Hypertensive effect of a bradykinin antagonist in normotensive rats

The purpose of these experiments was to study the possible contribution of bradykinin to normal blood pressure maintenance. The bradykinin analogue B4146, a competitive antagonist-partial agonist of bradykinin, was used in three groups of normotensive unanesthetized Wistar rats. Two intra-aortic injections of B4146 (1 mg in 0.2 ml of dextrose) were given 5 minutes apart (i.e., well after return of blood pressure to baseline, which occurred within 68 +/- 19 seconds). One group had been pretreated with the angiotensin converting enzyme inhibitor HOE 498, 1 mg/kg (Hoechst), and one received only dextrose as the first injection to serve as controls. The bradykinin antagonist produced an average increase in mean arterial pressure of approximately 13 mm Hg for all groups. In five animals, however, the first injection of B4146 produced a hypotensive effect, whereas the second one consistently produced a rise in blood pressure. Pretreatment with the angiotensin converting enzyme inhibitor did not affect the magnitude of the subsequent blood pressure increase in response to B4146. Since smaller doses of B4146, sufficient to block exogenous bradykinin, do not cause changes in normal blood pressure, we conclude that endogenous bradykinin does contribute to normal blood pressure maintenance, but its effect can be demonstrated only if very high doses of its antagonist are injected, maybe because a high concentration of the compound is necessary to displace not only circulating but possibly tissue receptor-bound bradykinin as well.     

The nonpeptide WIN 64338 is a bradykinin B2 receptor antagonist.

We report the synthesis and in vitro biological activity of the nonpeptide bradykinin receptor antagonist WIN 64338, [[4-[[2-[[bis(cyclohexylamino)methylene]amino]-3-(2- naphthyl)-1-oxopropyl]amino]phenyl]methyl]tributylphosphonium chloride monohydrochloride. WIN 64338 inhibits [3H]-bradykinin binding to the bradykinin B2 receptor on human IMR-90 cells with a binding inhibition constant (Ki) of 64 +/- 8 nM and demonstrates competitive inhibition of bradykinin-stimulated 45Ca2+ efflux from IMR-90 cells (pA2 = 7.1). The antagonist inhibits bradykinin-mediated guinea pig ileum contractility (pA2 = 8.2) and has significantly weaker activity against acetylcholine-induced contractility in the same preparation. WIN 64338 is not active in a rabbit aorta bradykinin B1 receptor assay, demonstrating that it is a selective bradykinin B2 receptor antagonist. The compound inhibits [3H]quinuclidinyl benzilate binding to the rat brain muscarinic receptor (Ki = 350 nM) but is 25- to 100-fold more selective for the bradykinin receptor compared with other receptors against which it has been tested. Synthesis of WIN 64338 has provided a nonpeptide competitive bradykinin B2 antagonist active in both bradykinin radioligand binding and functional assays.     

Vasodepressor cough syncope masked by sleep apnea-induced asystole

Vasodepressor Cough Syncope. Cough syncope is classified among the neural-reflex "situational" faints, but whether the clinical consequences in affected individuals result from reflex triggered bradyarrhythmia or vasodepressor-induced hypotension, or both, is often unknown. In this report we describe findings in a patient with a clinical history consistent with cough syncope, and in whom documented multiple asystolic spells were at first believed to be responsible for symptoms. However, pacemaker therapy initiated at an outside facility failed to suppress symptoms, and subsequent referral for more detailed autonomic study revealed the asystole to be due to sleep apnea, whereas cough-induced vasodepressor hypotension was the basis of syncope in this individual; the latter provided a pathophysiologic target for prevention of recurring symptoms. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1024-1027, September 2012).     

Low-dose bradykinin infusion reduces endogenous glucose production in surgical patients

The systemic effect of low-dose bradykinin infusion on total body glucose production and arterial substrate concentrations was examined during D5W infusion (1.0 mg/kg/min) in five normal-weight postsurgical subjects and compared to the response in four saline infused control patients, well matched for age, weight, and degree of postoperative stress. The primed-constant infusion of 6,6-d2-glucose was used to determine the rate of endogenous glucose production. After a basal period of 90 minutes, subjects in the study group were infused with bradykinin at increasing rates of 2.0 and 4.0 micrograms/kg/h, each infusion rate lasting for 90 minutes, whereas in controls corresponding amounts of saline were given. After 75 minutes of bradykinin, endogenous glucose production was significantly reduced as compared to basal values (1.63 +/- 0.21 mg/kg/min, P less than .0125 v 2.20 +/- 0.35 basal). This was accompanied by a significant reduction in arterial concentrations of glucose, lactate, pyruvate, and alanine. Corresponding concentrations of insulin, glucagon, glycerol, free fatty acids, and ketone bodies, as well as mean arterial blood pressure and heart rate was not affected by bradykinin. In the control group no significant changes in substrate and hormone concentrations, or the rate of glucose production were observed. The higher bradykinin infusion rate did not further affect substrate metabolism or systemic hemodynamics. These results demonstrate the inhibitory effect of low-dose bradykinin on glucose production in surgically stressed patients. The stimulation of hepatic prostaglandin synthesis by bradykinin may explain the results since prostaglandins are known to exert an inhibitory effect on hormone stimulated gluconeogenesis and glycogenolysis in liver tissue.     

Consequences of opiate agonist and antagonist in myocardial ischaemia suggest a role of endogenous opioid peptides in ischaemic heart disease.

OBJECTIVE: The aim was to evaluate the effects of an opiate agonist (U50,488H) and an opiate antagonist (naloxone) in myocardial ischaemia. METHODS: A left thoracotomy was performed and the left coronary artery was ligated in adult Sprague-Dawley rats of either sex (350-400 g). Blood pressure, heart rate and electrocardiogram were measured before and after injections of U50,488H or naloxone and throughout the 30 min postligation period. RESULTS: Following coronary artery occlusion, all rats in the control group developed arrhythmias, bradycardia, and hypotension. U50,488H potentiated and naloxone attenuated the ischaemia induced arrhythmias, bradycardia, and hypotension. CONCLUSIONS: The potentiating and blocking effects of U50,488H and naloxone, respectively, suggest that endogenous opioid peptides are involved in the pathophysiology of myocardial ischaemia and play an important role in ischaemic heart disease.     

Gastric cytoprotection by acetazolamide: role of endogenous prostaglandins

This study was designed to determine the influence of acetazolamide, a potent inhibitor of carbonic anhydrase, on the formation of gastric mucosal lesions induced by acidified aspirin (ASA) or absolute ethanol and on gastric cytoprotection induced by prostaglandin E2 (PGE2). Acetazolamide prevented dose-dependently ethanol-induced gastric lesions and this effect was accompanied by an increased biosynthesis of mucosal PGs, indicating that endogenous PGs may be involved in cytoprotection by acetazolamide. This is supported by the finding that acetazolamide failed to affect gastric ulcerations produced by acidified ASA when mucosal PG biosynthesis was almost completely suppressed. Pretreatment with acetazolamide did not influence the protective action of PGE2 on ethanol-induced mucosal lesions and only slightly inhibited the protective effect of PGE2 on ASA-induced gastric ulcerations. This study indicates that: (1) acetazolamide prevents ethanol- but not ASA-induced gastric mucosal lesions probably via stimulation of PG biosynthesis and (2) gastric alkaline secretion, mediated by carbonic anhydrase, is probably not an essential mechanism responsible for this cytoprotection induced by PGE2.     

Source of endogenous arachidonate and 5-lipoxygenase products in human neutrophils stimulated by bradykinin and A23187

The lipoxygenase products of arachidonic acid (AA) metabolism, 5-hydroxyeicosatetraenoic acid (5-HETE) and leucotriene B4 (LTB4), are considered to have an important pathophysiological role in inflammatory bowel disease by stimulating the inflammatory response and by contributing to the diarrhoea. The present studies were designed to investigate the effect of the physiological stimulants bradykinin (BK) and 5-hydroxytryptamine (5-HT), in addition to the influence of the calcium ionophore A23187, on the source of AA release and 5-lipoxygenation in human neutrophils (PMNs) in vitro. This was done to elucidate the specificity of the mechanism by which PMNs respond to physiological, extracellular Ca2+ dependent agonists. The results of the study indicate that stimulation of 1-14C-AA-prelabelled PMNs with BK liberates AA mainly from phosphatidylinositol, while A23187 causes release of AA from phosphatidylcholine, phosphatidylethanolamine, and possibly phosphatidylserine. Furthermore BK (10(-9)-10(-6)M) dose-dependently stimulated the formation of 5-HETE and LTB4, reaching a maximum at 10(-7)M, while 5-HT (10(-8)-10(-4)M) released only negligible amounts of eicosanoids, similar to those observed in control experiments. Stimulation with A23187 (10(-5)M) caused a high release of both 5-HETE and LTB4. These results offer evidence that BK, but not 5-HT, initiates formation of lipoxygenase products by binding to specific receptors on the external surface of PMNs, whereas A23187 accelerates 5-lipoxygenation through mechanisms which do not involve a cell surface receptor.     

Effects of a competitive antagonist of bradykinin on blood pressure and renal blood flow in anesthetized rats

To examine a possible role of endogenous bradykinin in the regulation of blood pressure (BP) and renal blood flow (RBF), a newly synthesized competitive antagonist of bradykinin (B4147) was studied in anesthetized rats. Also, the question of whether the hypotensive effect of the converting enzyme inhibitor, captopril, is mediated partly by an accumulation of endogenous bradykinin was considered. The intravenous infusion of B4147 (25 micrograms/min) inhibited the depressor effect of exogenous bradykinin (0.5 microgram, i.v.) by 69%. After an intravenous injection of B4147 at doses of 25, 50 and 100 micrograms, BP increased and RBF decreased in a dose-dependent fashion. The increase in BP was not blocked by pretreatment with an angiotensin II antagonist (1-Sar-8-Ile angiotensin II; 20 micrograms/kg per min) or an alpha 1-blocker (prazosin; 0.1 mg/kg). The administration of captopril (1 mg/kg) decreased mean BP from 110 +/- 3.5 to 71 +/- 1.9 mmHg (P less than 0.001). However, the injection of B4147 (50 micrograms) after the administration of captopril elicited an increase in BP of 43% of the initial decrease induced by captopril. These results suggest that the effects of B4147 on BP and RBF are not mediated through angiotensin II or sympathetic alpha 1-stimulation. Endogenous bradykinin could contribute to the maintenance of BP and RBF in anesthetized rats, probably counter-balancing the vasoconstrictor mechanisms. It is also suggested that bradykinin may partly participate in the acute hypotensive effect induced by the converting enzyme inhibitor captopril.     

Role of bradykinin in renoprotective effects by angiotensin II type 1 receptor antagonist in salt-sensitive hypertension.

To elucidate whether bradykinin is involved in the renoprotective effect produced by angiotensin II type 1 receptor antagonist (AT1A) in chronic salt-sensitive hypertension, Dahl salt-sensitive rats receiving a high-salt (8%) diet were treated either with an AT1A (candesartan, 1 mg/kg/day), a bradykinin B2 receptor antagonist (BKB2A; FR172357, 30 mg/kg/day) or a combination of AT1A and BKB2A for 7 weeks. None of the treatments changed the markedly increased systolic blood pressure induced by a high-salt diet. However, chronic treatment with AT1A significantly improved the histological hallmarks of renal damage-i.e., glomerular sclerosis and cell proliferation-despite the presence of severe hypertension. This beneficial action of AT1A was abolished by the concomitant administration of BKB2A. In agreement with these histologically based findings, increases in levels of creatinine clearance induced by AT1A were also reversed back to the basal levels when BKB2A was administered in conjunction with AT1A. Furthermore, urinary excretions of nitrate plus nitrite and prostaglandin E2 increased moderately in response to the administration of AT1A alone, but not in combination with BKB2A. Thus, the blockade of bradykinin signaling abrogates the renoprotective actions of the angiotensin II type 1 (AT1) receptor antagonism. Collectively, these data show that when AT1 action is chronically blocked, endogenous bradykinin plays a pivotal role in preventing the progression of glomerular injury in salt-sensitive hypertension.     

缓激肽B2受体拮抗剂对致敏豚鼠模型咳嗽反应性的影响

目的研究缓激肽受体B2拮抗剂FR173657对卵蛋白致敏和激发豚鼠咳嗽反应性的影响.方法正常和卵蛋白致敏豚鼠各40只,卵蛋白雾化吸入激发.24 h后,再各自分成对照组、小剂量FR173657组、中剂量FR173657组和大剂量FR173657组.每组10只,分别腹腔注射生理盐水、FR173657溶液0.03 mg/kg、0.3 mg/kg和3 mg/kg,观察吸入辣椒素溶液诱导的咳嗽反应.用非侵入性方法测量正常对照组、致敏对照组和致敏中剂量FR173657组豚鼠的特异性气道阻力.结果不同剂量的FR173657不影响正常豚鼠的咳嗽反应和气道阻力.致敏对照组豚鼠吸入10-4 mol/L辣椒素溶液诱导的咳嗽次数和特异性气道阻力分别为[(21.7±3.0)次/3 min]和[(9.4±0.5) cm H2O/s]与正常对照组[(8.3±1.4)次/3 min,(7.9±0.9) cm H2O/s] 比较,差异有显著性(P<0.05),中剂量FR173657能抑制这些改变,咳嗽次数和特异性气道阻力分别为[(12.2±1.3)次/3 min,(7.5±0.9) cm H2O/s],两组比较差异有显著性(P<0.05).结论缓激肽B2受体拮抗剂抑制致敏豚鼠卵蛋白激发后增高的咳嗽反应和气道阻力.因此,缓激肽可能是嗜酸细胞性气道炎症所致咳嗽的重要介质.     

The effects of a bradykinin B2 receptor antagonist in extended liver resection with ischemia in dogs

BACKGROUND/AIMS: In liver surgery, total clamping of the portal triad (Pringle's procedure) is commonly used, and sometimes causes liver failure. This study evaluated the effects of a bradykinin B2 receptor antagonist, FR173657 (FR), on ischemia-reperfusion injury during liver resection in dogs. METHODOLOGY: Experimental animals were divided into two groups. In the FR group (n=6), FR (100 nmol/kg/hr) was administered continuously via the portal vein from 30 min before the onset of ischemia until 2 hr after reperfusion. In the control group (n=6), vehicle was injected in the same manner. The right portal pedicle was clamped for 60 min, while the left portal branch was left patent to avoid portal congestion. Following reperfusion, the non-ischemic lobes were resected, and remnant liver function was evaluated. RESULTS: AST and ALT were significantly (p<0.05) lower in the FR group than in the control group. Hepatic tissue blood flow 30 min after reperfusion was significantly (p<0.05) higher in the FR group than in the control group. Histological tissue damage was mild, and polymorphonuclear neutrophil infiltration was significantly (p<0.05) reduced in the FR group compared with the control group. CONCLUSIONS: A bradykinin B2 receptor antagonist ameliorated the ischemia-reperfusion injury caused by Pringle's procedure during extended liver resection.     

Antihypertensive efficacy of olmesartan medoxomil,a new angiotensin II receptor antagonist,as assessed by ambulatory blood pressure measurements

Olmesartan medoxomil is a new angiotensin II receptor blocker. In this randomized, double-blind, placebo-controlled study, the efficacy and safety of olmesartan medoxomil was assessed in 334 patients with moderate to severe essential hypertension. Patients were randomized to receive placebo; 5, 20, or 80 mg olmesartan medoxomil q.d.; or 2.5, 10, or 40 mg olmesartan medoxomil b.i.d. Ambulatory and cuff blood pressure were measured prior to and after 8 weeks of treatment. Treatment with olmesartan medoxomil resulted in a significant placebo-adjusted reduction of mean 24-hour ambulatory diastolic blood pressure of 9.6 mm Hg, 12.2 mm Hg, and 10.6 mm Hg in the 5-, 20-, and 80-mg q.d. groups, respectively. Corresponding reductions in mean ambulatory systolic blood pressure were 14.5 mm Hg, 16.5 mm Hg, and 15.4 mm Hg. Similar reductions of diastolic and systolic blood pressure were seen with b.i.d. dosing. The diastolic trough-to-peak ratios of the q.d. doses of olmesartan medoxomil ranged from 57%-70%, indicating 24-hour effectiveness. The safety profile of olmesartan medoxomil was similar to that of placebo. Olmesartan medoxomil appears to be a safe and effective once-a-day treatment for hypertension.     

Thyroxine is a potential endogenous antagonist of macrophage migration inhibitory factor (MIF) activity

Abnormally low plasma concentrations of thyroid hormones during sepsis often occur in the absence of thyroidal illness; however, the mechanisms involved in the "euthyroid sick syndrome" remain poorly understood. Here, we describe a previously unrecognized interaction between the thyroid hormone thyroxine (T(4)) and the proinflammatory cytokine macrophage migration inhibitory factor (MIF), together with its clinical relevance in sepsis. We found that in both patients with severe sepsis, and our rodent model, low plasma T(4) concentrations were inversely correlated with plasma MIF concentrations. The MIF molecule contains a hydrophobic pocket that is important for many of its proinflammatory activities. Binding of L-T(4) (or its hormonally inert isomer D-T(4)) significantly, and dose-dependently, inhibited the catalytic activity of this pocket. Moreover, administration of exogenous D-T(4) significantly improved survival in mice with severe sepsis. To examine the specificity of the MIFT(4) interaction, wild-type and MIF knockout mice were subjected to the carrageenan-air pouch model of inflammation and then treated with D-T(4) or vehicle. D-T(4) significantly inhibited leukocyte infiltration in wild-type mice but not in MIF knockout mice, providing evidence that in vivo T(4) may influence MIF-mediated inflammatory responses via inhibition of its hydrophobic proinflammatory pocket. These findings demonstrate a new physiological role for T(4) as a natural inhibitor of MIF proinflammatory activity. The data may also, in part, explain the low plasma T(4) concentrations in critically ill, euthyroid patients and suggest that targeting the imbalance between MIF and T(4) may be beneficial in improving outcome from sepsis.     

Vasodepressor syncope in a cardiac transplant recipient: a case of vagal re-innervation?

At the time of hemodynamic assessment three years after cardiac transplantation, a patient developed symptoms and signs of a vasodepressor reaction. In addition to sudden deceleration of heart rate, a 26% fall in mean blood pressure and a 36% fall in cardiac output was observed. Subsequent investigations revealed the presence of respiratory sinus arrhythmia, profound heart rate acceleration on standing and an approximately normal heart rate response during the following exercise. Contrary to current thinking, these observations suggest that certain individuals may develop autonomic re-innervation following orthotopic cardiac transplantation.