The effect of atrial dilatation on the genesis of atrial arrhythmias.

The effect of atrial stretching on the genesis of atrial arrhythmias was studied in 26 dogs. Left atrial dilatation was produced by inflation of a balloon catheter. Electrophysiological studies were performed by programmed electrical stimulation of the atrium and ventricle. The irritability of the atrium markedly increased when it was distended and atrial arrhythmias (sustained or non-sustained atrial tachyarrhythmias) could regularly be induced by administration of an early extrastimulus or--more rarely--by atrial burst pacing. In 10 cases spontaneous atrial tachycardia appeared during atrial balloon dilatation. The atrial effective refractory period shortened and the atrial conduction time lengthened on atrial stretching, while other electrical variables (cycle length, sinus node recovery time, atrioventricular conduction time, intraventricular conduction, ventricular refractory period, QT interval) remained unchanged. Atrial balloon dilatation was not accompanied by marked haemodynamic changes, and the left ventricular pressure curve, the contractility of the left ventricle and the central venous pressure did not change significantly on atrial stretching. The experimental data suggest that the atrial dilatation plays an important part in the pathogenesis of atrial arrhythmias.

Intrapericardial infusion of endothelin-1 induces ventricular arrhythmias in dogs.

OBJECTIVES: Recently, extremely high levels of endothelin-1 (ET-1) were detected in the pericardial fluid of patients with heart disease; however, the pathophysiological importance of this finding is not known. The present study was designed to characterize ET-1 levels in canine pericardial fluid and to investigate the effects of local high concentrations of exogenous ET-1 in vivo. METHODS: In anesthetized, open-chest dogs ET-1 (Groups 1 and 2: 11 and 33 pmol.kg-1.min-1; n = 6 and 6, respectively) or physiological saline (Group 3, n = 5) were infused into the closed pericardial sac for 40 min. In serial pericardial fluid and aortic blood plasma samples, ET-1 levels were measured by radioimmunoassay, and analysed by high-performance liquid chromatography (HPLC). Systemic arterial blood pressure, heart rate, cardiac output (CO), standard ECG and right ventricular endocardial monophasic action potentials (MAPs) were recorded. RESULTS: Basal pericardial fluid ET-1 levels were significantly higher than respective plasma levels (342 +/- 210 vs. 8.0 +/- 5.2 pmol.l-1, n = 14, P < 0.001. In HPLC analysis pericardial fluid ET-1 was indistinguishable from ET-1(1-21). Infusion of exogenous ET-1 into the pericardial space induced ventricular arrhythmias in all instances, which were associated with 9.7-fold increase in pericardial fluid ET-1 levels. Ventricular tachycardias developed in 9 of 12 animals. The arrhythmogenic effect of ET-1 was more apparent in dogs with the larger dose. Before the onset of arrhythmias, intrapericardial infusion of ET-1 increased QT time (Group 1: 207 +/- 18 to 230 +/- 23 ms, P < 0.01; Group 2: 220 +/- 12 to 277 +/- 17 ms, P < 0.01) and MAP duration at 90% repolarization (at 300 ms cycle length) (Group 1: 192 +/- 9 to 216 +/- 9 ms, P < 0.01; Group 2: 205 +/- 9 to 255 +/- 9 ms, P < 0.001). Hemodynamic variables did not change significantly prior to the onset of ventricular tachyarrhythmias. In Group 3, arrhythmias were not observed and all electrophysiological and hemodynamic parameters remained unchanged. CONCLUSIONS: Administration of exogenous ET-1 into the pericardial space induces ventricular arrhythmias associated with prolongation of QT time and MAP duration. Whether pericardial fluid ET-1 under pathophysiological conditions can ever reach sufficiently high levels to induce ventricular arrhythmias remains to be elucidated.

Direct renovascular effect of somatostatin in the dog.

Recently, effects of somatostatin on the renal function have been described and the vasoactive properties of the peptide were proposed to contribute to this action. However, the available data on its effect in the renal vascular bed are very controversial. Therefore, we investigated the effect of local intaarterial somatostatin boluses in a wide range of doses (5 x 10(-11) - 5 x 10(-5) g) on the renal blood flow (RBF) in anesthetized dogs. RBF was measured by an electromagnetic flow probe. Somatostatin did not influence blood pressure or heart rate. RBF exhibited a significant, dose-dependent fall (ranging from 11.6 +/- 11.9% to 31.9 +/- 17.3%), with a threshold at a dose of 5 x 10(-10) g. These results offer conclusive evidence for the contribution of somatostatin-induced direct renal vasoconstriction to its renal effects, in addition to the demonstrated modulation of other vasoactive systems and tubular functions.

Investigating the dual nature of endothelin-1: ischemia or direct arrhythmogenic effect?

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide, which may also elicit severe ventricular arrhythmias. The aims of our study were to compare the effects of total left anterior descending coronary artery (LAD) occlusion to intracoronary (ic.) ET-1 administration and to investigate the pathomechanism of ET-1 induced arrhythmias in 3 groups of anesthetized, open-chest mongrel dogs. In group A (n=10) a total LAD occlusion was carried out for 30 min, followed by a 60 min reperfusion period. In groups B and C ET-1 was administered into LAD for 30 min at a rate of 30 pmol/min (n=6) and 60 pmol/min (n=8). Epi- and endocardial monophasic action potential (MAP) recordings were performed to detect electrophysiologic changes and ischemia Blood samples for lactate measurements were collected from the coronary sinus (CS) and from the femoral artery. Infrared imaging was applied to follow epimyocardial heat emission changes. At the end of the ET-1 infusion period coronary blood flow (CBF) was reduced significantly in groups B and C (deltaCBF30MIN B: 21+/-2%, p<0.05; C: 35+/-2%, p<0.05), paralleled by a significant epimyocardial temperature decrease in group C (deltaT30MIN: -0.65+/-0.29 degrees C, p<0.05). Two dogs died of ventricular fibrillation (VF) in the reperfusion period in group A. Ventricular premature contractions and non-sustained ventricular tachycardic episodes appeared in group B, whereas six dogs died of VF in group C. Significant CS lactate level elevation indicating ischemia was observed only in group A from the 30th min occlusion throughout the reperfusion period (control vs. 30 min: 1.3+/-0.29 vs. 2.2+/-0.37 mmol/l, p<0.05). Epi- and endocardial MAP durations (MAPD90) and left ventricular epicardial (LV(EPI)) upstroke velocity decreased significantly in group A in the occlusion period. ET-1 infusion significantly increased LV(EPI) MAPD90 in group B and both MAPD90-s in group C. In conclusion, ischemic MAP and CS lactate changes were observed only in group A. Although ET-1 reduced CBF significantly in groups B and C, neither MAP nor lactate indicated ischemic alterations. ET-1 induced major ventricular arrhythmias appeared before signs of myocardial ischemia developed, though reduced CBF presumably contributed to sustaining the arrhythmias.

Characterization and stimuli for production of pericardial fluid atrial natriuretic peptide in dogs.

Recently high immunoreactive atrial natriuretic peptide (ir-ANP) levels have been found in the pericardial fluid of patients undergoing cardiac surgery. The present study was designed to characterize pericardial fluid ANP in anesthetized dogs. Pericardial fluid ir-ANP levels were 3.4-fold higher than plasma levels and the molecular form, revealed by high performance liquid chromatography, was indistinguishable from ANP[99-126]. Elimination of [125I]ANP was 5-fold slower in the pericardial space than in plasma. Activity of the major ANP degrading enzyme, neutral endopeptidase (NEP, EC 3.4.24.11), was 15-times higher in the pericardial fluid than in plasma. Right atrial balloon distension and rapid right ventricular pacing induced maximally 2.3-fold and 1.5-fold increases of pericardial fluid ir-ANP, respectively. Pericardial fluid ir-ANP concentrations and right atrial pressure values showed significant correlation during the stimuli. Our present results show that high concentrations of ir-ANP can be found in the dog pericardial fluid even under unstimulated conditions. Slow elimination of ANP from the pericardial fluid compartment may contribute to the high peptide levels. However this slow elimination cannot be attributed to a lower NEP activity. High basal levels of ANP in the pericardial fluid could be further increased by atrial balloon stretch and rapid ventricular pacing. The increase of pericardial fluid ir-ANP appeared to be a stretch-dependent response. ANP released into the pericardial fluid may be involved in the regulation of cardiac function and coronary vascular tone.

Presence of immunoreactive endothelin-1 and atrial natriuretic peptide in human pericardial fluid.

This study was undertaken to characterize endothelin-1 (ET-1) and atrial natriuretic peptide (ANP) concentrations in human pericardial fluid, blood plasma, right atrial appendage and papillary muscle by use of specific radioimmunoassays. In patients undergoing cardiac surgery (n=16) pericardial fluid mean immunoreactive (ir-) ET-1 and ir-ANP levels were 36-fold and 4-fold higher than corresponding plasma levels, respectively. In high performance liquid chromatography (HPLC) pericardial fluid ir-ET-1 was indistinguishable from human ET-1[1-21] and the majority of pericardial fluid ir-ANP coeluted with human ANP[99-126]. Atrial tissue ir-ET-1 and ir-ANP concentrations were 17-fold and 870-fold higher than in ventricular tissue. Our present study demonstrated for the first time the presence of ir-ET-1 in the pericardial fluid in humans. Human pericardial fluid contained far the highest concentrations of ET-1 among all biological fluids tested thus far. The functions of pericardial fluid ET-1 and ANP on cardiac performance and coronary vascular tone require further investigations.

Enhanced accumulation of pericardial fluid adenosine and inosine in patients with coronary artery disease.

Adenosine and inosine are believed to have cardioprotective effects. However, little is known about their possible role in the metabolic autoregulation of human coronaries and in pathologic conditions with supply/demand imbalance of the heart such as coronary artery disease. Since these low molecular weight nucleosides freely diffuse through the monolayer of the visceral pericardium, adenosine and inosine concentrations in pericardial fluid may well reflect the conditions in cardiac interstitium. The pericardial fluid and systemic venous blood adenosine and inosine concentrations were measured in 98 human subjects undergoing heart surgery for coronary artery disease or valvular heart disease. Adenosine and inosine concentrations were measured by HPLC with UV detection. In subjects with coronary artery disease pericardial fluid nucleoside concentrations were significantly higher than in patients with valvular heart disease (adenosine: 1545 (996-3146) nmol/L [median (25th-75th quartiles)] vs. 738 (390-2527) nmol/L, P<0.01; inosine: 658 (321-1331) nmol/L vs. 347 (159-1037) nmol/L, P<0.05), while in both patient groups pericardial fluid nucleoside concentrations were higher by an order of magnitude than in venous plasma. Our results show the enhanced release of adenosine and inosine by the ischemic myocardium as a marker of supply/demand imbalance and support the hypothesis that these cardiac nucleosides may have an important role in the adaptation of coronary blood flow in human coronary artery disease.

Effect of acute cardiac lymph stasis on metabolic coronary adaptation in the dog.

Surgical blockade of cardiac lymph drainage was performed in dogs to examine the effect of acute cardiac lymph stasis on coronary adaptive mechanisms. Coronary blood flow (CBF) was measured using an electromagnetic flow probe on the left anterior descending (LAD) artery. Metabolic autoregulatory capacity was assessed by eliciting reactive hyperemic responses after flow interruptions of 10-60 second duration and by administering submaximal doses (250-500 micrograms) of adenosine, the putative transmitter of reactive hyperemia, into the left heart. The effect of lymph stasis was tested in two experimental groups, one hour and 48 hours after lymph obstruction and the data compared to control dogs. Although cardiac lymph stasis did not notably affect baseline arterial pressure and CBF, both reactive hyperemic response and adenosine-induced coronary vasodilation were reduced significantly (equal to or less than 50% control). On occasion, a complete absence of autoregulation was observed. These findings suggest that cardiac lymph stasis decreases vascular responsiveness to physiologic vasodilator stimuli and/or retards diffusion of biologically unstable substance(s) presumably involved in autoregulation. Persistently impaired coronary autoregulation in the lymphedematous heart may contribute to progressive ischemic damage as for example after myocardial infarction.

Coronary arteriopathy after lymphatic blockade: an experimental study in dogs.

The effects of lymph stasis on the histological and biochemical properties of the coronary arterial wall and on the coronary circulation were studied in 72 dogs. Cardiac lymph stasis was produced in 52 dogs by cardiac lymphatic blockade whereas in 20 dogs only a sham operation was performed. Blockade of cardiac lymph drainage promoted characteristic injury to the coronary arteries including subendothelial edema with plasma inbibition, interstitial and intracellular edema in the tunica media with degeneration in the smooth muscle layer, swelling of the adventitial space with dilated lymph vessels and, later, fibrosis. The biochemical properties of the coronary arterial wall also were adversely affected by cardiac lymph stasis. Thus, the collagen and hexosamine content of the coronary arteries increased and the metabolism of the coronary wall shifted in an anaerobic direction. Whereas coronary blood flow was slightly decreased with lymph blockade, the coronary circulatory reserve capacity and the adaptability of the coronary vascular system was markedly reduced. The histological changes were most apparent in the smaller coronary arteries. The coronary microvasculature was also pathologically altered with the development of numerous coronary arteriovenous microshunts. These findings in conjunction with other experimental and clinical information suggest that impaired cardiac lymph drainage contributes to the pathogenesis and progression of coronary artery disease.

Reversal of isoproterenol-induced calorigenic action in the heart during myocardial ischemia.

With the aid of infrared thermography, a powerful new tool for studying the biological state of cardiac regulatory mechanisms, the reversal of the isoproterenol-induced calorigenic action in the in situ dog heart was demonstrated after establishing acute myocardial ischemia. The thermographic manifestations indicated a modified activity pattern of the cardiac (coronary) beta-mechanism with a preserved sensitivity to its specific pharmacologic blockade. Results provide new evidence of the transformation (plasticity) of adrenoceptor qualities under pathologic circumstances.

Effect of cardiac glycosides on the coronaries: physiologic and morphologic studies in the dog heart.

The effect of K- strophanthoside on coronary blood flow (CBF) was studied in open chest dogs anaesthetized with pentobarbital sodium. K- strophanthoside (3.5 and 7.0 X 10(-8) mol X kg-1 i.v.) elicited a dose-dependent decrease of CBF and an increase of late diastolic coronary resistance. Intracoronary injections of the drug (1.2 X 10(-8) mol) produced selective coronary constriction. The haemodynamic pattern indicated a direct vasoconstrictor effect, independent of the extracoronary (cardiotonic) action of the drug. In the polarization microscope Romh anyi 's aldehyde bisulphite-toluidine blue (ABT) reaction as adapted for the detection of cardiac glycosides showed profuse binding of strophanthoside to the coronary vessel wall. K- strophanthoside significantly reduced the CBF increase elicited by adenosine infusion (2 X 10(-7) mol X kg-1) into the left heart. Verapamil (4 X 10(-7) mol X kg-1, i.v.), on the other hand, counteracted the strophanthoside action on CBF. The results suggest that restricted intracellular availability of Ca2+, a prerequisite of physiologic CBF increase, is opposed by cardiac glycosides.

Calcium antagonist verapamil inhibits adenosine-induced renal vasoconstriction in the dog.

Calcium-dependence of the adenosine-induced renal vasoconstriction was studied in dogs anaesthetized with pentobarbital. Close intraarterial (i.a.) infusion of adenosine (40 and 100 micrograms X min-1) elicited a significant blood flow decrease followed by partial recovery during the 2 min infusion periods as measured with an electromagnetic flow probe. I.a. infusion of verapamil (100 micrograms X min-1) blocked the constrictor response. Verapamil also reduced the vasoconstriction produced by i.a. angiotensin II (0.1 micrograms X min-1) or adrenaline (0.6 micrograms X min-1). Blood pressure remained unchanged throughout all the interventions. The results indicate that the adenosine-induced renal vascular response depends on the availability of extracellular Ca2+ to the contractile mechanism of smooth muscle, a property shared by other well known renal constrictor agents.

Pharmacologic assessment of the functional state in stenosed coronary circulation of the dog.

In open chest dogs under sodium pentobarbital anaesthesia the interaction of mechanical constriction on a large coronary branch and autoregulatory capacity of the relevant small resistance vessels was analyzed. Coronary blood flow (CBF) was measured with an electromagnetic flowmeter. Step-by-step mechanical constriction gradually abolished adenosine-induced coronary vasodilation, whereas the resting level of mean CBF remained unaltered. At this point verapamil (0.2 mg/kg i.v.), a vasodilator with a strong potency of blocking adenosine action, eventually decreased CBF and increased coronary resistance. Similar results were obtained with these drugs injected directly into a bypass established between the carotid and left common coronary arteries. The results suggest that (i) adenosine affects the same coronary segments which accomplish compensatory autoregulation (ii); with critical stenosis verapamil augments indirectly coronary resistance by inhibiting an "intrinsic" adenosine effect (iii); the functional state of stenosed coronaries can be assessed with the aid of these pharmacologic tests.

Time-dependent changes of collateral coronary reactivity in the dog.

Vascular reactivity of the developing coronary collaterals has been investigated by studying local flow responses elicited by adrenergic and hypoxic stimuli in the ischemic foci of the canine heart. Tissue blood flow was measured by means of the heat clearance technique. The myocardial area explored was rendered ischemic by ligating the left anterior descending coronary artery 2-90 days prior to the experiment. This area is supplied exclusively by collateral channels. Adrenergic sensitivity was tested by i.v. administration or noradrenaline and isoproterenol (1 mug/kh), as well as by supramaximal electrical stimulation of the stellate ganglion. Metabolic sensitivity of the vessels was tested by brief periods of general hypoxia. During the first 3 weeks of the myocardial infarction, the collateral vascular response induced by each form of the adrenergic activation was considerably different from that observed in the normal coronary bed: instead of the conventional beta-type dilation, noradrenaline and stellate stimulation induced constriction in the ischemic zone whereas isoproterenol, having only pure beta-stimulating effects proved to be ineffective. Following the 3rd postoperative week, a gradually increasing sensitivity to beta-dilator influences appeared on the collateral vessels. However, this transformation of the adrenergic effect was not accompanied by a similar restoration of the local vascular propensity for metabolic (hypoxic) dilation. The results suggest that time courses of the changes of the adrenergic and metabolic vascular reactivity in the collateral network, although probably interrelated, do not parallel each other.