Effects of anodal vs. cathodal pacing on the mechanical performance of the isolated rabbit heart.

Previous studies have suggested that anodal pacing enhances electrical conduction in the heart near the pacing site. It was hypothesized that enhanced conduction by anodal pacing would also enhance ventricular pressure in the heart. Left ventricular pressure measurements were made in isolated, Langendorff-perfused rabbit hearts by means of a Millar pressure transducer with the use of a balloon catheter fixed in the left ventricle. The pressure wave was analyzed for maximum pressure (Pmax) generated in the left ventricle and the work done by the left ventricle (Parea). Eight hearts were paced with monophasic square-wave pulses of varying amplitudes (2, 4, 6, and 8 V) with 100 pulses of each waveform delivered to the epicardium. Anodal stimulation pulses showed statistically significant improvement in mechanical response at 2, 4, and 8 V. Relative to unipolar cathodal pacing, unipolar anodal pacing improved Pmax by 4.4 +/- 2.3 (SD), 5.3 +/- 3.1, 3.5 +/- 4.9, and 4.8 +/- 1.9% at 2, 4, 6, and 8 V, respectively. Unipolar anodal stimulation also improved Parea by 9.0 +/- 3.0, 12.0 +/- 6.0, 10.1 +/- 7.7, and 11.9 +/- 6.0% at 2, 4, 6, and 8 V, respectively. Improvements in Pmax and Parea indicate that an anodally paced heart has a stronger mechanical response than does a cathodally paced heart. Anodal pacing might be useful as a novel therapeutic technology to treat mechanically impaired or failed hearts.     

Disorders of the heart contractile function in chronic hemolytic anemia and their prevention

The coronary blood flow and heart contractile function were studied on rats with phenylhydrazine-induced chronic hemolytic anemia. The coronary blood flow in the animals' hearts was increased 2.5-fold, whereas the main parameters of contractile function were reduced but insignificantly. After the coronary blood flow dropped to the control level, the pressure and contraction rate fell by 40% and the relaxation rate diminished 2-fold. Thus, the enhanced coronary blood flow in the hearts of animals with hemolytic anemia appears to be a factor that compensates for the maintenance of myocardial contractility at the subnormal level. Administration of the antioxidant ionol, an inhibitor of lipid peroxidation, coupled with phenylhydrazine did not prevent the development of anemia but made the coronary blood flow descend in the hearts of anemic animal only by 80%. Since the iron-containing products of red cell dissolution activate lipid peroxidation during hemolytic anemia, this might play a role in the occurrence of heart muscle injuries. It is suggested that ionol prevents such injuries to a considerable extent, thereby preventing the development of compensatory enhancement of the coronary blood flow and heart contractile function disturbances during its normalization.     

Heart rate as a determinant of the decay rate of the cardiac inotropic response to sympathetic nervous activity

The cardiac responses to sympathetic nerve stimulation were measured in a series of open-chest, anesthetized dogs. In half the animals, the hearts were in a sinus rhythm; in the remaining animals, the hearts were in an atrioventricular (AV) junctional rhythm. Cocaine markedly prolonged the decay times of the chronotropic responses after cessation of sympathetic stimulation, regardless of the type of rhythm. The decay times of the inotropic responses were only slightly prolonged by cocaine in animals with a sinus rhythm, but the prolongations were pronounced in animals with an AV junctional rhythm. The lower basal heart rate appeared to be more responsible for the greater decay times of the inotropic responses in the animals with an AV junctional rhythm than in those with a sinus rhythm. In a second series of dogs, complete heart block was produced, cocaine was given, AND the hearts were paced at four different frequencies. The mean decay time of the inotropic response to sympathetic stimulation varied inversely AND substantially with the pacing frequency. The change in contraction frequency probably affects the rate of neurotransmitter dissipation from the ventricular myocardium, by altering either the coronary blood flow or the massaging action of the cardiac contractions.     

Ectopic pacing at physiological rate improves postanoxic recovery of the developing heart

Recently, rapid and transient cardiac pacing was shown to induce preconditioning in animal models. Whether the electrical stimulation per se or the concomitant myocardial ischemia affords such a protection remains unknown. We tested the hypothesis that chronic pacing of a cardiac preparation maintained in a normoxic condition can induce protection. Hearts of 4-day-old chick embryos were electrically paced in ovo over a 12-h period using asynchronous and intermittent ventricular stimulation (5 min on-10 min off) at 110% of the intrinsic rate. Sham (n = 6) and paced hearts (n = 6) were then excised, mounted in vitro, and subjected successively to 30 min of normoxia (20% O(2)), 30 min of anoxia (0% O(2)), and 60 min of reoxygenation (20% O(2)). Electrocardiogram and atrial and ventricular contractions were simultaneously recorded throughout the experiment. Reoxygenation-induced chrono-, dromo-, and inotropic disturbances, incidence of arrhythmias, and changes in electromechanical delay (EMD) in atria and ventricle were systematically investigated in sham and paced hearts. Under normoxia, the isolated heart beat spontaneously and regularly, and all baseline functional parameters were similar in sham and paced groups (means +/- SD): heart rate (190 +/- 36 beats/min), P-R interval (104 +/- 25 ms), mechanical atrioventricular propagation (20 +/- 4 mm/s), ventricular shortening velocity (1.7 +/- 1 mm/s), atrial EMD (17 +/- 4 ms), and ventricular EMD (16 +/- 2 ms). Under anoxia, cardiac function progressively collapsed, and sinoatrial activity finally stopped after approximately 9 min in both groups. During reoxygenation, paced hearts showed 1) a lower incidence of arrhythmias than sham hearts, 2) an increased rate of recovery of ventricular contractility compared with sham hearts, and 3) a faster return of ventricular EMD to basal value than sham hearts. However, recovery of heart rate, atrioventricular conduction, and atrial EMD was not improved by pacing. Activity of all hearts was fully restored at the end of reoxygenation. These findings suggest that chronic electrical stimulation of the ventricle at a near-physiological rate selectively alters some cellular functions within the heart and constitutes a nonischemic means to increase myocardial tolerance to a subsequent hypoxia-reoxygenation.     

Direct observation of epicardial coronary capillary hemodynamics during reactive hyperemia and during adenosine administration by intravital video microscopy

Using high-resolution intravital charge-coupled device video microscopy, we visualized the epicardial capillary network of the beating canine heart in vivo to elucidate its functional role under control conditions, during reactive hyperemia (RH), and during intracoronary adenosine administration. The pencil-lens video-microscope probe was placed over capillaries fed by the left anterior descending artery in atrioventricular-blocked hearts of open-chest, anesthetized dogs paced at 60-90 beats/min (n = 17). In individual capillaries under control conditions, red blood cell flow was predominant during systole or diastole, indicating that the watershed between diastolic arterial and systolic venous flows is located within the capillaries. Capillary flow increased during RH and reached a peak flow velocity (2.1 +/- 0.6 mm/s), twice as high as control (1.2 +/- 0.5 mm/s), with enhancement of intercapillary cross-connection flow and enlargement of diameter (by 17%). With adenosine, capillary flow velocity significantly increased (1.8 +/- 0.7 mm/s). However, the increase in volumetric capillary flow with adenosine estimated from red blood cell velocity and diameter was less than the increase in arterial flow, whereas that during RH was nearly equivalent to the increase in arterial flow. There was a time lag of approximately 1.5 s for refilling of capillaries during RH, indicating their function as capacitance vessels. In conclusion, the coronary capillary network functions as 1) the major watershed between diastolic-dominant arterial and systolic-dominant venous flows, 2) a capacitor, and 3) a significant local flow amplifier and homogenizer of blood supply during RH, but with adenosine the increase in capillary flow velocity was less than the increase in arterial flow.     

Myocardial capillarity and maximal capillary diffusion capacity in exercise-trained dogs

Our purpose was to determine whether changes in myocardial capillarity underlie the exercise training-induced increases in coronary transport capacity previously observed in dogs (J. Appl. Physiol. 58: 468-476, 1985). The approach was to measure capillary diffusion capacity (PS) in working hearts and then measure capillary numerical density (CD), capillary surface area density (CSA), and capillary volume density (CV) in specimens from perfused-fixed hearts. Eight dogs (20-30 kg) were exercise trained (ET) for 12-18 wk and compared with a group of seven control dogs. PS for 51Cr-labeled ethylenediaminetetraacetic acid was determined during maximal adenosine coronary vasodilation with perfusion pressures equal to 100 mmHg in both groups. The trained dogs' maximal PS averaged 58 +/- 10 ml.min-1.100 g-1, which was significantly greater than the control value (31 +/- 6). Maximal PS was linearly related to CV (r = 0.61) and CSA (r = 0.78) in the ET group. However, there was no difference between control and trained average left ventricular CD, CSA, CV, or intercapillary distance. The data indicate that although coronary blood flow capacity and capillary transport capacity may be improved in exercise-trained dog hearts, these changes are not the result of an increase in myocardial capillarity. Rather, the increased maximal PS appears to be due to changes in the determinants of capillary blood flow and/or the relationship between capillary area available for exchange and capillary perfusion.     

An improved isolated working rabbit heart preparation using red cell enhanced perfusate

The performance of isolated working rabbit hearts perfused with Krebs-Henseleit (KH) buffer was compared with those in which the buffer was supplemented with washed human red blood cells (KH + RBC) at a hematocrit of 15 percent. When perfused with KH alone at 70 cm H2O afterload and paced at 240 beats/minute, coronary flow was more than double, whereas aortic flow was 40-60 percent of that in hearts perfused with KH + RBC, regardless of left atrial filling pressures (LAFP). Peak systolic pressure reached a plateau at 120 mm Hg in KH + RBC, but at 95 mm Hg in the KH group. Stroke work, however, was similar in the two groups. Despite the high coronary flow, oxygen uptake by hearts perfused with KH was substantially less and did not respond to increases in LAFP as in those perfused with KH + RBC. There was a 20 percent drop in ATP and glycogen content after 90 minutes' perfusion. In contrast, isolated hearts perfused with RBC-enriched buffer remained stable for at least 150 minutes. Irrespective of the perfusate, triacylglycerol content of the muscle remained at similar levels throughout the course of study. Increasing RBC in the perfusate from 15 percent to 25 percent had no additional effect on cardiac performance or oxygen consumption. Our findings demonstrate that in the isolated working rabbit heart inclusion of RBC in the perfusate improves mechanical and metabolic stability by providing an adequate oxygen supply.     

Restoration of impaired endothelium-dependent coronary vasodilation in failing heart: role of eNOS phosphorylation and CGMP/cGK-I signaling

In congestive heart failure (CHF), coronary vascular relaxation is associated with endothelial dysfunction and nitric oxide (NO) deficiency. This study explored the reversibility of this process in hearts recovering from CHF and its related mechanisms. Dogs were chronically instrumented to measure cardiac function and coronary blood flow (CBF). Heart failure was induced by right ventricular pacing at 240 beats/min for 3-4 wk, and cardiac recovery (CR) was allowed by the termination of cardiac pacing for 3-4 wk after the development of CHF, in which left ventricular contractile function was restored by 80-90%. The endothelium-dependent CBF response to bradykinin and acetylcholine was depressed in CHF and fully restored in CR. Myocardial NOx (nitrate/nitrite), endothelial NO synthase (eNOS) mRNA expression, total protein, and phosphorylated eNOS decreased significantly in failing hearts. However, myocardial NOx recovered to 78% of control and phosphorylated eNOS was fully restored in CR, despite the fact that eNOS mRNA expression and protein levels remained lower than control. Furthermore, the endothelium-independent CBF response to nitroglycerin did not change in CHF; however, it increased by 75% in CR, in conjunction with a near threefold increase in the phosphorylation of vasodilation-stimulated phosphoprotein (VASP) at Ser(239) in recovering hearts. Thus the complete restoration of endothelium-dependent coronary vascular relaxation during cardiac recovery from CHF was mediated by 1) a restoration of phosphorylated eNOS for partial recovery of the NO production and 2) an increase in cGMP/cGMP-dependent protein kinase-I pathway signaling activity for the enhancement of coronary vascular smooth muscle relaxation in response to NO.     

迷走神经与乙酰胆碱对缩窄的犬冠状动脉节段阻力的影响

在麻醉开胸犬,用电起搏维持心率恒定,研究了电刺激颈迷走神经(VNS)及冠状动脉内注入乙酰胆碱(ACh)对缩窄的冠状动脉的节段阻力及血流量的影响。在左旋支主干造成不同程度的冠状动脉缩窄。分别测定左旋支血流量(CBF_(cx))、主动脉压和主旋支远端冠状动脉压,记录心电图。实验发现,在冠状动脉临界狭窄和重度狭窄时,VNS 或冠脉给ACh 引起心外膜大冠状动脉阻力及冠状动脉主旋支总阻力增大,CBF_(cx)减少;随着缩窄程度加重,这些改变也愈明显,然而,心肌内小冠状动脉阻力却无显著改变。     

Effects of insulin on the metabolism of the isolated working rat heart perfused with undiluted rat blood

Working rat hearts were perfused with either buffer or with defibrinated, undiluted rat blood dialyzed to remove vasoconstrictor factors. With precautions taken for sterility in the preparation of the perfusate and the apparatus, hearts were obtained which were stable as judged by stroke rate and cardiac output. In these hearts, cardiac output and coronary flow averaged 46.0 and 1.7 ml/g heart per min, respectively. Perfusion with erythrocyte-free buffer depressed cardiac output by 30%, while coronary flow averaged 8.8 ml/g of heart per min. The mean stroke rate of blood-perfused hearts was 300 beats/min but only 240 beats/min during buffer perfusion. In blood-perfused hearts, insulin did not alter stroke rate but significantly lowered coronary flow. The hormone caused a transient increase in cardiac output in hearts perfused with buffer. Insulin did not alter glucose uptake in buffer-perfused hearts but increased lactate release in perfusions with blood. Both serum fatty acids and triacylglycerol fatty acids were significant metabolic fuels in hearts perfused with undiluted blood. The preparation described would appear to be potentially useful for the study of myocardial metabolism in vitro.     

Advanced Heart Block During Acute Myocardial Infarction Treated with an Electrode Pacing Catheter

The mortality rate is high from advanced atrioventricular block associated with acute myocardial infarction. There is reason to believe that if in these patients the hearts are electrically paced with an endocardial pacing catheter, the mortality rate can be considerably decreased. Five patients in second- and third-degree heart block associated with acute myocardial infarction were paced with a considerable lowering of the expected mortality rate. Twenty-three cases from the literature are also presented and discussed. A silastic bipolar electrode catheter was used in these five cases. Four of the five cases returned to normal sinus rhythm within the first 10 days. The average duration of pacing was 6.7 days. It is the opinion of the author that second- and third-degree heart block associated with acute myocardial infarction should have a pacing catheter introduced at the earliest possible moment for continuous or demand endocardial pacing.     

Regional myocardial perfusion under exchange transfusion with liposomal hemoglobin: in vivo and in vitro studies using rat hearts

The purpose of this study was to test the hypothesis that exchange transfusion with liposomal hemoglobin (LH) reduces the microheterogeneity of regional myocardial flows while sustaining cardiac function. Neo Red Cell mixed with albumin was used as the LH solution, in which the LH volume fraction was 17 approximately 18% and hemoglobin density was nearly two-thirds smaller than in rat blood. Regional myocardial flows in left ventricular free walls were measured by tracer digitalradiography (100-mum resolution) in anesthetized rats with or without 50% blood-LH exchange transfusion. Within-layer flow distributions showed lower heterogeneity with (n = 8) than without (n = 8) LH transfusion. No extravasation of hemoglobin was confirmed by 3,3-diaminobenzidin staining (n = 2). Carotid flow increased by 68% due to LH transfusion, whereas arterial pressure and heart rate remained unchanged. On the other hand, cross-circulated rat hearts (n = 7) were used to evaluate the effects of 50% blood-LH exchange on coronary flow and tone preservation under 300-beats/min pacing and 100-mmHg perfusion pressure. Blood-LH exchange caused a 71% increase of coronary flow and 10% decrease of percent flow increase during hyperemia after 30-s flow interruption. Myocardial O(2) supply and consumption increased by 9% and 10%, respectively, whereas myocardial O(2) extraction remained unchanged. The large increases of in vivo carotid flow and coronary flow in cross-circulated hearts due to LH coperfusion could be explained by the reduction of apparent flow viscosity. These results suggest that under LH coperfusion, the microheterogeneity of myocardial flows decreases with increased coronary flow while fairly preserving coronary tone and cardiac function.     

Loss of cardiac contractility and severe morphologic changes by acutely lowering the pH of the perfusion medium: protection by fatty acids

When the pH of the perfusion medium of rat Langendorff heart, paced at a rate of 300 beats/min, is abruptly lowered from pH 7.5 to 7.0, the hearts stop beating within 6 min in more than half of the cases. Reperfusion with pH 7.5 medium after 10 min pH 7.0 perfusion does not cause contractility to resume within 5 min. The causative factor is intracellular acidosis, resulting in severe morphological alterations of plasma membrane and mitochondria. It is probably initiated by the loss of membrane-bound calcium. Oleate, complexed with albumin included in the perfusion media, protects the hearts. This may be explained by maintenance of capillary flow and limitation of cellular acidosis.     

The coronary circulation in exercise training

Exercise training (EX) induces increases in coronary transport capacity through adaptations in the coronary microcirculation including increased arteriolar diameters and/or densities and changes in the vasomotor reactivity of coronary resistance arteries. In large animals, EX increases capillary exchange capacity through angiogenesis of new capillaries at a rate matched to EX-induced cardiac hypertrophy so that capillary density remains normal. However, after EX coronary capillary exchange area is greater (i.e., capillary permeability surface area product is greater) at any given blood flow because of altered coronary vascular resistance and matching of exchange surface area and blood flow distribution. The improved coronary capillary blood flow distribution appears to be the result of structural changes in the coronary tree and alterations in vasoreactivity of coronary resistance arteries. EX also alters vasomotor reactivity of conduit coronary arteries in that after EX, α-adrenergic receptor responsiveness is blunted. Of interest, α- and β-adrenergic tone appears to be maintained in the coronary microcirculation in the presence of lower circulating catecholamine levels because of increased receptor responsiveness to adrenergic stimulation. EX also alters other vasomotor control processes of coronary resistance vessels. For example, coronary arterioles exhibit increased myogenic tone after EX, likely because of a calcium-dependent PKC signaling-mediated alteration in voltage-gated calcium channel activity in response to stretch. Conversely, EX augments endothelium-dependent vasodilation throughout the coronary arteriolar network and in the conduit arteries in coronary artery disease (CAD). The enhanced endothelium-dependent dilation appears to result from increased nitric oxide bioavailability because of changes in nitric oxide synthase expression/activity and decreased oxidant stress. EX also decreases extravascular compressive forces in the myocardium at rest and at comparable levels of exercise, mainly because of decreases in heart rate and duration of systole. EX does not stimulate growth of coronary collateral vessels in the normal heart. However, if exercise produces ischemia, which would be absent or minimal under resting conditions, there is evidence that collateral growth can be enhanced. While there is evidence that EX can decrease the progression of atherosclerotic lesions or even induce the regression of atherosclerotic lesions in humans, the evidence of this is not strong due to the fact that most prospective trials conducted to date have included other lifestyle changes and treatment strategies by necessity. The literature from large animal models of CAD also presents a cloudy picture concerning whether EX can induce the regression of or slow the progression of atherosclerotic lesions. Thus, while evidence from research using humans with CAD and animal models of CAD indicates that EX increases endothelium-dependent dilation throughout the coronary vascular tree, evidence that EX reverses or slows the progression of lesion development in CAD is not conclusive at this time. This suggests that the beneficial effects of EX in CAD may not be the result of direct effects on the coronary artery wall. If this suggestion is true, it is important to determine the mechanisms involved in these beneficial effects.     

Effects of spinal cord stimulation in angina pectoris induced by pacing and possible mechanisms of action.

OBJECTIVE--To investigate the effects of spinal cord stimulation on myocardial ischaemia, coronary blood flow, and myocardial oxygen consumption in angina pectoris induced by atrial pacing. DESIGN--The heart was paced to angina during a control phase and treatment with spinal cord stimulation. Blood samples were drawn from a peripheral artery and the coronary sinus. SETTING--Multidisciplinary pain centre, department of medicine, Ostra Hospital, and Wallenberg Research Laboratory, Sahlgrenska Hospital, Gothenburg, Sweden. SUBJECTS--Twenty patients with intractable angina pectoris, all with a spinal cord stimulator implanted before the study. RESULTS--Spinal cord stimulation increased patients'' tolerance to pacing (p < 0.001). At the pacing rate comparable to that producing angina during the control recording, myocardial lactate production during control session turned into extraction (p = 0.003) and, on the electrocardiogram, ST segment depression decreased, time to ST depression increased, and time to recovery from ST depression decreased (p = 0.01; p < 0.05, and p < 0.05, respectively). Spinal cord stimulation also reduced coronary sinus blood flow (p = 0.01) and myocardial oxygen consumption (p = 0.02). At the maximum pacing rate during treatment, all patients experienced anginal pain. Myocardial lactate extraction reverted to production (p < 0.01) and the magnitude and duration of ST segment depression increased to the same values as during control pacing, indicating that myocardial ischaemia during treatment with spinal cord stimulation gives rise to anginal pain. CONCLUSIONS--Spinal cord stimulation has an anti-anginal and anti-ischaemic effect in severe coronary artery disease. These effects seem to be secondary to a decrease in myocardial oxygen consumption. Furthermore, myocardial ischemia during treatment gives rise to anginal pain. Thus, spinal cord stimulation does not deprive the patient of a warning signal.     

降钙素基因相关肽在豚鼠冠脉血流量和心脏传导系统作用的比较

本文目的在于深入研究降钙素基因相关肽（ＣＧＲＰ）对豚鼠冠状血流量以及心脏传导系统各部分的作用。采用Ｌａｎｇｅｎｄｏｒｆｆ法灌流心脏,同步记录心脏表面电图和希氏束电活动。观察应用ＣＧＲＰ前后的冠脉流量、自主心率、在相同心房周期下的房室结（ＡＨ）及希浦系传导时间（ＨＶ）、心脏出现３：２文氏传导及２：１房室传导阻滞所需的最长起搏周期（ＰＣＬ３：２,ＰＣＬ２：１）。ＣＧＲＰ（３－３０ｎｍｏｌ／Ｌ）可显著增     

Myocardial biochemical and hemodynamic adaptations to chronic tachycardia.

The purpose was to determine the biochemical and hemodynamic adaptations of the myocardium to chronic tachycardia. Cardiac pacemakers were implanted in Yorkshire pigs and set at a rate of 180 beats/min for a period of 35-42 days. Animals were then anesthetized with pentobarbital sodium. Myocardial blood flow and hemodynamics were determined at three different heart rates (i.e., 120, 180, and 220 beats/min). Tissue samples were then taken for microsphere and biochemical analyses. Chronically paced hearts maintained better cardiac function and had consistently higher left ventricular blood flow with a higher endocardial-to-epicardial ratio. The activities of citrate synthase and 3-hydroxyacyl-CoA dehydrogenase were 23 and 45% greater in the paced hearts, respectively. The sarcoplasmic reticulum adenosinetriphosphatase activity was 55% greater in the paced hearts, whereas the myosin adenosinetriphosphatase was the same as in the control hearts. Polyacrylamide gels of the ventricular myosin isoforms showed only the V3 type to be present in both the control and paced hearts. These findings show that the heart of a large mammal adapts to chronic tachycardia (i.e., 180 beats/min) by elevating the aerobic and calcium-sequestering capacities without altering its myosin type.     

Decreased connexin43 expression in the mouse heart potentiates pacing-induced remodeling of repolarizing currents

Gap junction redistribution and reduced expression, a phenomenon termed gap junction remodeling (GJR), is often seen in diseased hearts and may predispose toward arrhythmias. We have recently shown that short-term pacing in the mouse is associated with changes in connexin43 (Cx43) expression and localization but not with increased inducibility into sustained arrhythmias. We hypothesized that short-term pacing, if imposed on murine hearts with decreased Cx43 abundance, could serve as a model for evaluating the electrophysiological effects of GJR. We paced wild-type (normal Cx43 abundance) and heterozygous Cx43 knockout (Cx43+/-; 66% mean reduction in Cx43) mice for 6 h at 10-15% above their average sinus rate. We investigated the electrophysiological effects of pacing on the whole animal using programmed electrical stimulation and in isolated ventricular myocytes with patch-clamp studies. Cx43+/- myocytes had significantly shorter action potential durations (APD) and increased steady-state (Iss) and inward rectifier (I(K1)) potassium currents compared with those of wild-type littermate cells. In Cx43+/- hearts, pacing resulted in a significant prolongation of ventricular effective refractory period and APD and significant diminution of Iss compared with unpaced Cx43+/- hearts. However, these changes were not seen in paced wild-type mice. These data suggest that Cx43 abundance plays a critical role in regulating currents involved in myocardial repolarization and their response to pacing. Our study may aid in understanding how dyssynchronous activation of diseased, Cx43-deficient myocardial tissue can lead to electrophysiological changes, which may contribute to the worsened prognosis often associated with pacing in the failing heart.     

Hemodynamic action of calcitonin gene-related peptide in the isolated rat heart

The effects of calcitonin gene-related peptide (CGRP) on heart rate, coronary flow, pressure development, and time to ischemic contracture were studied in the isolated, perfused rat heart. A bolus of CGRP (2640 pmols) caused significant increases in heart rate and coronary flow; these effects were sustained for at least five minutes after injection. The increase in coronary flow was independent of heart rate, since CGRP caused an increase in coronary flow in non-beating (potassium-arrested) hearts. The dose-response of CGRP was studied using five doses (65, 218, 658, 1320 and 2640 pmols) given as bolus injections. Although the increase in heart rate was apparently dose-dependent, significant increases above baseline were observed only with the two highest doses. In contrast, coronary flow increased significantly above baseline with the injection of all but the lowest dose of CGRP. Ten minutes after injection of CGRP, all hearts were made ischemic. The time to onset of ischemic contracture was approximately 11 minutes for those hearts that received 65 pmols of CGRP; however, for those hearts receiving all other doses of CGRP, the time to onset of contracture was approximately 8 minutes. We conclude that CGRP significantly decreases the resistance of the coronary vascular bed, and that it may be an important regulator of regional blood flow in the heart.     

Biochemical consequences of electrical pacing in ischemic-reperfused isolated rat hearts

It is still unclear if performance recovery in postischemic hearts is related to their tissue level of high-energy phosphates before reflow. To test the existence of this link, we monitored performance, metabolism and histological damage in isolated, crystalloid-perfused rat hearts during 20 min of low-flow ischemia (90% coronary flow reduction) and reflow. To prevent interference from different ischemia times and perfusing media compositions, the ischemic ATP level was varied by changing energy demand (electrical pacing at 330 min–1). Under full coronary flow conditions, work output, as well as ATP and phosphocreatine contents were the same in control, spontaneously contracting (n = 23) and paced (n = 21) hearts. During low-flow ischemia, the higher work output (p < 0.0001) in paced hearts decreased their tissue content of ATP, phosphocreatine and total adenylates and purines (p < 0.05), as opposed to maintained values in control hearts. During reflow, the recovery of mechanical performance and O2 uptake was 94 ± 5% and 110 ± 9% (p = NS vs. baseline) in controls, vs. 71 ± 5% and 74 ± 6% in paced hearts (p < 0.004 vs. baseline). The levels of ATP and total adenylates and purines remained constant in control, but were markedly depressed (p < 0.05 vs. baseline) in paced hearts. Phosphocreatine+creatine was the same in both groups. These data, together with the observed lack of creatine kinase leakage and of structural damage, indicate that myocardial recovery during reflow reflects the tissue level of ATP, phosphocreatine and total adenylates and purines during ischemia, regardless of physical cell damage.