Venous reflux and venous distensibility in varicose and healthy veins.

OBJECTIVES: The aim of this study was to analyse venous diameter changes and venous reflux parameters, assessed during a standardised Valsalva manoeuvre in healthy subjects and in patients with varicose veins. METHODS: Measurements were carried out in 444 vein segments, (96 legs of 48 healthy volunteers, 52 legs of 35 patients with varicose veins). The common femoral vein (CVF), the femoral vein (FV) and the great saphenous vein (GSV) were investigated. The parameters of reflux and the relative venous diameter change (VD diff %) were measured simultaneously during a standardised Valsalva manoeuvre. RESULTS: Venous diameter changes during Valsalva manoeuvre (VD diff) were significantly greater in the GSV and in the deep veins of varicose patients compared to healthy subjects. The median (Interquartile range) of VD max in the CFV was: 13.1 (3.5) mm and 11.2 (3.4) mm (p=0.0002, Mann-Whitney - U test), in the FV 7.8 (2.7) mm and 6.9 (2.0) mm (p=0.01, Mann-Whitney), in the GSV: 7.3 (3.7) mm and 4.2 (1.1) mm (p<0.0001, Mann-Whitney) for the varicose and healthy veins respectively. Good correlation was seen for the retrograde peak reflux velocity (PRV) and VD diff % in varicose veins (r=0.71 (0.57 - 0.81) p<0.0001, Mann-Whitney). CONCLUSION: Relative venous diameter--changes during a standardised Valsalva manoeuvre are significantly larger in the deep and superficial veins of varicose vein patients compared with healthy veins, the increased distensibility correlates with venous reflux parameters in varicose vein patients.

[Pharmacological basis of antihypertensive drug therapy]. / Pharmakologische Grundlagen der medikamentösen antihypertensiven Therapie.

In order to lower arterial blood pressure, antihypertensive drugs decrease cardiac output, total peripheral resistance or both. Diuretics, beta-blockers, and central adrenergic inhibitors decrease cardiac output. ACE inhibitors, angiotensin II antagonists, calcium antagonists, alpha-blockers, central adrenergic inhibitors, and after a delay also diuretics and beta-blockers decrease peripheral resistance. Diuretics are first line therapy for treating low renin hypertension. Beta blockers are used for treating high renin hypertension and patients suffering additional coronary artery disease. ACE inihibitors can be given for treating high renin hypertension particularly in conjunction with diabetes, heart failure or left ventricular hypertrophy. Combining ACE inhibitors with diuretics potentiates the antihypertensive effect. Angiotensin II antagonists exert fewer side effects and better renal protection than ACE inhibitors. The main indication for calcium antagonists is low renin hypertension, their advantages being strong blood pressure reduction as well as in preventing stroke. Central alpha2 receptor agonists and other vasodilators are chosen only in selected cases and mostly in combination with other antihypertensive drugs.

Myocardial function and energy metabolism in carnitine-deficient rats.

Carnitine is essential for mitochondrial metabolism of long-chain fatty acids and thus for myocardial energy production. Accordingly, carnitine deficiency can be associated with cardiomyopathy. To better understand this disease, we determined myocardial function and energy metabolism in a rat model of carnitine deficiency. Carnitine deficiency was induced by a 3- or 6-week diet containing N-trimethyl-hydrazine-3-propionate, reducing cardiac and plasma carnitine by 70-85%. Myocardial function was investigated in isolated isovolumic heart preparations. Carnitine-deficient hearts showed left ventricular systolic dysfunction, reduced contractile reserve, and a blunted frequency-force relationship independently of the substrate used (glucose or palmitate). After glycogen depletion, palmitate could not sustain myocardial function. Histology and activities of carnitine palmitoyl transferase, citrate synthase, and cytochrome c oxidase were unaltered. Thus, as little as 3-6 weeks of systemic carnitine deficiency can lead to abnormalities in myocardial function. These abnormalities are masked by endogenous glycogen and are not accompanied by structural alterations of the myocardium or by altered activities of important mitochondrial enzymes.

[Common biostatistical errors in clinical studies]. / Häufige Fehler in der Biostatistik medizinischer Studien.

Roughly half to two third of all published biomedical studies that use statistical methods contain unacceptable errors. The present article points at common errors that may be avoided without requiring profound statistical knowledge. These errors mainly concern the minimal number of patients and sample size (statistical power), agreement between aim and conclusion, distribution of data as well as description of location and variability of data. An analysis of 150 papers in the New England Journal of Medicine and in Circulation demonstrates that these errors can also commonly be found in respected journals after statistical peer review. Editors of biomedical journals could reduce the problem by means of statistical guidelines.

[Circadian rhythm of cardiovascular emergencies]. / Zirkadiane Rhythmen bei kardiovaskulären Notfällen.

Many cardiovascular emergencies occur predominantly in the morning hours. This diurnal distribution is due to synchronized exogenous and endogenous rhythms, the latter being controlled by a biological clock. In the morning, these rhythms raise blood pressure, heart rate, platelet aggregability, coronary vascular tone and thus, increase the risk of cardiovascular events.

When calcium turns arrhythmogenic: intracellular calcium handling during the development of hypertrophy and heart failure.

Alterations of intracellular Ca2+ handling in hypertrophied myocardium have been proposed as a mechanism of ventricular tachyarrhythmias, which are a major cause of sudden death in patients with heart failure. In this review, alterations in intracellular Ca2+ handling and Ca2+ handling proteins in the development of myocardial hypertrophy and the transition to heart failure are discussed. The leading question is at what stage of hypertrophy or heart failure Ca2+ handling can turn arrhythmogenic. During the development of myocardial hypertrophy and the transition to failure, Ca2+ handling is progressively altered. Recordings of free myocyte Ca2+ concentrations during a cardiac cycle (Ca2+ transients) are prolonged early in the development of hypertrophy. However, resting (or diastolic) Ca2+ does not increase before end-stage heart failure has developed. These alterations are due to progressively defective Ca2+ uptake into the sarcoplasmic reticulum that seems to be caused by quantitative changes of gene expression of the Ca2+ ATPase of the sarcoplasmic reticulum. Increased expression and activity of the Na+/Ca2+ exchanger might compensate for this defective Ca2+ uptake, probably at the expense of increased arrhythmogenicity. When the Ca2+ handling proteins no longer efficiently counterbalance increasing intracellular Ca2+ - during stress conditions, resulting Ca2+ overload can lead to spontaneous intracellular Ca2+ oscillations, after depolarizations. Thus, after the transition to heart failure, Ca2+ overloaded sarcoplasmic reticulum, increasing resting intracellular Ca2+, and increased Na+/Ca2+ activity may all provoke afterdepolarizations, triggered activity, and finally, life-threatening ventricular arrhythmias. This increased susceptibility to ventricular arrhythmias in heart failure should not be treated with calcium antagonists.

Combined blockade of endothelin-1 and thromboxane A(2) receptors against postischaemic contractile dysfunction in rat hearts.

1. Endothelin-1 (ET-1) may play a role in myocardial ischaemia/reperfusion injury because both the release and vasoconstrictor effect of ET-1 are increased after ischaemia. Since the increased vasoconstrictor effect of ET-1 can be mediated by ET-1-induced release of thromboxane A(2) (TXA(2)), the aim of this study was to test whether combined blockade of ET and TXA(2) receptors protects the coronary flow, contractile performance, and cardiac energy metabolism during ischaemia and reperfusion. 2. Bosentan (antagonist for ET(A) and ET(B) receptors, 1 microM based on concentration-response curves of ET-1), SQ 30,741 (antagonist of TXA(2) receptors, 0.1 microM), or the combination thereof was administered to isolated perfused rat hearts undergoing 15 min of global ischaemia and 60 min of reperfusion. 3. Neither bosentan or SQ 30,741 alone, nor the combination thereof, improved the incomplete postischaemic recovery of coronary flow, left ventricular developed pressure, phosphocreatine, or ATP. However, they attenuated ischaemia-induced acidosis but this did not translate into a measurable effect on haemodynamic or metabolic variables. 4. Thus, combined blockade of ET and TXA(2) receptors does not protect the coronary flow, contractile performance, and cardiac energy metabolism during ischaemia and reperfusion in isolated perfused rat hearts. This finding suggests that neither ET-1 nor ET-1-induced release of TXA(2) play a major role in the postischaemic recovery of the cardiac contractile function and energy metabolism.

Accuracy of biplane analysis of left ventricular ejection fraction based on two consecutive single plane studies.

BACKGROUND AND PURPOSE: Mainly due to the high costs of biplane equipment many cardiac laboratories run single plane angiographic equipment only. Consequently, a biplane ventriculogram may only be done with two consecutive single plane studies. The aim of this investigation was to assess the accuracy of a biplane analysis of two consecutive single plane studies. METHODS: A total of 42 patients (62 +/- 10 years, 76% males), able to tolerate two consecutive ventriculograms without arrhythmia during the first study underwent two consecutive biplane studies (LAO 60, RA0 30), using 40 ml of contrast each. After the first injection, the x-ray tube was moved in a neutral position, and then was replaced in the 30 RAO/60 LAO position. Digital data was analyzed by two separate investigators using commercially available software. RESULTS: Intra-observer variability of left ventricular ejection fraction (LVEF) showed a high degree of agreement (single plane 1 vs. 2: r = 0.98; standard error of regression (Sy.x.): 2.8); the variability was slightly higher with two investigators (single plane: r = 0.92, Sy.x: 5.5 ) and with biplane analysis (biplane 1 vs. 2: r = 0.90, Sy. x: 5.7). End-diastolic volume index (EDVI) increased significantly from the first to the second study (84 +/- 28 ml/m2 vs 87 +/- 30 ml/m2; p = 0.017): Still LVEF of the two consecutive biplane studies showed very good agreement (biplane 1 vs. 2: mean difference (MD), -1.0; standard deviation of the difference (SDD), 5.2%). This agreement was almost as good as the one of LVEF values calculated from two consecutive single plane, but biplane analyzed studies compared to simultaneous biplane studies (MD, -0.5; SDD, 4.3%). CONCLUSION: Despite the significant increase in EDVI after contrast injection, LVEF values determined from two consecutive studies remained virtually unchanged. Biplane analysis of LVEF values based on consecutive single plane studies resulted in similar and reliable values as determined by two consecutive biplane studies.

Bradykinin-dependent cardioprotective effects of losartan against ischemia and reperfusion in rat hearts.

It is unclear whether losartan, an angiotensin II type 1 (AT1) receptor antagonist, protects the heart against acute ischemia-reperfusion injury. Therefore we evaluated cardiac protection conferred by pre- and postischemic treatment as well as by exclusive postischemic treatment with losartan. Furthermore, we sought to determine both the extent of this protection and its dependence on bradykinin in comparison with quinaprilat, a cardioprotective angiotensin-converting enzyme inhibitor. Cardiac protection was assessed as recovery of coronary flow, left ventricular developed pressure, phosphocreatine, and adenosine triphosphate (ATP) in isolated perfused rat hearts after 15 min of global ischemia and 30 min of postischemic reperfusion. We found that, in hearts pre- and postischemically treated with losartan (1 microM) or quinaprilat (0.1 microM), these variables all recovered significantly better than those in untreated control hearts. In hearts that were only postischemically treated with losartan, these variables also recovered significantly better than those in control hearts. In contrast, in hearts treated with the combination of the bradykinin B2 receptor antagonist Hoe 140 with quinaprilat or losartan, the recovery of the variables no longer differed from that in control hearts. In conclusion, losartan protects the heart against acute ischemia-reperfusion injury. This protection can be achieved by pre- and postischemic treatment as well as by exclusive postischemic treatment with losartan. Furthermore, the extent of this protection is equivalent to that conferred by quinaprilat and, unexpectedly, dependent on bradykinin.

Ventricular fibrillation-induced intracellular Ca2+ overload causes failed electrical defibrillation and post-shock reinitiation of fibrillation.

Despite high efficacy, electrical defibrillation shocks can fail or ventricular fibrillation (VF) is reinitiated after the application of the initial shock. The goal of this study was to determine whether [Ca2+]i overload, induced by VF itself, can cause failed electrical defibrillation and post-shock reinitiation of VF. For this purpose, we simultaneously measured [Ca2+]i transients (assessed by indo-1 fluorescence) and defibrillation energies (assessed by a modified implantable cardioverter defibrillator) in intact perfused rat hearts during pacing-induced sustained VF (10 min) in the absence of ischemia. We found that increasing [Ca2+]i during VF (by increasing [Ca2+]o from 3 to 6 mM) increased the defibrillation threshold (DFT) from 1.9 +/- 0.6 to 3.5 +/- 0.5 J/g (P<0.05) and also increased the total defibrillation energy (TDE) required for stabilization of sinus rhythm from 15.6 +/- 7.7 to 48.6 +/- 7.42 J/g (P<0.05). In addition, both DFT and TDE correlated linearly with [Ca2+]i (r=0.69 and 0.83, P<0.05). Furthermore, shortening the duration of VF from 10 to 1.5 min tended to limit [Ca2+]i overload and decreased TDE. Finally, all successful defibrillation shocks led to a sudden reduction of VF-induced [Ca2+]i overload (-115 +/- 3%). In contrast, failed shocks did not alter [Ca2+]i. Incomplete reduction of [Ca2+]i overload after initially successful shocks were often followed by synchronized spontaneous [Ca2+]i oscillations and subsequent reinitiation of VF. In conclusion, the present study showed for the first time that VF-induced [Ca2+]i overload can cause failed electrical defibrillation and post-shock reinitiation of VF. Because VF inevitably causes [Ca2+]i overload, this finding might be a crucial mechanism of failed defibrillation and spontaneous reinitiation of VF.

Intracellular Ca2+ handling and vulnerability to ventricular fibrillation in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) with ventricular hypertrophy show an increased vulnerability for the development of potentially lethal ventricular arrhythmias such as ventricular fibrillation (VF). The mechanisms of this increased vulnerability are not fully understood but may be related to abnormal intracellular Ca2+ ([Ca2+]i) handling under stress conditions. We therefore investigated whether [Ca2+]i handling is abnormal in hypertrophied hearts of SHR without heart failure during stimulation stress, and if so whether abnormal [Ca2+]i handling is a determinant of the increased vulnerability to VF in SHR. [Ca2+]i was measured by indo-1 surface fluorescence in perfused hearts of 8- to 10-month-old control Wistar-Kyoto rats (WKY) and age-matched SHR. The state of [Ca2+]i handling was analyzed during three different forms of stimulation stress: rapid pacing, the long rest period after cessation of rapid pacing, and preprogrammed ventricular stimulation that was simultaneously used for the determination of VF threshold. The pulse number VF threshold was used as an index to determine vulnerability to VF and to analyze the relationship of [Ca2+]i handling to vulnerability. Although VF thresholds were lower in SHR than in WKY, we found that both demonstrated similar [Ca2+]i handling during stimulation stress. The extent and rate of [Ca2+]i accumulation during rapid pacing and those of the [Ca2+]i decline after cessation of pacing were similar in SHR and WKY. In addition, the relationship between [Ca2+]i and VF threshold was unaltered in SHR. Thus, we conclude that [Ca2+]i handling is normal in hypertrophied hearts of SHR without heart failure during stimulation stress and that it is not a determinant of the increased vulnerability to VF in SHR.

Endothelin-1-induced release of thromboxane A2 increases the vasoconstrictor effect of endothelin-1 in postischemic reperfused rat hearts.

BACKGROUND: The release and vasoconstrictor effect of endothelin-1 (ET-1) are increased after myocardial ischemia, suggesting a role for ET-1 in ischemia/reperfusion injury. However, the mechanisms of the increased vasoconstriction by ET-1 are unknown. The aim of this study was to test whether ET-1-induced release of thromboxane A2 (TXA2) contributes to the vasoconstrictor effect of ET-1 in nonischemic hearts and whether such release can increase the vasoconstrictor effect of ET-1 in postischemic reperfused hearts. METHODS AND RESULTS: ET-1-induced release of TXA2 was assessed by measurement of the concentrations of its stable metabolite thromboxane B2 (TXB2) in the coronary effluent of nonischemic and reperfused isolated rat hearts before and after administration of 0.01 nmol ET-1 using an enzyme immunoassay. The contribution of ET-1-induced release of TXA2 to the vasoconstrictor effect of ET-1 was assessed by measurement of the effects of ET-1 with and without the cyclooxygenase inhibitor indomethacin or the TXA2/endoperoxide receptor antagonist SQ 30,741 using 31P magnetic resonance spectroscopy. In nonischemic hearts, ET-1 led to a small increase in TXB2 in the coronary effluent (3.9 +/- 1.5 pg/mL; n = 3), but neither indomethacin nor SQ 30,741 significantly diminished the vasoconstrictor effects of ET-1 (reduction of coronary flow, 4.0 +/- 0.4 and 4.5 +/- 0.3 mL/min, respectively, versus 4.9 +/- 0.5 mL/min for ET-1 alone; n = 8, 6, and 9, respectively). In postischemic reperfused hearts, however, ET-1 led to a greater increase in TXB2 (13.7 +/- 1.5 pg/mL; P < .05 versus nonischemic hearts; n = 3), and both indomethacin and SQ 30,741 diminished the vasoconstrictor effects of ET-1 (reduction of coronary flow, 2.6 +/- 0.3 and 2.2 +/- 0.3 mL/min, respectively, versus 4.0 +/- 0.1 mL/min for ET-1 alone; n = 8, 8, and 6, respectively; P < .05). Furthermore, indomethacin and SQ 30,741 prevented the detrimental effects of ET-1 on left ventricular developed pressure, intracellular pH, and phosphocreatine during reperfusion. CONCLUSIONS: ET-1-induced release of TXA2 does not significantly contribute to the vasoconstrictor effect of ET-1 in nonischemic hearts but can increase the vasoconstrictor effect of ET-1 in postischemic reperfused hearts.

Rapid adaptation of myocardial calcium homeostasis to short episodes of ischemia in isolated rat hearts.

Short episodes of ischemia and reperfusion (ischemic preconditioning) have been shown to attenuate the detrimental rise in intracellular free Ca2+ ([Ca2+]i) caused by subsequent sustained ischemia. The purpose of this study was to investigate the detailed time course of [Ca2+]i during such short episodes of ischemia and reperfusion. [Ca2+]i was measured at a high time resolution by surface fluorometry and indo-1 in isolated perfused rat hearts during three episodes of 5 minutes of ischemia followed by 5 minutes of reperfusion. We found that the rise in systolic [Ca2+]i was significantly smaller during the second (191% +/- 67%) and third (194% +/- 75%) episodes of ischemia than during the first episode (289% +/- 75%, P < 0.05 vs both subsequent episodes). This attenuated rise in systolic [Ca2+]i was preserved during perfusion with low extracellular Na+ (105.5 mmol/L [Na+]o). During short episodes of ischemia and reperfusion, [Ca2+]i rises less during the second and third ischemic episode than during the first episode. Thus one transient ischemic stimulus led to a rapid adaptation of [Ca2+]i homeostasis to subsequent ischemic conditions. Such a rapid adaptation might be an important mechanism of the ischemic preconditioning phenomenon in protecting against ischemic injury.

Importance of calcium for the vulnerability to ventricular fibrillation detected by premature ventricular stimulation: single pulse versus sequential pulse methods.

Vulnerability to ventricular fibrillation (VF) is frequently evaluated by VF threshold, a variable which may not be free of confounding factors and which may not be sensitive to all factors contributing to vulnerability. Therefore, we tested whether VF threshold determination affects intracellular free Ca2+ ([Ca2+]i) and whether VF thresholds are sensitive to changes in [Ca2+]i. For this purpose, we analysed [Ca2+]i by surface fluorometry and indo-1 in intact perfused rat hearts undergoing VF threshold determination by a single pulse method and tested whether such thresholds are lowered by increased [Ca2+]i. Additionally, we sought to determine the importance of Ca2+ for the vulnerability to VF under nonischemic conditions. For this purpose, we measured VF thresholds by a new pulse number method which scanned the vulnerable period by an increasing number of sequential pulses at increasing prematurity but constant intensity. We found that VF threshold determination by a single pulse method led to a rise in systolic [Ca2+]i. However, this rise does not perturb VF threshold interpretation because such thresholds were insensitive to changes in [Ca2+]i. Nevertheless, [Ca2+]i is of importance for the vulnerability to VF under nonischemic conditions because the number of VF-free tolerated premature pulses was dependent on [Ca2+]i. This relationship may only be detectable if evaluated by sequential pulse methods. These findings suggest that the method of VF threshold determination may be crucial for the result of studies testing Ca2+ antagonists or situations of altered [Ca2+]i and could explain controversial results of VF threshold studies testing Ca2+ antagonists by varying methods.

Preconditioning ischemia time determines the degree of glycogen depletion and infarct size reduction in rat hearts.

The cardioprotective effect of preconditioning is associated with glycogen depletion and attenuation of intracellular acidosis during subsequent prolonged ischemia. This study determined the effects of increasing preconditioning ischemia time on myocardial glycogen depletion and on infarct size reduction. In addition, this study determined whether infarct size reduction by preconditioning correlates with glycogen depletion before prolonged ischemia. Anesthetized rats underwent a single episode of preconditioning lasting 1.25, 2.5, 5, or 10 minutes or multiple episodes cumulating in 10 (2 x 5 min) or 20 minutes (4 x 5 or 2 x 10 min) of preconditioning ischemia time, each followed by 5 minutes of reperfusion. Then both preconditioned and control rats underwent 45 minutes of ischemia induced by left coronary artery (LCA) occlusion and 120 minutes of reperfusion. After prolonged ischemia, infarct size was determined by dual staining with triphenyltetrazolium chloride and phthalocyanine blue dye. Glycogen levels were determined by an enzymatic assay in selected rats from each group before prolonged ischemia. We found that increasing preconditioning ischemia time resulted in glycogen depletion and infarct size reduction that could both be described by exponential functions. Furthermore, infarct size reduction correlated with glycogen depletion before prolonged ischemia (r = 0.98; p < 0.01). These findings suggest a role for glycogen depletion in reducing ischemic injury in the preconditioned heart.

Intracellular calcium transients underlying interval-force relationship in whole rat hearts: effects of calcium antagonists.

OBJECTIVES: Much of the understanding about the cardiac interval-force relationship of the whole heart, including mechanical restitution and postextrasystolic potentiation (PESP), has been inferred from isolated muscle studies. We tested whether results from isolated muscles about intracellular Ca2+([Ca2+]i) transients underlying the interval-force relationship can be substantiated in whole hearts. Additionally, we investigated whether Ca2+ antagonists could alter [Ca2+]i transients underlying mechanical restitution and postextrasystolic potentiation. METHODS: [Ca2+]i transients were studied in isolated perfused rat hearts by surface fluorometry and Indo-1. Using computer-controlled pacing protocols, we performed restitution curves for left ventricular developed pressure and [Ca2+]i (developed pressure and [Ca2+]i plotted as a function of extrasystolic intervals). To quantify restitution curves, we fitted monoexponential functions to plots and analyzed their shift and slope. Then, we used Ca2+ antagonists, low extracellular Ca2+([Ca2+]o) and PESP to modify restitution curves. [Ca2+]i transients in isolated rat hearts were interpreted as Ca2+ released from the sarcoplasmic reticulum. RESULTS: Interval-dependent changes in developed pressure were strongly correlated to interval-dependent changes in the amplitude of [Ca2+]i transients in isolated whole rat hearts. Additionally, nifedipine and low [Ca2+]o led to similar downward shifts but not to a changed slope of restitution curves for [Ca2+]i. On the other hand, PESP increased the slope of restitution curves for [Ca2+]i. Furthermore, the effect of PESP on developed pressure was blunted by high concentrations of Ca2+ antagonists. CONCLUSIONS: The results from isolated muscles about [Ca2+]i transients underlying the interval-force relationship could be substantiated in whole hearts. Additionally, low [Ca2+]i (induced by nifedipine or low [Ca2+]o) decreased the maximal Ca2+ release of the sarcoplasmic reticulum but did not change the release kinetics. On the other hand, PESP presumably accelerated Ca2+ release kinetics of the sarcoplasmic reticulum.

Role of intracellular calcium in the antiarrhythmic effect of procainamide during ventricular fibrillation in rat hearts.

Increased intracellular calcium (calcium overload) is considered one of the factors that can initiate ventricular fibrillation. In addition, ventricular fibrillation itself can cause and possibly maintain calcium overload. The goal of this study was to determine whether the class IA antiarrhythmic agent procainamide can reduce calcium overload during ventricular fibrillation and, if so, whether this reduction could be responsible for the recovery of the left ventricular function after defibrillation. For this purpose, the effects of 0.1 mmol/L of procainamide perfusion on left ventricular developed pressure, cardiac rate, and intracellular calcium during pacing-induced ventricular fibrillation were measured in isolated perfused rat hearts. Intracellular calcium was assessed by surface fluorometry after indo 1 loading. The concentration of procainamide was selected such that approximately half of the hearts would functionally recover from fibrillation. Cardiac rate and intracellular calcium were compared among four groups, depending on both the perfusate used and the recovery of left ventricular developed pressure at the end of the experiment. We found that procainamide reduced intracellular calcium to steady-state levels in hearts in which left ventricular function completely recovered (developed pressure > 67% of the steady-state value). However, intracellular calcium remained elevated in partially recovered hearts (33% < or = pressure < or = 67%) and in nonrecovered hearts (pressure < 33%). Thus procainamide can reduce calcium overload during ventricular fibrillation, and this reduction could be responsible for the recovery of left ventricular function after defibrillation. This reduction was use dependent, that is, dependent on high cardiac rates during fibrillation rather than on the decrease of cardiac rates before or during defibrillation.

Bradykinin improves postischaemic recovery in the rat heart: role of high energy phosphates, nitric oxide, and prostacyclin.

OBJECTIVE: The aim was to define: (1) whether bradykinin administration during reperfusion improves postischaemic myocardial recovery; (2) whether high energy phosphate compounds are involved in the protective effects of bradykinin; and (3) whether bradykinin-induced release of prostacyclin and nitric oxide mediate the protective effects of bradykinin. METHODS: In the Langendorff rat heart preparation, coronary flow, left ventricular developed pressure, and, using 31P magnetic resonance spectroscopy, the high energy phosphate compounds phosphocreatine and beta-ATP were assessed during 15 min of global ischaemia and 30 min of reperfusion. Administration of 10(-7) M bradykinin was started before ischaemia and maintained throughout the experiment (BK-pre). This was compared to 10(-7) M bradykinin given exclusively with reperfusion (BK-post). Then 10(-7) M bradykinin was given simultaneously with 10(-4) M N omega-nitro-L-arginine-methyl ester (BK-LNAME) or 10(-5) M indomethacin (BK-indo). RESULTS: In comparison to control hearts, BK-pre exerted a significant protective effect on the postischaemic recovery of coronary flow [71(5)% v 43(4)%, P < 0.05], left ventricular pressure [81(8)% v 42(5)%, P < 0.05], phosphocreatine [105(4)% v 67(8)%, P < 0.05], and beta-ATP [78(9)% v 48(7)%, P < 0.05]. With BK-post, recovery of coronary flow [71(4)% v 43(4)%, P < 0.05] and left ventricular pressure [78(4)% v 42(5)%, P < 0.05] significantly improved; however the recovery of phosphocreatine [70(4)% v 67(8)%, NS] and beta-ATP [58(2)% v 48(7)%, NS] was not different from control. When bradykinin and L-NAME or indomethacin was given the beneficial effects of bradykinin on ischaemic hearts were abolished. CONCLUSIONS: (1) Bradykinin improved postischaemic myocardial recovery when given before ischaemia or starting exclusively with reperfusion; (2) this was only partially related to a protective action on the high energy phosphate compounds during ischaemia; (3) the beneficial effects of bradykinin on ischaemic hearts are dependent from an unrestrained action of prostacyclin and nitric oxide.

Differential effects of endothelin-1 on normal and postischemic reperfused myocardium.

Using an isolated rat heart preparation and 31P magnetic resonance spectroscopy, we studied the effects of endothelin-1 (ET-1) and U-46619, a thromboxane-A2 analogue, on coronary flow (CF), left ventricular developed pressure (LVP), and high-energy phosphate metabolism under control conditions (normal myocardium) and during postischemic reperfusion (reperfused myocardium). The selected doses of ET-1 and U-46619 reduced CF in the normal myocardium to a similar extent (47.8 +/- 1.5% and 48.7 +/- 4.6%, respectively). In contrast to ET-1, U-46619 induced a depression of LVP (20.2 +/- 6.9% versus 6.8 +/- 4.7%; p < 0.05) which was accompanied by an intracellular acidosis, indicating that a low-flow ischemia occurred. In reperfused hearts, the ET-1-induced decrease in CF was more pronounced compared to U-46619 (79.5 +/- 1.6% versus 59.0 +/- 5.9%; p < 0.05) and to ET-1-induced decrease in CF in the normal myocardium (74.0 +/- 7.9% versus 32.4 +/- 6.3%; p < 0.05). This was accompanied by a large decrease in LVP and in levels of high-energy phosphate compounds. Therefore, the effects of ET-1 but not of U-46619 are enhanced in reperfused hearts. This may contribute to the delayed recovery of the postischemic reperfused myocardium.