen, its effect on intracoronary thrombus formation, coagulation, platelet function, and duration and intensity of bleeding events was investigated. METHODS: Cyclic coronary flow reductions (CFRs) were induced in the left anterior descending coronary artery of 24 anaesthetised mongrel dogs by mechanical injury of the endothelium combined with critical stenosis. There were four treatment regimens (six dogs per group): Control (isotonic saline); PEG 0.08 (0.15 mg/kg bolus + 0.08 mg/kg.h infusion); PEG 0.15 (0.30 mg/kg bolus + 0.15 mg/kg.h infusion); PEG 0.30 (0.60 mg/kg bolus + 0.30 mg/kg.h infusion). RESULTS: A linear increase in steady-state plasma concentrations to 35.4 +/- 1.6 antithrombin units (ATU)/ml, 59.2 +/- 3.0 ATU/ml and 112.7 +/- 8.4 ATU/ml was achieved with the three doses of PEG-hirudin. The activated partial thromboplastin time (APTT) was increased 1.7-fold with PEG 0.08, 1.9-fold with PEG 0.15 and 2.2-fold with PEG 0.30. The frequency of CFRs during the first hour after drug administration was diminished by about 20% with all three doses of PEG. During the second hour, CFRs were decreased by 61% in all treated groups. Thrombin-induced platelet aggregation was completely abolished by all PEG-hirudin regimens. Buccal bleeding time and blood loss were not increased after either treatment. CONCLUSION: In this canine model of coronary artery stenosis, the thrombin inhibitor, PEG-hirudin, effectively reduces platelet-dependent thrombus formation without interfering with primary haemostasis.

Animals↗
PubMed1998

[Endothelin receptor block in acute pancreatitis--improvement of microcirculation and decrease of capillary permeability also distant from the pancreas].

We have previously demonstrated that therapy with a new specific endothelin-1 receptor antagonist (ET-RA) significantly reduced mortality in acute necrotizing pancreatitis (ANP) in the rat. Improved survival was not associated with decreased intrapancreatic trypsinogen activation or parenchymal necrosis but with reduced fluid sequestation into the third space suggesting that ET-RA counteracts systemic rather than local sequelae of severe pancreatitis. The present study further tests this hypothesis by evaluating the effect of the specific ET-1 antagonist LU-135252 on capillary blood flow, capillary density, and capillary permeability not only in the pancreas but also in the colon, and monitoring fluid losses and renal and respiratory function. The experiments demonstrate that therapy with the specific ET-RA started 6 hours after disease onset stabilizes increased capillary permeability in ANP not only in the pancreas but also in the colon. This is associated with reduced ascites and improved renal and respiratory function. Furthermore, ET-RA enhances decreased capillary blood flow and capillary density in the pancreas and colon. The present results are consistent with our previous observation that ET-RA improves outcome in ANP by counteracting systemic microcirculatory disorders (particularly capillary leakage) which are believed to contribute to organ failure in early pancreatitis in this model as well as in severe human pancreatitis.

Animals↗
PubMed1998

Effects of endothelin and endothelin receptor antagonism in arteriolar and venolar microcirculation.

BACKGROUND: Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor potentially involved in several cardiovascular diseases. The effect of ET-1 and the selective ETA receptor antagonist LU 135252 on skeletal muscle microcirculation in hypertensive rats was investigated. METHODS: The cremaster muscle of anaesthetised spontaneously hypertensive rats was superfused with 10(-8) M ET-1 with and without pre-treatment with LU 135252 10 and 30 mg/kg i.v. Vascular diameters were measured microscopically, recorded on videotape and quantified off-line. RESULTS: Superfusion with ET-1 led to a pronounced arteriolar constriction, which was the stronger the smaller the arterioles were (A1: 45%, A4: 90%). Venolar vasoconstriction was much less pronounced and independent of the vessel size (V1-V4: approx. 25%). LU 135252 (10 and 30 mg/kg i.v. was able to block arteriolar vasoconstriction dose-dependently, most pronouncedly so in the smallest arterioles. Venolar vasoconstriction was only antagonised by the higher dose. During the 30 minutes observation period cardiovascular parameters were not changed significantly with either dose of LU 135252. CONCLUSION: Selective ETA receptor blockade in hypertensive rats reduced ET-1 induced arteriolar vaso-constriction in resistance arterioles to a much higher degree then venolar constriction. As elevated ET-1 levels are seen in patients with primary hypertension, this new therapeutic principle may have promising clinical potential to treat hypertension by reducing peripheral arterial resistance.

Animals↗
PubMed1997

Preclinical considerations and results with the combination of verapamil and trandolapril: blood pressure reduction and beyond.

OBJECTIVE: Preclinical studies were designed to investigate whether the combination of verapamil and trandolapril was more potent than either drug alone for the treatment of hypertension and concomitant cardiovascular or metabolic diseases. HYPERTENSION: In spontaneously hypertensive rats (SHR) oral treatment with the combination of verapamil plus trandolapril not only significantly reduced elevated blood pressure for 24 h but, after terminating treatment, the antihypertensive effect lasted longer than 48 h, indicating potentiation of each compound's effect. In stroke-prone SHR, life-long oral treatment with low doses of verapamil, trandolapril or their combination significantly prolonged life in each case, but results obtained with the combination were additive compared with monotherapy. HYPERTENSION AND DIABETES: In an animal model of non-insulin-dependent diabetes, the obese Zucker rat, 2 weeks oral treatment with verapamil, trandolapril or both combined significantly improved leukocyte rheology, but only the combination treatment normalized the microcirculation. In insulin-dependent diabetes (streptozotocin-induced) in SHR, oral treatment with the combination for 12 weeks additively reduced blood pressure and totally normalized proteinuria and albuminuria. Verapamil was least effective. Trandolapril showed intermediate protection against insulin-dependent diabetes-related renal failure. CHRONIC RENAL FAILURE: In SHR, almost in parallel with the progression of hypertension, progressive renal failure develops, as indicated by increasing proteinuria and albuminuria. With lifelong treatment in these rats, verapamil + trandolapril combined inhibited the progression towards end-stage renal failure more effectively than either compound used as monotherapy and also significantly prolonged survival. In a second study, in older rats with hypertension and proteinuria, chronic treatment with the combination reduced renal insufficiency in parallel with a reduction in glomerulosclerosis independently of a blood pressure reduction and significantly more potently than each drug alone. CORONARY ARTERY DISEASE: In pigs subjected to consecutive left anterior descending artery occlusions, intravenous verapamil dose-dependently reduced ischaemic myocardial K+ loss. Trandolapril alone was ineffective. Combining two ineffective doses (0.02 mg/kg verapamil plus 0.1 mg/kg trandolapril) led to a significant, additive reduction in extracellular K+ concentrations during ischaemia. Combined intracoronary application of 0.5 mg/kg trandolapril and 0.1 mg/kg verapamil before occlusion in dogs improved myocardial contractility 3 h after reperfusion to a greater extent than monotherapy and reduced the incidence of reperfusion arrhythmias. In dogs exposed to hypoxaemia after ischaemic reperfusion injury, paradoxical coronary constriction was observed. Treatment with trandolapril (0.05 mg/kg) plus verapamil (0.1 mg/kg) inhibited this vasoconstriction in response to repeated hypoxia. In anaesthetized dogs, cyclic coronary flow reductions were induced. Trandolapril reduced these by 70-80% from a dose of 0.1 mg/kg onwards. Verapamil (0.2 mg/kg) had no effect. Combining ineffective doses of trandolapril (0.05 mg/kg) and verapamil (0.1 mg/kg) led to a 70% fall in the flow reductions. Further experiments using either the bradykinin B2 antagonist HOE 140 or the angiotensin II AT1-receptor antagonist Exp 3174 showed that this effect was not mediated by increases in bradykinin levels but by a decrease in angiotensin II. CONGESTIVE HEART FAILURE: Two weeks after occlusion of the left anterior descending artery, surviving rats were randomly allocated to no treatment or to verapamil at 20 or 40 mg/kg per day or to trandolapril at 0.3 or 0.7 mg/kg per day or to combinations of both drugs, orally for 24 weeks. (ABSTRACT TRUNCATED)

Animals↗
PubMed1996

Trandolapril plus verapamil inhibits the coronary vasospasm induced by hypoxia following ischemia-reperfusion injury in dogs.

1. Dogs were exposed to hypoxemia followed by a coronary angiogram at three different times: under control conditions, after ischemia-reperfusion injury, then 30 min later. 2. In the study group, the dogs were treated with trandolapril (0.05 mg/kg) and verapamil (0.1 mg/ kg) just prior to the final hypoxic challenge. 3. Under control conditions, the left anterior descending coronary artery (LAD) dilated in response to hypoxia. Following ischemia-reperfusion injury, however, it constricted significantly in response. 4. In the control group, repeat hypoxia 30 min later resulted in vasoconstriction of the LAD which was comparable to the preceding response. 5. However, in the study group, treatment with trandolapril plus verapamil inhibited the vasoconstriction in response to repeat hypoxia.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Individual and combined effects of verapamil or trandolapril on attenuating hypertensive glomerulopathic changes in the stroke-prone rat.

Previous studies have demonstrated differences in the progression to glomerulosclerosis with the use of calcium channel blockers (CCB). The results with angiotensin-converting enzyme (ACE) inhibitors are more consistent. Moreover, only two studies have examined the combined effects of these drug classes on the development of glomerulosclerosis. The aim of the study presented here was to test the hypothesis that nonhypotensive doses of the combination (VT) of a nondihydropyridine CCB, verapamil (V), and an ACE-inhibitor, trandolapril (T), will slow the development of glomerulosclerosis better than either agent alone in stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were randomized to treatment in one of three groups with nonhypotensive doses of these agents; a fourth group served as control (C). The control rats developed significant increases in proteinuria compared with the other groups (C, 190 +/- 35 mg.kg-1.d-1 versus VT, 19 +/- 12 mg.kg-1.d-1; P < 0.05). This finding correlated with the degree of glomerulosclerosis (mean severity grading for C, 3.31 +/- 0.21 versus VT, 1.6 +/- 0.51; P < 0.05). Moreover, there was no significant reduction in arterial pressure between these groups (C, 282 +/- 5 versus VT, 259 +/- 13 mm Hg; P = 0.12). Despite persisting hypertension, the rise in proteinuria was also attenuated in both the V group (57 +/- 21 mg.kg-1.d-1) and the T group (43 +/- 24 mg.kg-1.d-1). However, compared with the control rats, kidney morphology was unchanged. Lastly, creatinine clearance was better preserved in the VT group compared with the control group (C, 0.57 +/- 0.01 versus VT, 0.74 +/- 0.06 mL.min-1.100 g-1; P < 0.05). It was concluded that the combination of nonhypotensive doses of VT attenuates the rise in proteinuria and progression to glomerulosclerosis. This study supports the concept that VT may have effects on the glomerulus that are independent of blood pressure reduction.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Effects of the potassium channel blocking agent ambasilide on ventricular arrhythmias induced by acute myocardial ischemia and sympathetic activation.

The ineffectiveness of traditional antiarrhythmic agents in preventing sudden cardiac death has increased the interest in drugs that prolong refractoriness. Ambasilide is a new potassium channel blocking agent that appears to prolong refractoriness at short and long cycle lengths. We assessed the effects of ambasilide, 5 mg/kg intravenous (i.v.) bolus plus 5 mg.kg-1.hr-1 i.v. infusion, in 16 anesthetized cats in which ventricular arrhythmias could be induced reproducibly by the combination of acute myocardial ischemia and increased sympathetic activity. Ambasilide decreased heart rate and blood pressure and prolonged QRS duration (26%, p < 0.05), QTc (17%, p < 0.0001), and JTc (16%, p < 0.005). Ambasilide also shifted the strength-interval curve for ventricular refractoriness by 17 to 22 msec to the right (p < 0.001). Ventricular fibrillation was observed in 7 animals and never occurred after ambasilide (p < 0.001); however, 4 (57%) of these cats had sustained ventricular tachycardia requiring cardiac massage. Ambasilide prevented nonsustained ventricular tachycardia in 2 (40%) of 5 animals. The antiarrhythmic effect of ambasilide persisted when heart rate was kept constant by atrial pacing. In no case was proarrhythmia observed. Ambasilide had a significant electrophysiologic effect at the ventricular level in the cat because it did prolong QTc and ventricular refractoriness. Therefore ambasilide showed an antifibrillatory effect but provided only a partial protection against lethal arrhythmias induced by acute myocardial ischemia and sympathetic activation.

Acute Disease↗
PubMed1995

Previous exposure to bradykinin unmasks an endothelium-dependent relaxation to the converting enzyme inhibitor trandolaprilat in isolated canine coronary arteries.

Experiments were designed to investigate the mechanism underlying the endothelium-dependent relaxation to trandolaprilat, a converting enzyme inhibitor, in canine coronary arteries previously exposed to bradykinin. Rings suspended in organ chambers were exposed to bradykinin for 3 min and washed repeatedly for 150 min. Trandolaprilat caused relaxations [IC50(-log M)8.59] in rings with endothelium previously exposed to bradykinin. This response was observed already at concentrations where trandolaprilat did not augment relaxations to bradykinin. When the rings were exposed to acetylcholine or to Des-Arg9-bradykinin (B1 agonist) trandolaprilat caused only a minimal response. Carboxypeptidase B but not aprotinin impaired the relaxation to trandolaprilat, suggesting a contribution of bradykinin. After exposure to [3H]-bradykinin, no detectable amounts of the peptide were released by trandolaprilat or found in the preparations. The relaxation to trandolaprilat was not affected by the B1 antagonist Leu8-des-Arg9-bradykinin. HOE-140, a B2 antagonist impaired the maximal response to trandolaprilat, while exhibiting competitive antagonism against bradykinin (pA2 9.00). The maximal relaxation to trandolaprilat was impaired in the presence of nitro-L-arginine and methylene blue. The potency, but not the maximal effect of bradykinin was reduced by these inhibitors. Exogenous bradykinin, but not trandolaprilat, caused an endothelium-dependent hyperpolarization. At equipotent submaximal concentrations, bradykinin released both nitric oxide and endothelium-derived hyperpolarizing factor although trandolaprilat stimulated the production of nitric oxide only. These findings suggest that acute endothelium-dependent relaxations to trandolaprilat in preparations previously exposed to bradykinin are mediated by nitric oxide and may be due partially to protection of bound bradykinin but also to some other unresolved mechanism(s) as well.

Animals↗
PubMed1995

The combined 5-HT2 receptor and calcium channel inhibitor LU49938 restores endothelium dependent responses in the regenerated endothelium of the porcine coronary artery.

OBJECTIVE: The aim was to evaluate the effect of the combined 5-hydroxytryptamine-2 (5-HT2) receptor antagonist and calcium channel inhibitor LU49938 ((2S)-5-[N-methyl-N-(n-hexyl)] amino-2-isopropyl-2(3.4.5-trimethoxyphenyl)-valeronitrilhydrochloride ) on the endothelium dependent responsiveness of porcine coronary arteries with native and regenerated endothelium. METHODS: Male Yorkshire pigs were assigned randomly to one of four groups: (1) controls; (2) pigs receiving LU49938 daily (5 mg.kg-1) for four weeks; (3) pigs undergoing balloon de-endothelialisation of the left anterior descending coronary artery; and (4) pigs undergoing balloon de-endothelialisation and receiving LU49938 daily. At four weeks, quantitative coronary angiography, organ chamber experiments, and morphometric studies of the tissues were performed. RESULTS: Treatment with LU49938 did not affect the endothelium dependent responses in native porcine coronary arteries. Intracoronary injection of serotonin caused significantly greater coronary vasoconstriction in group 3 compared with group 4. The cross sectional area of the intima and media of previously de-endothelialised left anterior descending coronary artery increased significantly in group 3, but not in group 4. In arteries with regenerated endothelium, augmented endothelium dependent contractions were noted not only in response to serotonin, but also in response to platelets, noradrenaline, and endothelin-1. The endothelium dependent relaxations to platelets, serotonin, and UK14304 were impaired in the regenerated endothelium, but not those to adenosine diphosphate and SIN-1. However, following four weeks of treatment with LU49938, the pertussis toxin sensitive endothelium dependent responses were restored. The augmented endothelium dependent contraction to endothelin-1 was not altered by the treatment. CONCLUSIONS: Chronic treatment with LU49938 restores endothelium dependent, pertussis toxin sensitive, G protein mediated responses in the regenerated endothelium of the porcine coronary artery, and inhibits the intimal thickening following arterial injury.

Adrenergic alpha-Antagonists↗
PubMed1995

Effect of endothelin-1 and BQ 123 on arterioles and venules of hypertensive rats.

We investigated the effect of the ETA-receptor antagonist BQ 123 (1.0, 5.0, and 10 mg/kg/h i.v.) on the endothelin-1 (ET-1) (10(-8) M)-induced vasoconstriction of arterioles in the cremaster muscle preparation of anesthetized SHRs. ET-1 10(-8) M led to a constriction of the arterial microvessels most marked in A4 arterioles (-92.9%) and least marked in A1 (-17.3%). The ET-1-induced constriction of venules was much less pronounced and showed no dependence on the vessel type. BQ 123 1.0 mg/kg/h was ineffective in antagonizing the vasoconstrictor effect of ET-1 in arterioles. With 5.0 mg/kg/h BQ 123, the ET-1-induced arterial vasoconstriction was inhibited by 68% in A4, by 44% in A3, by 39% in A2, and by 10% in A1 arterioles. BQ 123 10 mg/kg/h blocked the vasoconstrictor effect of ET-1 in all arteriole types by 79-93% and also reduced diastolic blood pressure in SHRs significantly at the end of the infusion period (-12.6 mm Hg). The ET-1-induced slight venous constriction was not affected by BQ 123.

Animals↗