Hemodynamic action of verapamil in dogs with controlled aortic pressure--influence of sympathetic activation

Verapamil was given to 18 anesthetized dogs (alpha-chloralose 100 mg/kg) as a bolus injection (200 micrograms/kg) followed by constant rate infusion (10 micrograms/kg per min). Hemodynamic parameters were evaluated before and during verapamil administration. After a suitable period of time for complete reversal of hemodynamic effects, verapamil administration as well as hemodynamic measurements were repeated during graded aortic occlusion. This technique stabilized central aortic pressure so that the level of reflex baroreceptor stimulation could be kept constant. Atrio-ventricular conduction disturbances observed in 5 dogs during balloon occlusion are attributed to lack of sympathetic stimulation. Without balloon occlusion, verapamil produced significant decreases in peripheral systemic vascular resistance and pressure and marked increases in cardiac output. Heart rate, pulmonary arterial and pulmonary wedge pressures did not change significantly. During graded aortic occlusion, systemic resistance and cardiac output were less markedly affected but there was an increase in both pulmonary arterial and wedge pressures.     

In vivo enhancement of platelet activating factor-induced prostacyclin production by OKY-046, a selective inhibitor of thromboxane A2 synthase.

Platelet-activating factor (PAF), a likely mediator of endotoxin action, causes thromboxane A2 (TXA2) release and pulmonary hypertension in pigs. We examined the effect of selective TXA2 synthase inhibition with OKY-046 on cyclooxygenase metabolites during PAF-induced pulmonary hypertension. Six closed-chest pigs received PAF in escalating doses (0.1, 0.3, 1.0, and 3.0 nmol intravenously, i.v.) before and after (E)-3[4-(1-imidazolyl methyl) phenyl]-Z-propenoic acid hydrochloride monohydrate OKY-046, 10-mg/kg i.v. bolus plus 20-mg/kg/h infusion. Plasma samples at peak PAF effect had radioimmunoassay (RIA) for the stable metabolites of TXA2 (TXB2) and prostacyclin (6-keto-PGF1 alpha). Tachyphylaxis was not noted in 5 control pigs given sequential repeats of the PAF dosing series. Pulmonary vascular resistance (PVR) was 240 +/- 30 (SE) dyne s cm-5 at baseline and increased to 3,100 +/- 1,300 after 1.0 nmol PAF (p less than 0.05). When the same amount of PAF was given after OKY-046, PVR increased only to 820 +/- 280 dynes/s/cm-5. TXB2 was 34 +/- 7 pg/0.1 ml at baseline and increased to 70 +/- 4 pg/0.1 ml with PAF 1.0 nmol (p less than 0.001). TXB2 levels were unchanged from 34 +/- 4 pg/0.1 ml when PAF 1.0 nmol was administered after OKY-046 (NS vs. pre-OKY-046). In contrast, 6-keto-PGF1 alpha, 6 +/- 2 pg/0.1 ml at baseline, increased to 24 +/- 4 pg/0.1 ml after PAF 1.0 nmol and increased further to 50 +/- 8 pg/0.1 ml when PAF 1.0 nmol was given after OKY-046 (p less than 0.05 vs. pre-OKY-046).(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal effects of alpha-adrenoceptor blockade during furosemide diuresis in conscious rats.

Clearance experiments were performed in conscious rats in order to investigate whether intravenous infusion of the non-selective alpha-adrenoceptor antagonist phentolamine could block compensatory sodium reabsorption during furosemide-induced volume contraction. By measuring inulin clearance, urinary excretion rates of sodium and water, and lithium clearance, the effects on proximal and distal nephron segments were dissociated. The renal effect of intravenous infusion of 0.3 mg/kg/hr phentolamine (n = 6) was compared with time control animals (n = 9). Furosemide was administered as constant intravenous infusion (7.5 mg/kg/hr) with simultaneous phentolamine infusion at four dose levels: 0 (n = 9), 0.3 (n = 6), 1.0 (n = 7) and 3.0 mg/kg/hr (n = 6). Phentolamine infusion reduced norepinephrine-induced increase in blood pressure at all three dose levels (n = 5). Phentolamine infusion induced transient antidiuresis and a prolonged antinatriuretic response. Compared with rats given furosemide only, phentolamine attenuated dose-dependently the diuretic and natriuretic peak response to furosemide. This effect was associated with dose-dependent reductions in mean arterial pressure. The reduced natriuretic response was due to a reduced fractional sodium excretion in the distal nephron segment (at all doses of phentolamine) and a reduction of the glomerular filtration rate (1.0 and 3.0 mg/kg/hr phentolamine). The fractional lithium excretion (FELi) increased to 65 +/- 3% at 0.3 mg/kg/hr phentolamine during the natriuretic peak response of furosemide, while it only increased to 52 +/- 3% during furosemide alone. At steady-state conditions (120-180 min. after start of furosemide infusion) after infusion with furosemide plus 0.3 mg/kg/hr phentolamine the animals were still volume-depleted, but the compensatory tubular Na reabsorption in the proximal tubules was inhibited (FELi = 48 +/- 2% versus 39 +/- 1% in rats given furosemide alone). During furosemide infusion plasma epinephrine increased 700% and plasma norepinephrine increased 50%. These results are compatible with increased systemic sympathetic nervous activity and a contributory role of proximal tubular alpha-adrenoceptors in mediating compensatory sodium reabsorption during acute furosemide-induced volume contraction.     

PAF, rather than histamine, participates in mouse anaphylactic hypotension

We determined the roles of platelet-activating factor (PAF) and histamine in anaphylactic hypotension in ovalbumin-sensitized anesthetized BALB/c mice. The effects of PAF and histamine on hemodynamic variables were studied by measuring the systemic arterial (Psa), portal venous (Ppv) and central venous (Pcv) pressures. Intravenous PAF evoked a biphasic Psa response, an initial rapid and transient drop followed by marked hypotension, accompanied by a decrease in Pcv. Histamine caused only mild systemic hypotension. Both agents similarly increased Ppv by approximately 4 cm H(2)O at high doses. After an injection of antigen, Psa initially increased slightly and then decreased from the baseline of 94 +/- 1 mm Hg to 46 +/- 1 mm Hg at 10 min after antigen administration, with Pcv decreasing by 2.5 cm H(2)O. Ppv increased by 3.5 cm H(2)O at 5 min after antigen injection. Pretreatment with either CV-6209 (PAF receptor antagonist, 1 mg/kg) or diphenhydramine (histamine H(1) receptor antagonist, 20 mg/kg) significantly attenuated an antigen-induced decrease in Psa. The inhibitory action of CV-6209 was greater than that of diphenhydramine, and the combination of these 2 antagonists almost completely inhibited the anaphylactic hypotension. In contrast, the antigen-induced increase in Ppv was attenuated by CV-6209 alone but augmented by diphenhydramine. It is concluded that anaphylactic hypotension is mainly mediated by PAF and, to a lesser extent, by histamine in anesthetized BALB/c mice.     

Effects of WEB 2086, a novel antagonist of platelet activating factor, in active and passive anaphylaxis

WEB 2086, a novel specific platelet activating factor (PAF) antagonist derived from triazolodiazepines, inhibited in a dose-related manner the PAF-dependent component of anaphylaxis as well as PAF-induced effects in mice and guinea pigs. In mice a lethal anaphylactic shock and a PAF-induced (100 micrograms/kg i.v.) death was inhibited by i.v. WEB 2086. The ED50 values were 13.6 and 0.37 mg/kg i.v., respectively. In actively sensitized guinea pigs, the anaphylactic lung reaction (bronchoconstriction), but not the corresponding hypotension, was prevented by oral (0.05-0.5 mg/kg) doses of WEB 2086. In contrast, in passively sensitized animals a dose-dependent inhibition of the pulmonary (bronchoconstriction) and blood pressure (hypotension) reaction due to anaphylaxis was achieved by i.v. WEB 2086. Similarly, oral (0.05-0.5 mg/kg) and i.v. (0.005-0.05 mg/kg) WEB 2086 inhibited PAF-induced reduction in respiratory flow (bronchoconstriction) and hypotension in guinea pigs. The ED50 values were 0.070 and 0.066 mg/kg p.o., and 0.017 and 0.015 mg/kg i.v., respectively. In conclusion, PAF seems to play a more major role in passive than in active anaphylaxis in guinea pigs. These results provide further evidence for an important role of PAF in anaphylaxis and support the hypothesis that PAF is involved in asthma and other allergic diseases.     

Protective effect of a specific platelet-activating factor antagonist, BN 52021, on bupivacaine-induced cardiovascular impairments in rats

Administration of the local anaesthetic bupivacaine (1.5 or 2 mg/kg, i.v.) to rats elicited a marked decrease of mean arterial blood pressure (MBP) and heart rate (HR) leading to death (in 67% or 90% of animals respectively). Intravenous injection of the specific platelet-activating factor (PAF) antagonist BN 52021 (10 mg/kg), 30 min before bupivacaine administration (2 mg/kg i.v.) suppressed both the decrease of MBP and HR. In contrast, doses of 1 mg/kg BN 52021 given 30 min before or 10 mg/kg administered 5 min before i.v. injection of bupivacaine were ineffective. When BN 52021 (20 mg/kg i.v.) was injected immediately after bupivacaine (2 mg/kg), a partial reversion of the decrease of MBP and HR was observed, whereas the dose of 10 mg/kg was ineffective. A partial recovery of bupivacaine-induced ECG alterations was observed after pretreatment of the rats with BN 52021. Since the administration of BN 52021, at all doses studied, did not alter MBP and HR at the doses used, the bulk of these results clearly demonstrate a protective action of BN 52021, a specific antagonist of PAF, against bupivacaine-induced cardiovascular toxicity. Thus, consistent with its direct effect on heart, PAF appears to be implicated in bupivacaine-induced cardiovascular alterations.     

Effect of glucagon on amitriptyline-induced cardiovascular toxicity in rats

The aim of this study was to investigate the effect of glucagon on cardiovascular parameters in anesthetized rat model of tricyclic antidepressant overdose. Toxicity was induced by infusion of amitriptyline 0.94 mg/kg/min until a 40-45% of reduction in mean arterial pressure was observed. Amitriptyline infusion rats were then randomized into three groups. Control group of rats (group 1) received a bolus of 5% dextrose followed by the continuous infusion of dextrose, whereas treatment groups received 1 mg/kg (group 2) or 2 mg/kg (group 3) bolus doses of glucagon followed by continuous infusion (0.1 mg/kg/min) of glucagons for 60 min. Mean arterial pressure, heart rate, and electrocardiogram were recorded. Amitriptyline caused a significant decrease in mean arterial pressure and a prolongation in QRS, yet it did not change the heart rate. High-bolus dose of glucagon (2 mg/kg) followed by glucagon infusion significantly increased mean arterial pressure at 40, 50, and 60 min (P < 0.05) and shortened the prolonged QRS at 50 and 60 min (P < 0.05) when compared with control group. There was also a significant increase in heart rate. In conclusion, bolus doses followed by a continuous infusion of glucagon were found to be effective in reversing the hypotension and QRS prolongation in the rat model of amitriptyline toxicity. Further studies are needed to reveal the exact mechanism of the proposed effect.     

RENAL HAEMODYNAMIC AND EXCRETORY RESPONSES TO BRADYKININ IN ANAESTHETIZED DOGS

1. Effects of bradykinin (BK) on renal haemodynamics and urine formation were examined in anaesthetized dogs. 2. Renal arterial infusion of BK at doses of 5 or 50 ng/kg per min produced dose-dependent increases in renal blood flow (RBF), without affecting systemic arterial pressure or glomerular filtration rate. There were also significant and dose-dependent increases in urine flow (UF), urinary excretion of sodium (UNaV) and fractional excretion of sodium (FENa) and decreases in urine osmolality during BK infusion. 3. Renal haemodynamic and excretory responses to the BK infusion were completely abolished by the simultaneous administration of Hoe 140 (icatibant, 100 ng/kg per min intrarenally), a selective BK B2-receptor antagonist. 4. In the presence of NG-nitro-L-arginine (NOARG; 40 micrograms/kg per min intrarenally), a nitric oxide (NO) synthase inhibitor, BK-induced renal vasodilative and natriuretic effects were markedly attenuated, although responses of UF and urine osmolality to BK remained unchanged. The water diuretic effect of BK was abolished in dogs given both NOARG and ibuprofen (12.5 mg/kg bolus injection plus 12.5 mg/kg per h of sustained infusion intravenously), a cyclooxygenase inhibitor. 5. These results clearly indicate that renal haemodynamic and excretory responses to BK were mediated exclusively by the B2-receptor. Renal vasodilative and natriuretic responses are mainly linked to NO generation, while both NO and prostaglandin biosynthesis are involved in the BK-induced water diuresis.     

Renal Effects of α-Adrenoceptor Blockade During Furosemide Diuresis in Conscious Rats

Abstract: Clearance experiments were performed in conscious rats in order to investigate whether intravenous infusion of the non-selective α-adrenoceptor antagonist phentolamine could block compensatory sodium reabsorption during furosemide-induced volume contraction. By measuring inulin clearance, urinary excretion rates of sodium and water, and lithium clearance, the effects on proximal and distal nephron segments were dissociated. The renal effect of intravenous infusion of 0.3 mg/kg/hr phentolamine (n=6) was compared with time control animals (n=9). Furosemide was administered as constant intravenous infusion (7.5 mg/kg/hr) with simultaneous phentolamine infusion at four dose levels: 0 (n=9), 0.3 (n=6), 1.0 (n=7) and 3.0 mg/kg/hr (n=6). Phentolamine infusion reduced noepinephrine-induced increase in blood pressure at all three dose levels (n=5). Phentolamine infusion induced transient antidiuresis and a prolonged antinatriuretic response. Compared with rats given furosemide only, phentolamine attenuated dose-dependently the diuretic and natriuretic peak response to furosemide. This effect was associated with dose-dependent reductions in mean arterial pressure. The reduced natriuretic response was due to a reduced fractional sodium excretion in the distal nephron segment (at all doses of phentolamine) and a reduction of the glomerular filtration rate (1.0 and 3.0 mg/kg/hr phentolamine). The fractional lithium excretion (FE_Li) increased to 65±3% at 0.3 mg/kg/hr phentolamine during the natriuretic peak response of furosemide, while it only increased to 52±3% during furosemide alone. At steady-state conditions (120–180 min. after start of furosemide infusion) after infusion with furosemide plus 0.3 mg/kg/hr phentolamine the animals were still volume-depleted, but the compensatory tubular Na reabsorption in the proximal tubules was inhibited (FE_Li=48±2% versus 39±1%> in rats given furosemide alone). During furosemide infusion plasma epinephrine increased 700% and plasma norepinephrine increased 50%. These results are compatible with increased systemic sympathetic nervous activity and a contributory role of proximal tubular α-adrenoceptors in mediating compensatory sodium reabsorption during acute furosemide-induced volume contraction.     

The role of nitric oxide and platelet-activating factor in the inhibition by endotoxin of pentagastrin-stimulated gastric acid secretion.

Administration of E. coli endotoxin (1 mg/kg i.v.) abolished the acid secretory response induced by a bolus injection of pentagastrin (100 micrograms/kg i.v.) in the continuously perfused stomach of the anaesthetized rat. Endotoxin administration did not modify mean systemic arterial blood pressure. Pretreatment with NG-nitro-L-arginine methyl ester (L-NAME; 5-20 mg/kg i.v.), but not dexamethasone (5 mg/kg s.c. twice) or indomethacin (5 mg/kg i.m.), substantially restored the secretory responses to pentagastrin. The actions of L-NAME were reversed by the prior administration of L-arginine (100 mg/kg i.v.), but not by its enantiomer D-arginine (100 mg/kg i.v.). L-NAME (10 mg/kg i.v.) increased blood pressure but this does not seem to be the mechanism by which endotoxin-induced acid inhibition was prevented, since similar systemic pressor responses induced by noradrenaline (15 micrograms/kg per min i.v.) had no such effect. The platelet-activating factor (PAF) receptor antagonist, WEB 2086 (2 mg/kg), induced a partial reversal of the inhibition by endotoxin of acid responses to pentagastrin. In endotoxin-treated rats, the combined administration of L-NAME (10 mg/kg) and WEB 2086 (2 mg/kg) completely restored the degree of H+ output induced by pentagastrin to levels similar to those of control, vehicle-treated animals. These findings suggest that endotoxin-induced acute inhibition of acid responses to pentagastrin involves NO synthesis and the release of PAF.     

The dopamine congener, ibopamine, in congestive heart failure

The hemodynamic effects of the dopamine congener, ibopamine, were investigated in nine patients with chronic congestive heart failure. A placebo-controlled design was utilized. Placebo and ibopamine in doses of 100, 200, and 300 mg were given orally as a single dose to each patient on 4 successive days. Dopamine at 1, 2, 4, and 6 micrograms/kg/min intravenously, was used as an internal standard. Ibopamine did not significantly change heart rate, systemic and pulmonary arterial pressures, pulmonary capillary wedge pressure, or mean right atrial pressure. Significant decreases of systemic arterial resistance (19%) and total pulmonary arterial resistance (21%), and significant increases of cardiac index (20%) and stroke volume index (16%) were elicited by ibopamine at doses of 200 and 300 mg. Peak effects occurred at 1 to 2 h with a duration of action of less than 4 h. The 2 changes were comparable with those obtained by dopamine 2-4 micrograms/kg/min. Except for mild changes at 30 min postdosing, the inotropic indices of the systolic time intervals were not altered significantly by ibopamine. Ibopamine elicits significant hemodynamic effects in patients with chronic congestive heart failure; in large part, these effects appear to be mediated through vasodilatory properties rather than direct positive inotropy.     

Continuous i.v. infusion versus multiple bolus doses of metoclopramide for prevention of cisplatin-induced emesis

Continuous infusion of metoclopramide was compared with bolus dosing in a randomized, double-blind study in 27 patients receiving cisplatin therapy. Hospitalized patients receiving their first course of cisplatin (120 mg/sq m administered i.v. over four hours) were randomized to receive either bolus doses or a continuous infusion of metoclopramide. In the infusion group (14 patients), a loading dose of metoclopramide 3 mg/kg (total body weight) as the hydrochloride salt was infused over one hour immediately before the administration of cisplatin, followed by a continuous infusion of metoclopramide 0.5 mg/kg/hr (as the hydrochloride salt) for 12 hours. Each patient received a total metoclopramide dose of 9 mg/kg over 13 hours. These patients also received five bolus doses of 5% dextrose injection (as placebo) over 15 minutes, with the first dose given one hour before the cisplatin and four more doses at two-hour intervals. In the bolus-dose group (13 patients), metoclopramide 2 mg/kg as the hydrochloride salt was added to each of the bolus doses, while the continuous infusion was a placebo of 5% dextrose injection. All patients also received dexamethasone 10 mg i.v. and diphenhydramine hydrochloride 50 mg i.v. Patients were monitored for 24 hours after initiation of metoclopramide administration for number of emesis episodes and for adverse effects. In the infusion group, 11 of 14 (79%) patients had two or fewer episodes of emesis. In the bolus group, 10 of 13 (77%) had two or fewer vomiting episodes. Mild sedation occurred in both the infusion (79%) and bolus-dose (77%) groups. Despite the use of diphenhydramine, extrapyramidal reactions were seen in one bolus-dose patient and two infusion patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Patent Evaluation: Tricyclic Antihistamines as Anti-asthmatic Agents

Summary

Novelty: A very large series of bis-benzo or benzopyrido piperidines, piperidylidenes and piperazines are claimed. These compounds are said to possess PAF and histamine antagonist activity and therefore may be useful in treating asthma, allergic rhinitis, rheumatoid arthritis and osteo-arthritis.

Biology: Data are given showing in vitro PAF antagonist activity, with IC₅₀s in the range of 0.61–175 μM. In vivo data on spasmogen induced bronchospasm in guinea pigs shows activity on both PAF and histamine at doses of 3 mg/kg.

Chemistry: A large number of examples are given showing a number of structural variants. The most active in vitro is (±)-8-chloro-6,11-dihydro-11-[4-(4-pyridinylmethyl)-1-pipera zinyl]-5-H-benzo[5,6]cyclohepta[1,2-b]pyridine-N-oxide.     

Characterization of cardiovascular events mediated by platelet activating factor during systemic anaphylaxis.

Previous studies have shown that an anaphylactic reaction in the isolated perfused heart is characterized by drastic coronary constriction, arrhythmias, and severe impairment of contractility. In vivo anaphylaxis is associated with myocardial ischemia and rapid cardiovascular failure. Recently, not only histamine but also platelet activating factor (PAF) has been implicated in cardiac manifestation of anaphylaxis. The present study was designed to separate the effects of PAF from those of histamine on cardiovascular function during systemic anaphylaxis. In guinea pigs, sensitization was produced by subcutaneous (s.c.) application of ovalbumin. Fourteen days after sensitization, the effects of an intravenous (i.v.) infusion of ovalbumin were tested in anesthetized artificially ventilated guinea pigs. The renewed application of the antigen induced severe cardiac dysfunction. Within 3 min, cardiac output (CO) had already decreased by 90% and left ventricular end-diastolic pressure (LVEDP) increased significantly, indicating left ventricular pump failure. Concurrently, ECG recordings uniformly showed signs of acute myocardial ischemia. In addition, arrhythmias occurred in terms of atrioventricular block. After 4 min, blood pressure (BP) rapidly decreased. All animals died within 10 min. Pretreatment with the H1-receptor antagonist mepyramine (1 mg/kg i.v.) in combination with the H2-receptor antagonist cimetidine (10 mg/kg i.v.) delayed onset of myocardial ischemia, arrhythmias and cardiac pump failure. After 10 min, however, LV contractility and BP steadily decreased, leading to severe hypotension within 30 min. If the selective PAF antagonist WEB 2086 (1 mg/kg i.v.) was administered in addition to cimetidine and mepyramine, myocardial ischemia and LV contractile failure were markedly inhibited further. In contrast, pretreatment with WEB 2086 alone had no beneficial effects on the anaphylactic cardiovascular changes. Therefore, we conclude that histamine is the predominant mediator during the early phase of systemic anaphylaxis whereas PAF-mediated effects are involved in cardiac dysfunction during the protracted late phase of anaphylaxis.     

The effect of eltanolone on pulmonary vascular resistance in landrace swine.

This paper reports on the haemodynamic effects of eltanolone observed in Landrace swine during the investigation of the drug with respect to safety in malignant hyperthermia-susceptible individuals. Pigs were sedated with intramuscular ketamine, followed by induction of anaesthesia employing thiopentone administered via an ear-vein. After intubation, anaesthesia was maintained using nitrous oxide in oxygen. A total of eight pigs were then further anaesthetised on two separate occasions using one of two dose schedules. A bolus of 1.5 mg kg(-1) of eltanolone was administered, followed by a continuous infusion at either 2 or 10 mg kg(-1) h(-1). There were no significant changes in heart rate, mean arterial pressure, cardiac output or systemic vascular resistance following eltanolone. In all cases eltanolone induced marked rises in pulmonary artery pressure and pulmonary vascular resistance (P<0.01) at all measuring points and in right ventricular stroke work at 6-10 min after drug exposure. We conclude that the selective influence of eltanolone on the pulmonary vasculature is probably species-specific, but may have clinical significance in patients with pulmonary hypertension.     

Role of endothelin-1 and thromboxane A2 in the pulmonary hypertension induced by heparin-protamine interaction in anesthetized dogs

This study aimed to study the role of thromboxane A2 (TXA2) and endothelin-1 (ET-1) in the pulmonary hypertension induced by interaction of heparin-protamine in anesthetized dogs. The effect of inhaled nitric oxide (NO) was also investigated in this model. Dogs were anesthetized and instrumented for acquisition of mean arterial blood pressure, mean arterial pulmonary pressure (MPAP), and pulmonary pressure gradient (PPG). Cardiac index (CI), heart rate, and index of systemic vascular resistance were also obtained. Intravenous administration of heparin (500 IU/kg) 3 minutes before protamine (10 mg/kg) caused marked pulmonary hypertension, as evaluated by the increase in MPAP and PPG. This was accompanied by systemic hypotension, CI decrease, and tachycardia. Indomethacin (10 mg/kg), dazoxiben (10 mg/kg), or tezosentan (10-mg/kg bolus plus 10-mg/kg/h infusion) significantly reduced the increase in MPAP and PPG, but had no effect on the systemic hypotension. Similar results were obtained with inhaled NO (3 ppm). Plasma TXB2 levels were markedly elevated during the pulmonary hypertension, and this was abolished in indomethacin-treated dogs. Our study shows that interaction of heparin-protamine in anesthetized dogs lead to TXA2- and ET-1-mediated pulmonary hypertension. Drugs that interfere with the synthesis of these mediators as well as inhaled NO may be of beneficial value to control this disorder.     

血小板激活因子拮抗剂SRI 63-441对内毒素所致大鼠肠系膜微循环变化的影响(英文)

大鼠静脉注射大肠杆菌内毒紊30mg/kg引起体循环平均动脉压和肠系膜微动脉血流速度(MABFV)的迅速下降,微动脉先收缩而后扩张。预先给予血小板激活因子受体拮抗剂SR163-441可缓解内毒素引起的低血压和MABFV的降低,阻断肠系膜微动脉的扩张。提示血小板激活因子是引起内毒素休克微循环障碍的重要介质。     

Effect of the PAF antagonists, CV-3988 and L-652,731 on the pulmonary and hematological responses to guinea pig anaphylaxis

To define the role of PAF in the acute phase of guinea pig anaphylaxis, we have measured the pulmonary (bronchoconstrictor) and hematological (thrombocytopenia, leukopenia, hemoconcentration, plasma TxB2 increase) responses to PAF infusion and compared these responses to the effect of antigen exposure in actively and passively sensitized guinea pigs. We have also determined the effect of the structurally unrelated PAF antagonists, CV-3988 and L-652,731 on these responses. Intravenous administration of PAF (50-400 ng/kg) caused a dose-related bronchoconstriction, thrombocytopenia, leukopenia, hemoconcentration and increase in plasma TxB2. These PAF-induced responses were inhibited, to a variable degree, by pretreatment with CV-3988 (3 and 10 mg/kg, i.v.) and L-652,731 (3 mg/kg, i.v.). Intravenous administration of ovalbumin to actively or passively sensitized guinea pigs caused bronchoconstriction, thrombocytopenia, leukopenia and hemoconcentration, but there was no increase in TxB2. Moreover, the anaphylactic bronchoconstriction, thrombocytopenia, leukopenia (actively sensitized) and hemoconcentration were not inhibited by CV-3988 (10 mg/kg, i.v.) and L-652,731 (3 mg/kg, i.v.). The different profile of changes produced by PAF and allergic anaphylaxis and the failure to alter the responses to allergic anaphylaxis with PAF antagonists suggest that PAF is not an important mediator of the acute phase of guinea pig anaphylaxis.     

The effect of epinephrine following practolol on the pulmonary circulation of dogs

Epinephrine (1 and 2 μg/kg/min) was infused in 10 urethane-anesthetized dogs following administration of practolol. Practolo. was administered to block the cardiac β-adrenoceptors and thereby permit a better assessment of the direct action of epinephrine on the pulmonary circulation.Following practolol, both infusion rates of epinephrine were associated with an increase in cardiac output, stroke volume, mean pulmonary arterial and venous pressures and no change in heart rate and pulmonary blood volume. It is concluded that epinephrine, in the doses used, produces a mild increase in ‘tone’ of the pulmonary arterial and venouse system.     

Effects of Endotoxin on Neurally-mediated Gastric Acid Secretion in the Rat

The effects of a peripheral administration of E. coli endotoxin on neurally-mediated gastric acid secretion and the role of endogenous opioids or PAF receptors in endotoxin effects have been evaluated in the continuously perfused stomach of the anaesthetized rat. Gastric acid secretion stimulated by distension (20 cm H₂O) was reduced dose-dependently by single intravenous bolus injection of endotoxin (0.1–10 μg kg^?1). Doses of 5 μg kg^?1 induced a peak reduction of distension-stimulated acid output and significantly reduced the secretory response induced by an intravenous bolus of 2-deoxy-d -glucose (150 mg kg^?1). This dose of endotoxin did not significantly modify mean systemic arterial blood pressure throughout the experimental period. Pretreatment with the opioid receptor antagonist naloxone (1 mg kg^?1, i.v.) or the platelet-activating factor (PAF) receptor antagonist WEB 2086 (2 mg kg^?1, i.v.) did not reverse the inhibitory effects of endotoxin (5 μg kg^?1, i.v.) on acid secretion stimulated by both distension and 2-deoxy-d -glucose. These findings suggest that endotoxin-induced acute inhibition of neurally-mediated acid responses, stimulated by gastric distension or administration of 2-deoxy-d -glucose, do not involve the activation of endogenous opioids or PAF receptors.