Influence of adenosine triphosphate on the isolated perfused mesenteric artery of the rabbit

The vascular effects of adenosine triphosphate (ATP) were examined in the isolated perfused mesenteric arteries of the rabbit. Bolus injections of ATP (1 X 10(-8) to 10(-6) mol) induced a dose-dependent vasoconstrictor response at resting perfusion pressure, while continuous perfusion with ATP briefly elicited a vasoconstrictor response which was not maintained. Perfusion with phentolamine (2.65 X 10(-6) M, an alpha-adrenergic receptor blocker), indomethacin (8.37 X 10(-6) M, an inhibitor of cyclooxygenase), atropine (1 X 10(-7) M, a muscarinic receptor blocker), and hydralazine (2 X 10(-4) M, a vascular smooth muscle inhibitor) for a period of 1 h had no effect on vasoconstrictor responses to ATP. However, pretreatment with reserpine (2 mg X kg-1 X day-1 for 2 days), an agent which depletes catecholamines, potentiated responses to ATP. On the other hand, when vascular tone was increased with an isoosmotic 60 mM K+ depolarizing Krebs bicarbonate solution, bolus injections of ATP elicited a prominent dose-dependent vasoconstriction followed by a prominent vasodilation. The degree of vasodilation but not of vasoconstriction elicited by ATP was greater in small terminal arteries with branches (less than 0.5 mm outside diameter (o.d.) ) than in the medium size arteries (less than or equal to 1 mm o.d.) without terminal branches. Both the vasoconstrictor and vasodilator responses were unaffected by a perfusion with atropine, indomethacin, or eicosatetraynoic acid (ETYA, 1 X 10(-4) M) for 1-2 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of cyclooxygenase and thromboxane synthetase inhibition on furosemide-stimulated plasma renin activity

We studied the effects of a specific thromboxane (TX) synthetase inhibitor (U-63,557A) and a cyclooxygenase inhibitor on furosemide-induced renin release. Furosemide (2.0 mg X kg-1) was injected into Sprague-Dawley rats pretreated with indomethacin (10 mg X kg-1, i.v.), U-63,557A (1.0-32.0 mg X kg-1, i.v.), or vehicle (Na2CO3 0.03 M). Plasma renin activity was measured in blood samples collected 0, 10, 20, and 40 min after the injection of furosemide. Blood was also collected after the administration of vehicle, indomethacin, or U-63,557A for serum TXB2, a measure of platelet TXA2 synthesis. The results demonstrated that plasma renin activity rose with time following furosemide in the various groups of rats; indomethacin suppressed the furosemide-induced increments in plasma renin activity, while U-63,557A at doses of 4-8 mg X kg-1 augmented it. At doses below 4 mg X kg-1 or above 8 mg X kg-1, U-63,557A did not augment renin secretion. Indomethacin and U-63,557A reduced serum thromboxane by 81 and 90%, respectively. Thus, these experiments suggest that thromboxane synthetase inhibition, within a narrow dosage range, potentiates furosemide-induced renin release while cyclooxygenase inhibition suppresses it.     

Prostaglandin I2 as a potentiator of acute inflammation in rats.

Prostaglandin I2 potentiated the paw swelling induced by carrageenin in rats. Prostaglandin I2 (0.1 microgram) showed similar activity to PGE1 (0.01 microgram). This potentiating property disappeared in 60 minutes and was completely abolished by diphenhydramine (25 mg kg-1, i.p.). In vascular permeability tests, PGI2 itself (2.5 X 10(-10) mol, 88 ng) caused no dye leakage reaction, but PGE1 (2.5 X 10(-10) mol, 88.5 ng) caused a significant dye leakage. This effect of PGE1 was statistically significant compared with vehicle- or PGI2-treated groups (p less than 0.05). Prostaglandin I2 potentiated the increased vascular permeability induced by 5-hydroxytriptamine (2.5 X 10(-10) mol), bradykinin (5 X 10(-10) mol) and histamine (2 X 10(-10) to 2 X 10(-8) mol). The potentiation was the most evident in the case of histamine.     

Effects of dipyridamole and furosemide on renal function during adenine dinucleotide infusion in rats

In anaesthetized rats kept on normal diet an i.v. infusion of NAD (200 nmole X kg-1 X X min-1) induced a decrease in renal plasma flow (CPAH), glomerular filtration rate (GFR) and electrolyte excretion accompanied by an increase in plasma adenosine concentration. Separate infusions of a small dose of NAD (50 nmole X kg-1 X min-1) or dipyridamole (25 micrograms X kg-1 X min-1) did not affect renal function or plasma adenosine concentration. However, when the above small doses of both agents were given simultaneously, GFR, CPAH and electrolyte excretion fell significantly, indicating potentiation of NAD action by dipyridamole, associated with increased plasma adenosine level. An i.v. infusion of furosemide failed to abolish the depression of renal function in response to NAD. The data suggest that the causal factor of this depression was adenosine and not NAD itself.     

Antiarrhythmic effect of magnesium sulfate against occlusion-induced arrhythmias

The antiarrhythmic effect of magnesium sulfate (Mg) as well as the hemodynamics were studied using the coronary ligation and reperfusion models in rats.In the study on coronary ligation arrhythmia, i.v. administration of Mg (0.6, 2, 6, 20 and 60 \sgmaelig;mol) was conducted at 5 min after coronary ligation. Mg had an action to decrease the total number of premature ventricular contraction (PVC), the duration of ventricular tachycardia (VT), the frequency of VT and ventricular fibrillation (Vf) and the mortality ratio for 30 min after coronary ligation. In the 6-60 \sgmaelig;mol groups, significant antiarrhythmic action (p < 0.01 vs. control) was attained.In the study on reperfusion arrhythmia, i.v. administration of Mg (20, 60 and 200 \sgmaelig;mol) was conducted at 4 min after coronary ligation, and at 1 min after ligation, the coronary artery was reperfused. Mg had an action to decrease the frequency of Vf, the mortality ratio and the duration of VT and Vf and to extend the interval between the initiation of reperfusion and the occurrence of VT and Vf for 10 min after reperfusion. In the 200 \sgmaelig;mol group, significant antiarrhythmic action (p < 0.05 vs. control) was attained. Administration of Mg decreased the heart rate and blood pressure.We concluded that Mg can control myocardial ischemia-induced and reperfusion-induced arrhythmia and that sudden cardiac death which occurs as a result of arrhythmia can be prevented.     

Effect of 5-azacytidine on the differentiation of human leukemia K-562 cells

The treatment of K-562 cells with 10(-5) M to 10(-7) M 5-azacytidine induced a marked increase in benzidine-positive cells. Similarly, the exposure of K-562 cells to 2 X 10(-3) M butyric acid or 5 X 10(-7) M 1-beta-arabinofuranosylcytosine or 1 X 10(-3) M hydroxyurea induced an erythroid differentiation of K-562 cells. The activity of DNA-methyltransferase and the level of methylcytosine in newly synthesized DNA were significantly decreased when the cells were treated with 5-azacytidine or butyric acid, while 1-beta-arabinofuranosylcytosine or hydroxyurea had no inhibitory effect on DNA-methylation of K-562 cells. These results suggest that the inhibition of DNA-methylation is not necessarily a specific phenomenon for erythroid differentiation of K-562 cells.     

The role of coronary alpha 1-adrenoceptors of the dog heart in dopamine-induced cardiostimulation evidenced by treatment with prazosin

To assess the participation of postjunctional coronary alpha 1-adrenoceptors in the dopamine-induced general circulatory stimulation, pentobarbital-anesthetized open chest dogs were infused with the agent (1-16 micrograms.kg-1.min-1 i.v.) before and after the administration of the alpha 1-selective adrenergic antagonist prazosin (0.15 mg.kg-1). Coronary responses were characterized by the changes of blood flow (electromagnetic flowmeter) and those of calculated vascular conductance. Left ventricular contractile force was measured with a strain gauge arch. In the control state, whereas coronary blood flow increased simultaneously with the dose-dependent hypertensive effect of dopamine, the calculated augmentation of coronary vascular conductance was relatively slight (maximum: greater than or equal to 50%) compared to the very great increase of cardiac inotropism (up to greater than or equal to 250%) and myocardial O2 consumption (up to greater than or equal to 250%). After blocking the alpha 1-adrenoceptors, in spite of the elimination of the hypertensive effect, the inotropic and blood flow actions of dopamine remained unaltered and the calculated value of vascular conductance indicated an enhanced vasodilation (up to 200%). The alpha 2-blocker yohimbine (0.5 mg.kg-1) failed to elicit actions of similar magnitude. It was concluded that postjunctional alpha-adrenoceptor-dependent coronary vasoconstrictor influences compete with metabolically coupled vasodilation during the cardiostimulatory action of dopamine.     

Thermodynamics of the conversion of penicillin G to phenylacetic acid and 6-aminopenicillanic acid

The thermodynamics of the enzymatic conversion (penicillin acylase) of aqueous penicillin G to phenylacetic acid and 6-aminopenicillanic acid have been studied using both high-pressure liquid-chromatography and microcalorimetry. The reaction was carried out in aqueous phosphate buffer over the pH range 6.0-7.6, at ionic strengths from 0.10 to 0.40 mol kg-1, and at temperatures from 292 to 322 K. The data have been analyzed using a chemical equilibrium model with an extended Debye-Hückel expression for the activity coefficients. For the reference reaction, penicillin G- (aq) + H2O(l) = phenylacetic acid-(aq) + 6-aminopenicillanic acid-(aq) + H+ (aq), the following parameters have been obtained: K = (7.35 +/- 1.5) X 10(-8) mol kg-1, delta G0 = 40.7 +/- 0.5 kJ mol-1, delta H0 = 29.7 +/- 0.6 kJ mol-1, and delta C0p = -240 +/- 50 J mol-1 K-1 at 298.15 K and at the thermochemical standard state. The extent of reaction for the overall conversion is highly dependent upon the pH.     

Effects and interactions of natural cannabinoids on the isolated heart

A Langendorff perfused rat heart preparation was designed to process dose-response effects of cardioactive drugs on rate, coronary flow, and supraaortic differential pressure (delta P; an index of cardiac performance). In this preparation, delta 9- -tetrahydrocannabinol (THC) 2 X 10(-6) M to 10(-5) M induces in the isolated perfused rat heart a biphasic increase in rate (maximal at 8 X 10(-6) M). Tachycardia is associated with decreases in (delta P) and no change or decreased coronary flow. Cardiac toxicity is observed with 3 X 10(-5) M. Cannabidiol (CBD) at concentrations of 9 X 10(-6) M to 10(-4) M has limited effect on rate while increasing delta P and coronary flow. Cannabinol (CBN) 8 X 10(-6) M to 3 X 10(-4) M depresses rate and delta P while coronary flow remains constant. Simultaneous equimolar administration of THC with CBD antagonizes or mitigates the cardiac effects of THC on rate, delta P, and coronary flow.     

Maximum coronary blood flow and minimum coronary resistance in exercise-trained dogs

Exercise training has been found to increase coronary vascularity of the heart in experimental animals. Maximum coronary flow and minimum coronary resistance were determined in 16 dogs with the injection of microspheres (15 micron) into the left atrium at rest and during the intravenous infusion of adenosine (0.7 mg X min-1 X kg-1). Heart rate was paced at 150 beats/min. Dogs were divided into three groups with microsphere injections made before and after 4-5 wk of daily exercise (group 1); before and after 8-10 wk of daily exercise (group II); and before and after 8-10 wk of cage rest (group III). Results of average left ventricular maximum myocardial flow before and after daily exercise were 4.08 +/- 0.34 and 4.89 +/- 0.33 ml X min-1 X g-1 for group I, 5.13 +/- 0.32 and 5.55 +/- 0.56 ml X min-1 X g-1 for group II, and 5.24 +/- 0.43 and 4.34 +/- 0.55 ml X min-1 X g-1 for group III. Arterial pressure, maximum coronary flow, and minimum coronary resistance were not significantly different before and after any condition in all three groups of dogs. Peak reactive hyperemia coronary flow was not altered by daily exercise. These results indicate that maximum coronary flow and minimum coronary resistance were not altered by either 4-5 or 8-10 wk of exercise training.     

Effect of theophylline treatment on the functional hyperaemic and hypoxic responses of cerebrocortical microcirculation

The purpose of the present study was to elucidate the importance of extracellular adenosine (ADO) in the regulation of cerebrocortical microcirculation during rest, hypoxia, and brain activation. Cerebrocortical microcirculation and fluorescence of reduced nicotinamide adenine dinucleotide (NADH) were measured by surface fluororeflectometry through a cranial window. Arterial hypoxia and brain activation were produced by respirating the animals with a gas mixture containing 6-7% O2 and by injecting 4-6 mg/kg metrazol into the lingual artery, respectively. These reactions were used as test before and after theophylline (THEO) treatment. In some of the experiments only the cortical area beneath the cranial window was treated with THEO (10(-4) M), in others 2 X 10(-4) mol/kg THEO was injected intraperitoneally. Potency of THEO in antagonizing the cerebral blood flow (CBF) increasing effect of topically applied ADO was also tested. It was found that superfusion of the brain cortex with artificial cerebrospinal fluid (mock CSF) containing 10(-4) M THEO does not alter resting CBF, but inhibits the CBF increasing effect of 10(-6) M and 10(-5) M ADO by approximately 70% and 40%, respectively. Intraperitoneally injected THEO increased CBF by approximately 60%, which has been attributed mostly to its action on the systemic circulation. Under control conditions, arterial hypoxia and epileptic seizures increased CBF by approximately 150% and 300%, respectively. Since neither topical nor systemic THEO treatment altered the vasodilatory and CBF increasing potency of arterial hypoxia and attenuated these effects of epilepsy slightly, it was concluded that extracellular ADO is not a critical factor in the regulation of cerebrocortical microcirculation.     

血管钠肽抑制异丙肾上腺素增强的大鼠心肌细胞钙瞬变

采用光谱荧光法研究血管钠肽(vasonatrin peptide,VNP)对心肌细胞内钙瞬变的作用及其机制,观察钠尿肽鸟苷酸环化酶(guanylate cyclase,GC)受体的特异性阻断剂(HS-142-1)、8-溴-环磷酸鸟苷(8-Br-cGMP)和镁蓝(methylene blue,MB)对心肌细胞内钙瞬变的影响。结果显示,异丙肾上腺素(isoproterenol,Iso)(10~(-10)～10~(-6)mol/L)可剂量依赖性地引起心肌细胞内钙瞬变增强,相对于对照组分别增强(13±8)%(P>0.05)、(26±13)%(P<0.05)、(66±10)%(P<0.01)、(150±10)%(P<0.01)和(300±25)%(P<0.01)。此效应可被β肾上腺素受体阻断剂普萘洛尔(10~(-6)mol/L)所阻断。VNP(10~(-10)～10~(-6)mol/L)可剂量依赖性地抑制Iso(10~(-8)mol/L)引起的心肌细胞内钙瞬变幅值的升高,相对于Iso(10~(-8)mol/L)分别减弱(99±3)%(P>0.05)、(96±2)%(P<0.05)、(84±6)%(P<0.01)、(66±3)%(P<0.01)和(62±3)%(P<0.01)。8-Br-cGMP(10~(-7)～10~(-3)mol/L)也可剂量依赖性地抑制Iso(10~(-8)mol/L)引起心肌细胞内钙瞬变的增强。HS-142-1(2×10~(-5)mol/L)使VNP的作用几乎完全消失。MB是GC的抑制剂,10~(-5)mol/L MB不但使VNP的作用完全消失,而且增强Iso对心肌细胞内钙瞬变的效应。VNP和HS-142-1本身对心肌细胞内钙瞬变无显著影响。而MB使心     

Iridoid and aromatic glycosides from Scrophularia ningpoensis Hemsl. and their inhibition of [Ca2+](i) increase induced by KCl

Bioassay-guided fractionation of EtOH extract of the roots of Scrophularia ningpoensis Hemsl. resulted in the isolation of three new iridoid glycosides, i.e., 6'-O-caffeoylharpagide (1), 6'-O-feruloylharpagide (2), and 6'-O-beta-glucopyranosylharpagoside (3), and five new aromatic glycosides, i.e., 2-(3-hydroxy-4-methoxyphenyl)ethyl O-alpha-arabinopyranosyl-(1-->6)-O-alpha-rhamnopyranosyl-(1-->3)-O-beta-glucopyranoside (4), phenyl O-beta-xylopyranosyl-(1-->6)-O-beta-glucopyranoside (5), 3-methylphenyl O-beta-xylopyranosyl-(1-->6)-O-beta-glucopyranoside (6), 6-O-cinnamoyl beta-fructofuranosyl-(2-->1)-O-alpha-glucopyranosyl-(6-->1)-O-alpha-glucopyranoside (7), and 6-O-feruloyl beta-fructofuranosyl-(2-->1)-O-alpha-glucopyranosyl-(6-->1)-O-alpha-glucopyranoside (8), together with four known compounds, i.e., 6'-O-alpha-D-galactopyranosyl harpagoside (9), 6'-O-(p-coumaroyl) harpagide (10), harpagoside (11), and angoroside C (12). Activity of the isolated compounds on [Ca2+](i) increase induced by KCl was evaluated on rat cardiac myocytes using confocal laser scanning microscopy. Iridoid glycosides 1, 10, and 11, and aromatic glycosides 5 and 6 significantly inhibited the increase of [Ca2+](i) induced by KCl at 100 microM.     

Pharmacological evidence for the involvement of multiple calcitonin gene-related peptide (CGRP) receptors in the antisecretory and antiulcer effect of CGRP in rat stomach.

We have investigated the effect of the C-terminal fragment of human calcitonin gene-related peptide (human-CGRP8-37), a CGRP antagonist, on alpha-CGRP and salmon Calcitonin (sCT)-induced inhibition of gastric acid secretion stimulated by pentagastrin (24 nmol kg-1 h-1 i.v.) and gastric lesions induced by acetylsalycilic acid (ASA; 25 mM) in rats anaesthetized with urethane. Close intra arterial infusion of alpha-CGRP (2-5 nmol kg-1) and sCT (5 nmol kg-1) produced a reduction in gastric acid hypersecretion induced by pentagastrin. The concomitant infusion with human-CGRP8-37 (10 nmol kg-1) reversed the effect of both agonists. ASA-ulcers were reduced in a dose-dependent manner by infusion of alpha-CGRP (1-2 nmol kg-1 i.a.), but not by sCT (10 nmol kg-1 i.a.). Human-CGRP8-37 at a dose of 10 nmol kg-1 i.a. was unable to reverse the alpha-CGRP antiulcer effect. An higher dose of human-CGRP8-37 (50 nmol kg-1 i.a.) showed agonistic properties reducing ASA ulcers. These results suggest that the inhibitory effects of alpha-CGRP on stimulated acid secretion and aspirin ulcers are mediated by different mechanisms and/or different receptors.     

Cardiac adaptations to endurance training in rats with a chronic myocardial infarction

The hemodynamic response to maximal exercise was determined in sedentary and trained rats with a chronic myocardial infarction (MI) produced by coronary artery ligation and in rats that underwent sham operations (SHAM). Infarct size in the MI groups of rats comprised 28-29% of the total left ventricle and resulted in both metabolic and hemodynamic changes that suggested that these animals had moderate compensated heart failure. The training regimen used in the present study produced significant increases in maximal O2 uptake (VO2max) when expressed in absolute terms (ml/min) or when normalized for body weight (ml.min-1.kg-1) and consisted of treadmill running at work loads that were equivalent to 70-80% of the animal's VO2max for a period of 60 min/day, 5 days/wk over an 8- to 10-wk interval. This training paradigm produced two major cardiocirculatory adaptations in the MI rat that had not been elicited previously when using a training paradigm of a lower intensity. First, the decrement in the maximal heart rate response to exercise (known as "chronotropic incompetence") found in the sedentary MI rat was completely reversed by endurance training. Second, the downregulation of cardiac myosin isozyme composition from the fast ATPase V1 isoform toward the slower ATPase (V2 and V3) isoforms in the MI rat was partially reversed by endurance training. These cardiac adaptations occurred without a significant increase in left ventricular pump function as an increase in maximal cardiac output (Qmax) and maximal stroke volume (SVmax) did not occur in the trained MI rat.(ABSTRACT TRUNCATED AT 250 WORDS)     

Repeated antigen challenge induced airway hyperresponsiveness to neurokinin A and vagal non-adrenergic, non-cholinergic (NANC) stimulation in guinea pigs.

The effect of repeated weekly antigen challenges by aerosol on bronchopulmonary responses to ACh, histamine, neurokinin A or atropine-resistant (NANC) component of vagal stimulation, has been studied in guinea pigs. Bronchospastic responses were measured in anaesthetized animals, 7 days after the last challenge with antigen (or vehicle). No difference was observed between control and antigen challenged guinea pigs in their responsiveness to acetylcholine (1-300 mumol kg-1 i.v.) or histamine (1-300 mumol kg-1 i.v.). On the other hand, amplitude of bronchospasm induced by neurokinin A (1-3 mumol kg-1 i.v.) or NANC vagal stimulation (20 Hz, 1 msec, 10 V, trains of 5-20 sec) was significantly increased in guinea pigs previously challenged with antigen, as compared to controls. These results suggest that repetitive antigen exposure in sensitized guinea pigs generates an increase in the responsiveness to exogenously administered or endogenously released tachykinins, at a time when no generalized hyperresponsiveness to other spasmogens could be observed.     

Influence of insulin on plasma concentration and renal excretion of sodium and potassium in normal, electrolytes depleted and aldosterone treated dogs

Effects of insulin on plasma concentration and renal excretion of sodium and potassium were compared in conscious dogs 1) maintained in water and electrolytes balance (Series 1, 10 dogs), 2) depleted of electrolytes by repeated i.v. loading with 20% mannitol (Series 2, 10 dogs), and 3) aldosterone treated (0.8 micrograms.kg-1.h-1 i.v., Series 3, 10 dogs). In each Series intravenous infusion of insulin at a rate of 0.05 U.kg-1.h-1 elicited transient increase in plasma sodium concentration and prolonged hypokalemia. Repeated loading with mannitol in Series 2 elicited significant elevation of plasma sodium, ADH and aldosterone concentrations, as well as decrease in extracellular fluid volume. Infusion of insulin in this Series elicited smaller decrease in plasma potassium concentration and longer lasting hypernatremia than in dogs in water-electrolytes balance. Aldosterone infusion in Series 3 did not change hypokalemic effect of insulin but attenuated hypernatremia. Infusion of insulin in Series 1 elicited increase of sodium excretion and decrease in potassium excretion. These effects were absent in Series 2 and 3. The results indicate that depletion of electrolytes and blood aldosterone elevation modify the effects of insulin on plasma concentration and renal excretion of sodium and potassium.     

Tissue-specific clastogenic effects of chromium and selenium salts in vivo

The clastogenic effects of inorganic compounds of chromium (K2Cr2O7) and selenium (Na2SeO3) on the chromosomes of rat lymphocytes and bone marrow have been investigated. In vitro exposure of rat lymphocytes to K2Cr2O7 gave highly significant and dose-related increases in abnormal metaphases at 6 concentrations from 7 X 10(-6) M to 3.2 X 10(-5) M. Similar in vitro exposure of lymphocytes to Na2SeO3 showed that it was clastogenic at concentrations of 7.5 X 10(-6) M, 1 X 10(-5) M and 2.5 X 10(-5) M. However, with in vivo exposures of K2Cr2O7 (i.p. and i.v.) it was only possible to demonstrate clastogenicity in lymphocytes at sublethal concentrations (36 mg/kg X 2 i.v.) and then only if the results were tested against all controls combined (1900 metaphases, 19 animals). On the other hand, very highly significant clastogenic effects were obtained in bone marrow cells exposed in vivo to K2Cr2O7 at 21 mg/kg i.p. and 12, 18, 24 and 36 mg/kg i.v. In vivo exposure to Na2SeO3, with concentrations up to 6 mg/kg X 2 i.v., caused no significant increase in abnormal metaphases in lymphocytes but 5 and 6 mg/kg X 2 i.v. caused a significant increase in abnormal metaphases in bone marrow. These results suggest that K2Cr2O7 and Na2SeO3 are acting as 'S' dependent chemicals. Although not directly comparable, they are compatible with the warnings given by other authors both on the detection of aberrations in lymphocytes after chronic exposure in man and on short-term testing of lymphocytes at low doses related to human exposure.     

Parasympathetic involvement in PAF-induced contraction in canine trachealis in vivo

We studied the contractile response elicited by platelet-activating factor (PAF) administered intra-arterially into the tracheal circulation of 34 dogs in vivo. A method that avoided tachyphylaxis encountered in prior investigations was developed for isometric measurement of multiple dose-response effects. PAF was a very potent contractile agent; active tension was elicited with 10(-11) mol ia PAF. To determine the mechanism by which contraction was induced, dose-response curves were generated in groups of five animals each treated with either 0.5 mg/kg (approximately 1.5 X 10(-5) mol) iv + 10(-3) mg/kg (3 X 10(-8) mol) ia atropine, 5 mg/kg iv indomethacin (INDO), or 7.5 mg/kg iv hexamethonium (HEX). After pretreatment with atropine, contraction still was elicited with 10(-11) mol ia PAF. However, maximal contraction was only 16.2 +/- 2.74 g/cm (vs. 35.7 +/- 5.74 g/cm for untreated controls; P less than 0.02). The dose at which maximal contraction was elicited after atropine was 10(-7) mol ia (vs. 1.9 X 10(-9) mol for controls; P less than 0.001). Pretreatment with INDO caused minimal attenuation, and HEX had no effect on the response elicited by ia PAF. We demonstrate a method for assessing the effects of PAF in central airways that avoids tachyphylaxis and permits dose-response studies in the same animal. We also demonstrate that PAF is an extremely potent mediator that elicits tracheal smooth muscle contraction at least in part by postganglionic activation of parasympathetic nerves. A direct contractile effect of PAF which is not related to secretion of products of the cyclooxygenase pathway is also suggested.     

Cardiac and coronary consequences of intracoronary platelet activating factor infusion in the domestic pig

In previous studies we have shown that platelet-activating factor (PAF) is a potent vasoactive substance with deleterious effects on coronary blood flow (CBF) and myocardial performance. The present study further investigates the effects of PAF during its sustained intracoronary infusion in the blood-perfused domestic pig (n = 16). PAF infusion (1-9 nmol/min) produced triphasic changes in CBF (n = 7): an initial brief phase of coronary dilation (14 +/- 2% above baseline), followed by severe reduction in CBF due to increase in coronary vascular resistance and a third phase of escape that was characterized by return of CBF towards baseline in spite of continuing PAF infusion. In 9 remaining pigs PAF infusion had a biphasic response: the first phase of coronary dilation rapidly turned into severe coronary constriction accompanied by severe systemic hypotension and death within a few min. PAF infusion caused a profound rise in systemic arterial and coronary venous thromboxane B2 levels, while 6-keto-PGF1 alpha and leukotriene C4-immunoreactivity levels were not changed. Indomethacin completely blocked the rise in thromboxane level during PAF infusion and abolished the constrictor effect of PAF on the coronary vessels. These data suggest that PAF might play a detrimental role on the coronary circulation and cardiac function, primarily through thromboxane A2 mediated mechanism.