Ischemia-reperfusion injury at the microvascular level: treatment by endothelin A-selective antagonist and evaluation by myocardial contrast echocardiography.

BACKGROUND: The purpose of this study was to verify whether endothelin A-antagonist administration at the time of coronary reperfusion preserves postischemic microvasculature and whether myocardial contrast echo (MCE) is able to detect pharmacologically induced changes in microvascular reflow. METHODS AND RESULTS: Twenty dogs underwent 90 minutes of LAD occlusion (OCC) followed by 180 minutes of reperfusion (RP). Five minutes before LAD reopening, an intravenous bolus (5 mg/kg) of LU 135252 was given in 10 dogs and vehicle in the remaining 10. At baseline (BSL), OCC, and 90 and 180 minutes of RP, microvascular flow (BF) was assessed by microspheres, and MCE was performed with intravenous echo contrast. MCE videointensity and BF were expressed as risk area/control ratio. Myocardial thickness of the risk area was calculated by 2D echo. No differences in BF between the 2 groups were observed at BSL, OCC, and 90 minutes of RP. At 180 minutes of RP, BF was decreased in controls (70+/-7.4% of BSL; P:<0.005 versus BSL) and preserved in LU 135252-treated animals (89+/-4% of BSL; P=NS versus BSL; P<0.05 versus controls). Videointensity at MCE closely followed the changes in BF observed in both groups throughout the protocol. Myocardial thickness at 180 minutes of RP increased to 138.6+/-9.9% of BSL in controls and remained at 108.9+/-7.4% of BSL in treated dogs (P<0.05). CONCLUSIONS: Endothelin A-antagonist treatment at the time of reperfusion significantly limited the progressive decrease in postischemic microvascular reflow and the increase in myocardial thickness. MCE allowed a reliable evaluation of pharmacologically induced changes in microvascular flow.

Perflubron emulsion improves tolerance to low-flow ischemia in isolated rabbit hearts.

The efficacy of the temporary oxygen carrier perflubron emulsion (PFC) in maintaining oxygen delivery, tissue oxygenation, high-energy phosphates (HEPs), and myocardial function was investigated during low-flow ischemia. Perfusion rate, oxygen tensions, and cardiac function were measured during stabilization (5 min), controlled-flow (22 ml/min x 20 min), and low-flow (0.22 ml/min x 120 min) periods in isolated rabbit hearts. Hearts were perfused with Krebs-Henseleit (KH) solution (Control), or 10 or 20% PFC (vol/vol; n = 8 per group) 5 min before and throughout the low-flow period. Myocardial tissue was then frozen for biochemical and metabolic measurements. Myocardial oxygenation was measured at incremental flow rates by using 20% PFC (n = 4) or KH (n = 6). In PFC hearts, oxygen delivery and intramyocardial tissue Po2 were improved at all evaluated time points and flow rates, respectively (p < 0.05). In Control hearts, left ventricular end-diastolic pressure was elevated at 60, 90, and 120 min of low-flow ischemia (p < 0.05). Tissue lactate was higher (p < 0.05) and HEPs lower (p < 0.05) in Control hearts during low-flow ischemia. These results indicate that PFC treatment improves myocardial oxygenation, maintains HEPs, prevents ischemic contracture, and may increase the margin of safety during low-flow ischemia in isolated rabbit hearts.

Evaluation of dynamic changes in microvascular flow during ischemia-reperfusion by myocardial contrast echocardiography.

BACKGROUND: Dynamic changes of myocardial blood flow have been observed after reperfusion of an occluded coronary artery. MCE performed by intracoronary contrast injection can provide an estimate of microvascular flow. We hypothesized that MCE performed using intravenous infusion of a new generation contrast agent and electrocardiogram-gated harmonic imaging would be able to assess serial changes of microvascular perfusion. OBJECTIVE: To study the potential of myocardial contrast echocardiography (MCE) to assess serial changes of microvascular flow during ischemia-reperfusion. METHODS: Sixteen dogs underwent 90 or 180 min of left anterior descending coronary occlusion, followed by 180 min of reperfusion. Regional blood flow (RBF) was measured with fluorescent microspheres at baseline, during coronary occlusion, and at 5, 30, 90, and 180 min during reperfusion. At the same time points, MCE was performed with intravenous infusion of AF0150 (4 mg/min). Gated end-systolic images in short axis were acquired in harmonic mode and digitized on-line. Background-subtracted videointensity measured from MCE and RBF obtained from fluorescent microspheres were calculated for the risk area and for a control area, and were expressed as the ratio of the two areas. RESULTS: After initial hyperemia, a progressive reduction in flow was observed during reperfusion. MCE correctly detected the time course of changes in flow during occlusion-reperfusion. Videointensity ratio significantly correlated with RBF data (r=0.79; p < 0.0001). CONCLUSIONS: The progressive reduction in blood flow occurring within the postischemic microcirculation was accurately detected by MCE. This approach has potential application in the evaluation and management of postischemic reperfusion in humans.

Effect of platelet depletion and inhibition of platelet cyclooxygenase on C5a-mediated myocardial ischemia.

Activation of the complement cascade is involved in the myocardial injury resulting from transient ischemia and reperfusion. We previously showed that the complement anaphylatoxin C5a causes myocardial ischemia in vivo, mediated in part via thromboxane (Tx) A2. In the present study, we assess the role of platelets in the C5a-induced myocardial ischemia and Tx release. The left anterior descending coronary artery of anesthetized pigs was perfused with arterial blood at constant pressure and measured flow (coronary blood flow). Segment function (percent segment shortening) was measured with sonomicrometry, and regional coronary venous blood was sampled and assayed for TxB2 (by radioimmunoassay). We found that the C5a-induced decrease in coronary blood flow and percent segment shortening and the release of Tx were indistinguishable whether the left anterior descending coronary artery bed was perfused with normal arterial blood, with arterial blood obtained from animals depleted of platelets (cyclophosphamide, n = 6), or with arterial blood from aspirin-treated animals (n = 9) in which the platelets were unable to produce Tx. These data demonstrate that platelet-derived Tx does not contribute to the C5a-induced myocardial ischemia and Tx release in this model and that these cells do not play an integral role in this phenomenon.

Pulmonary gas trapping differences among animal species in response to intravenous infusion of perfluorocarbon emulsions.

In animals, increased lung volume and a concomitant failure of lungs to collapse normally upon autopsy can occur following intravenous injection of higher vapor pressure perfluorocarbons (PFCs) administered as emulsions. Responses vary considerably depending on the PFC, dose and animal model. The study objective was to examine animal species differences with respect to this apparent pulmonary gas trapping (PGT) phenomenon which has not been observed in human clinical trials. A dose-related increase in postmortem lung volume following treatment with either a concentrated perflubron emulsion or Fluosol was observed. It was most pronounced in pigs, rabbits and monkeys, and essentially nonexistent in mice and dogs. No clear effects on arterial blood gases were seen in most species, but PaO2 levels were reduced transiently in monkeys given the highest PFC doses. Reversibility of pulmonary effects occurred more rapidly with perflubron emulsions than with Fluosol. Vacuolated mononuclear cells, reflecting the presence of PFC particles in the lung, and alveolar distention varied between species, but no lesions or edema were observed. Species differences in collateral ventilation, airway morphology and pulmonary intravascular macrophages may influence their sensitivity and contribute to the interspecies differences in response to intravenously administered PFC emulsions.

Severe neutrophil depletion by leucocyte filters or cytotoxic drug does not improve recovery of contractile function in stunned porcine myocardium.

OBJECTIVE: The contribution of neutrophils to myocardial injury during stunning remains controversial because of conflicting results in neutropenic animals. The goal of this study was to compare the recovery of function in stunned myocardium using two distinct methods for inducing neutropenia in pigs. METHODS: Three groups of pigs were studied: control (n = 6), and made neutropenic by either Leukopak blood filters (n = 7), or cyclophosphamide (n = 7, 50 mg.kg-1 intravenously 4 d prior to study). In anaesthetised open chest pigs, with the heart paced at 110 beats.min-1, the left anterior descending coronary artery was perfused with an extracorporeal circuit at controlled coronary pressure (CP) and the regional coronary blood flow was measured. Systolic wall thickening was determined by sonomicrometry in the left anterior descending and circumflex coronary artery regions. The protocol consisted of 15 min of low flow ischaemia (CP = 40 mm Hg), followed by a staged reperfusion over 10 min back to baseline (CP = 90 mm Hg), and continued for 2 h. Blood filtration was initiated prior to ischaemia and stopped after 90 min reperfusion. RESULTS: In both treated groups during ischaemia and the initial 60 min of reperfusion the neutrophil count was severely depleted to < 5% compared to the control group. Aortic pressure, coronary blood flow during ischaemia, area at risk, and systolic wall thickening in the circumflex region were similar between groups. Recovery of systolic wall thickening in the left anterior descending region after reperfusion was equivalent in all three groups. In the filter group, arrhythmias during ischaemia and reperfusion were significantly less. CONCLUSION: As assessed in the pig model of myocardial stunning and using two different methods, severe neutropenia does not reduce the depression of contractile function.

Role of cardiac mast cells in complement C5a-induced myocardial ischemia.

Activated complement component C5a causes myocardial ischemia mediated by thromboxane (Tx) A2 and leukotrienes C4/D4. Blood cells are not involved in either the mediator release or the myocardial effects of C5a, suggesting that a C5a-sensitive, cardiac resident inflammatory cell is responsible. The goals of this study were to determine whether 1) cardiac mast cell activation accompanies the C5a response, 2) inhibition of mast cell degranulation inhibits the response, and 3) histamine release plays a role in the C5a-induced myocardial ischemia. The left anterior descending coronary artery (LAD) of open-chest pigs (n = 13) was perfused with arterial blood at constant pressure (95 mmHg). Coronary blood flow (CBF) was measured (in-line flowmeter) and regional function [percent segment shortening (%SS)] determined with sonomicrometry. A coronary vein was cannulated for measurement of plasma TxB2 and histamine (a marker of mast cell degranulation). Intracoronary C5a (500 ng) decreased coronary blood flow (45% of preinfusion levels) and LAD %SS (65% of preinfusion) and was accompanied by increases in coronary venous TxB2 (delta 63.3 ng/ml) and histamine (delta 200 nM). Mast cell inhibition with lodoxamide (2 mg/kg iv, n = 8) attenuated the C5a-induced fall in CBF (14 vs. 53% decrease, P < 0.01) and %SS (10 vs. 38% decrease, P < 0.01) and also reduced the C5a-induced increase in both coronary venous histamine (delta 26 vs. 278 nM, P < 0.05) and TxB2 (delta 0.34 vs. 63.3 ng/ml, P < 0.01). However, histamine H1 (pyrilamine) and H2 (ranitidine) receptor blockade had no effect on the C5a-induced fall in CBF or LAD %SS.(ABSTRACT TRUNCATED AT 250 WORDS)

Complement C5a-mediated myocardial ischemia and neutrophil sequestration: two independent phenomena.

The intracoronary infusion of complement C5a causes a decrease in coronary blood flow and contractile dysfunction mediated by thromboxane (TxA2) and leukotrienes. Although these effects are accompanied by polymorphonuclear leukocyte (PMN) sequestration, the role of PMNs and the source of these eicosanoids remain unknown. To assess the contribution of PMNs to the C5a-induced myocardial ischemic response, the left anterior descending (LAD) coronary artery of pigs (n = 13) was cannulated and pump perfused at constant pressure with either normal arterial blood or neutropenic arterial blood (PMN count 0.02 x 10(3) cells/microliters) obtained from animals treated with cyclophosphamide (50 mg/kg iv, given 4 days before). The coronary vein draining the LAD region was cannulated for measurement of leukocyte count and TxB2 levels. Two groups of animals were studied: group 1 (n = 7) neutropenic animals were instrumented and normal animals served as blood donors and group 2 (n = 6) normal animals were instrumented and neutropenic animals served as blood donors. The myocardial response to intracoronary C5a (500 ng) was determined in each animal during coronary perfusion with normal arterial blood and also with neutropenic arterial blood. During perfusion with normal arterial blood, C5a decreased coronary flow to 52.3% and contractile function to 58.8% of preinfusion values. This was accompanied by a transient myocardial accumulation of PMNs (arterial-coronary venous gradient of 5.4 x 10(3) cells/microliters) and increased TxB2 levels in coronary venous blood (from 0.31 to 17.5 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

T wave changes persisting after ventricular pacing in canine heart are altered by 4-aminopyridine but not by lidocaine. Implications with respect to phenomenon of cardiac 'memory'.

BACKGROUND: Cardiac "memory" refers to changes in T wave polarity induced by ventricular pacing that persist long after resumption of normal atrioventricular conduction. METHODS AND RESULTS: We studied the occurrence and mechanism of T wave changes in the open-chest anesthetized dog subjected to three discontinuous 20-minute periods of right ventricular pacing. ECG changes were recorded in the standard limb leads during normal conduction (prepacing) and three trains (T1, T2, and T3) of right ventricular pacing at a rate 50% higher than normal (pacing), each followed by a period of normal conduction (postpacing) lasting as long as necessary for T wave changes to return to control values. During each of these phases, heart rate, QRS, corrected QT (QTc) duration, and T wave amplitude were measured. In the first group (control), T wave inversions occurred during normal atrioventricular conduction after a period of right ventricular pacing. These T wave anomalies appeared in the absence of any change in heart rate, QRS, or QTc duration. The magnitude of the T wave amplitude change was significantly greater after each successive pacing period. Furthermore, the changes in T wave morphology persisted for a longer period after each successive pacing train. In a second experimental group, lidocaine, which depresses the sodium window current, was administered to six dogs that were subjected to the same pacing protocol. Lidocaine decreased the QTc interval and prolonged QRS duration but did not alter the magnitude of changes in T wave amplitude and time to recovery described in control animals during the three postpacing intervals. In contrast, in the third group, 4-aminopyridine, a drug that blocks the transient outward current (ito), abolished the changes in T wave morphology that occurred during any postpacing interval. CONCLUSIONS: These results demonstrate that the manifestation of cardiac memory in the in situ dog heart is not altered by lidocaine but is abolished by 4-aminopyridine. Thus, cardiac memory may be based on a physiological property of the myocardium that is related to specific K+ channels.

Intracoronary C5a induces myocardial ischemia by mechanisms independent of the neutrophil: leukocyte filters desensitize the myocardium to C5a.

Activation of the complement cascade with the generation of anaphylatoxins accompanies the inflammatory response elicited by acute myocardial ischemia and reperfusion. Although complement is activated in the interstitium during acute myocardial ischemia, we have studied mechanisms whereby complement might exacerbate ischemia by using a model employing intracoronary injection of C5a in nonischemic hearts. Intracoronary injection of complement component C5a induces transient myocardial ischemia, mediated through the production of the coronary vasoconstrictors thromboxane A2 and peptidoleukotrienes (LTC4, LTD4), and causes sequestration of polymorphonuclear leukocytes (PMN) in the coronary vascular bed. To further investigate the role of the PMN in the C5a-induced vasoconstriction, the left anterior descending coronary artery (LAD) in pigs was perfused at constant pressure and measurements of coronary blood flow, myocardial contractile function (sonomicrometry), arterial/coronary venous blood PMN count, and thromboxane B2 (TxB2) levels were performed. The myocardial response to intracoronary C5a (500 ng) was determined before, during, and after perfusion with blood depleted of PMNs using leukocyte filters (Sepacell R-500, Pall PL-100). In additional animals, the myocardial response to the PMN chemotactic agent, LTB4, and the effects of intracoronary C5a during constant flow perfusion were measured. Control intracoronary injection of C5a decreased flow (41% of baseline) and contractile function (39% of baseline), PMNs were trapped (5.1 x 10(3) cells/microliters), and TxB2 concentration increased in coronary venous blood. The response to C5a during coronary perfusion with arterial blood depleted of PMNs with Sepacell or Pall filters (less than 0.1 x 10(3) cells/microliters) was greatly blunted, with flow and contractile function falling by less than 14 and 8%, respectively, from baseline, and release of TxB2 was greatly attenuated. However, the myocardial ischemia and TxB2 release remained depressed in response to C5a after removal of the filters and perfusion with either arterial blood containing normal levels of PMNs or stored arterial blood never exposed to filters. In contrast, the repeat C5a challenge resulted in equivalent myocardial extraction of PMNs, thus indicating a dissociation of PMN sequestration from the acute ischemic response and release of TxB2. In separate experiments, the intracoronary injection of LTB4 also resulted in a pronounced myocardial extraction of PMNs (8.6 x 10(3) cells/microliters) greater than during C5a, but did not depress coronary flow or function. Perfusion at constant flow greatly diminished the ischemic response to C5a, indicating that vasoconstriction and resultant ischemia is the main cause of the contractile dysfunction. These data indicate that leukocyte filters inhibit the myocardial ischemia and release of TxB2 induced by C5a via mechanisms not related to PMN depletion.(ABSTRACT TRUNCATED AT 400 WORDS)

Specific alpha 1-adrenergic receptor subtypes modulate catecholamine-induced increases and decreases in ventricular automaticity.

Fifty percent of adult canine Purkinje fibers manifest a decrease in automaticity in response to alpha 1-adrenergic stimulation with 10(-10)-10(-8) M norepinephrine (NE), and 50% manifest an increase. In contrast, most neonatal Purkinje fibers show an increase in automaticity in response to these concentrations of NE. We studied the modulation of NE effects, using the subtype selective alpha 1-adrenergic antagonists chloroethylclonidine (CEC) and WB 4101. CEC selectively antagonized the decrease in automatically such that, in both age groups, all Purkinje fibers showed NE-induced increases in automaticity. In Purkinje fibers from dogs treated with pertussis toxin, NE no longer induced a CEC-sensitive decrease in automaticity. In contrast, WB 4101 selectively antagonized the NE-induced increase in automaticity in both age groups. In the presence of WB 4101, NE decreased automaticity uniformly in adult Purkinje fibers and tended to induce no change in automaticity in neonatal Purkinje fibers. In the presence of prazosin (10(-6) M) or combined CEC (10(-7) M) and WB 4101 (10(-7) M), no alpha-agonist-induced increase or decrease in rate was observed. Pretreatment of membranes from newborn and adult dog and rat ventricles with CEC resulted in a selective and irreversible inactivation of 25% of specific binding sites labeled with [125I]IBE2254. In cultured neonatal rat ventricular myocytes, exposure to CEC resulted in a 35% decrease in the density of specific binding sites labeled with [125I]IBE2254 but did not influence alpha-adrenergic stimulation of inositol phosphate accumulation. In contrast, WB 4101 inactivated NE-stimulated inositol phosphate accumulation. Our results suggest that 1) at least two distinct alpha 1-adrenergic receptor subtypes are present in neonatal and adult cardiac tissue, 2) the CEC-sensitive subtype is linked to a decrease in automaticity via a pertussis toxin-sensitive substrate, 3) the WB 4101-sensitive subtype is linked to an increase in automaticity (possibly via a mechanism related to phosphoinositide breakdown), and 4) although CEC- and WB 4101-sensitive alpha 1-adrenergic receptor subtypes are present in the neonate, only the WB 4101-sensitive subtype is expressed functionally to induce effects on ventricular automaticity.

Cardiac dysfunction caused by recombinant human C5A anaphylatoxin: mediation by histamine, adenosine and cyclooxygenase arachidonate metabolites.

We had found previously that complement-derived anaphylatoxins C3a and C5a function as mediators/modulators of cardiac immune hypersensitivity reactions. The purpose of this study was to determine the secondary mediators responsible for the cardiac effects of C5a. Recombinant human C5a (rhC5a) caused dose-dependent tachycardia, slowing of atrioventricular nodal conduction, a short lasting increase followed by a prolonged decrease in left ventricular contractility, and coronary vasoconstriction. These changes were associated with the release of histamine, thromboxane A2 and adenosine into the coronary effluent. Our data indicate that the positive inotropic and chronotropic effects of rhC5a are mediated by histamine release and consequent activation of H2-receptors, the coronary-vasoconstricting effect is due to thromboxane release and the negative dromotropic effect is associated with adenosine release. Furthermore, the decrease in contractility caused by rhC5a is likely to result from the H1-mediated negative inotropic effect of histamine compounded by the ischemic conditions created by the coronary vasoconstricting effects of thromboxane A2 and, perhaps, leukotrienes. Our findings demonstrate that C5a has marked cardiac effects at concentrations approximating those attained in vivo in a multitude of pathophysiological conditions in which complement is activated, including myocardial infarction. Thus, anaphylatoxins may play a role in the development of ischemic cardiac dysfunction.

Cardiac anaphylaxis. Complement activation as an amplification system.

Complement is activated, and C3a and C5a anaphylatoxins are generated during hypersensitivity reactions clinically associated with cardiopulmonary collapse. The administration of C3a or C5a to nonsensitized isolated guinea pig hearts mimics the events caused by antigen challenge of sensitized hearts (i.e., cardiac anaphylaxis) in the absence of complement. Thus, complement-derived anaphylatoxins may participate in immediate hypersensitivity reactions in which the heart is a target organ. To assess the contribution of complement activation and anaphylatoxin generation to cardiac dysfunction, we have elicited anaphylaxis in isolated guinea pig hearts in the presence of complement and found that the ensuing dysfunction is markedly enhanced. This amplification is most likely attributable to anaphylatoxin formation because 1) inactivation of C3 or selective C3 depletion, i.e., the loss of the component responsible for the formation of the anaphylatoxins C3a and C5a, prevents complement-induced exacerbation of cardiac anaphylaxis, whereas reconstitution with C3 and C5, or even only C3, restores it; in fact, the greater the C3 content at the time of antigen challenge, the more intense the anaphylactic crisis; and 2) the severity of cardiac anaphylaxis is markedly reduced by preexposure to C3a, and this reduction is directly related to the dose of C3a injected and to the amount of endogenous cardiac histamine depleted by C3a before antigen challenge. Complement-derived anaphylatoxins appear to promote the same mediator release that has been initiated by the antigen-antibody reaction; thus, complement activation functions as an amplification system in cardiac anaphylaxis.

C3a-induced contraction of guinea pig ileum consists of two components: fast histamine-mediated and slow prostanoid-mediated.

Guinea pig ileum is the classical experimental model for assessing the biological activity of complement-derived anaphylatoxins. Nevertheless, it is still at issue whether C3a-induced ileal contraction is entirely dependent on histamine release. We report that the contraction of the intestinal smooth muscle in response to C3a is characterized by two components, fast and slow, whose incidence and amplitude is strictly dependent on C3a concentration; the larger the concentration of C3a, the greater the incidence and magnitude of the fast component and the less frequent the slow component. The fast and slow components were characterized by a sigmoid and bell-shaped concentration-response curve, respectively. The fast component was associated with the release of endogenous histamine, increased in magnitude with the quantity of histamine released and was prevented by the histamine H1 receptor antagonist pyrilamine. On the contrary, there was no correlation between the quantity of histamine released by C3a and the magnitude of the slow component. Instead, the slow component was associated with the release of PGE2 and was prevented by the cyclooxygenase inhibitor indomethacin. Neither component was affected by the leukotriene receptor antagonist FPL 55712. Our data indicate that C3a-induced ileal contraction is partially histamine dependent in that histamine mediates only the fast component, whereas cyclooxygenase metabolites are responsible for the slow component.

Activation of the third complement component (C3) and C3a generation in cardiac anaphylaxis: histamine release and associated inotropic and chronotropic effects.

Activation of the complement system with generation of C3a and C5a anaphylatoxins occurs during immediate hypersensitivity reactions; furthermore, the administration of C3a and/or C5a into isolated hearts causes a dysfunction that closely resembles cardiac anaphylaxis. To determine whether complement is activated and anaphylatoxins are generated in the course of immediate hypersensitivity reactions of the heart, we have challenged presensitized isolated guinea pig atria and papillary muscles with the specific antigen in the presence of a source of complement. We have found that the anaphylactic reaction of these cardiac preparations is characterized by complement activation and C3a generation, as well as by histamine release and positive inotropic and chronotropic effects. The amounts of C3a generated and histamine released directly correlated with the extent of C3 consumption. Furthermore, when C3a and C5a inactivation by serum carboxypeptidase N was prevented by DL-2-mercapto-methyl-3-guanidino-ethylthiopropanoic acid, anaphylactic histamine release was enhanced, and chronotropic and inotropic responses were potentiated and prolonged. Notably, the administration of C3a to nonsensitized guinea pig atria and papillary muscles caused positive chronotropic and inotropic effects, which were associated with histamine release and were antagonized by the H2 receptor blocker cimetidine, thereby mimicking the effects of anaphylaxis. Our findings indicate that complement activation and anaphylatoxin generation are typical of cardiac anaphylaxis and suggest that anaphylatoxins function as mediator-modulators of immediate hypersensitivity reactions of the heart.

Cardiac dysfunction caused by purified human C3a anaphylatoxin.

The purpose of this investigation was to define the cardiac effects of complement-derived C3a anaphylatoxin, in view of the possibility that cardiac dysfunction may occur as a result of complement activation. Purified human C3a was administered by intracoronary bolus injections into isolated guinea pig hearts. As a function of dose, C3a caused tachycardia, impairment of atrioventricular conduction, left ventricular contractile failure, coronary vasoconstriction, and histamine release. These effects were abolished by cleavage of the COOH-terminal arginine by carboxypeptidase B. The magnitude of C3a-induced tachycardia correlated with the amount of endogenous cardiac histamine released into the coronary effluent. Whereas the tachycardia was markedly reduced by the histamine H2 antagonist cimetidine, the contractile failure and the coronary vasoconstriction caused by C3a were antagonized by the leukotriene antagonist FPL 55712 and by the cyclooxygenase inhibitor indomethacin, respectively. This suggests that histamine, leukotrienes, and vasoactive prostanoates may mediate the various cardiac effects of C3a. Our findings indicate that C3a anaphylatoxin has marked cardiac effects at concentrations that are likely to be attained with a degree of C3 activation commonly seen in various disease states. Thus, our data are compatible with the hypothesis that generation of anaphylatoxins may induce cardiac dysfunction in clinical conditions.