Hemodynamic effects of periodic obstructive apneas in sedated pigs with congestive heart failure.

Because of similar physiological changes such as increased left ventricular (LV) afterload and sympathetic tone, an exaggerated depression in cardiac output (CO) could be expected in patients with coexisting obstructive sleep apnea and congestive heart failure (CHF). To determine cardiovascular effects and mechanisms of periodic obstructive apnea in the presence of CHF, 11 sedated and chronically instrumented pigs with CHF (rapid pacing) were tested with upper airway occlusion under room air breathing (RA), O(2) breathing (O2), and room air breathing after hexamethonium (Hex). All conditions led to large negative swings in intrathoracic pressure (-30 to -39 Torr) and hypercapnia (PCO(2) approximately 60 Torr), and RA and Hex also caused hypoxia (to approximately 42 Torr). Relative to baseline, RA increased mean arterial pressure (from 97.5 +/- 5.0 to 107.3 +/- 5.7 Torr, P < 0.01), systemic vascular resistance, LV end-diastolic pressure, and LV end-systolic length while it decreased CO (from 2.17 +/- 0.27 to 1.52 +/- 0.31 l/min, P < 0.01), stroke volume (SV; from 23.5 +/- 2.4 to 16.0 +/- 4.0 ml, P < 0.01), and LV end-diastolic length (LVEDL). O2 and Hex decreased mean arterial pressure [from 102.3 +/- 4.1 to 16.0 +/- 4.0 Torr (P < 0.01) with O2 and from 86.0 +/- 8.5 to 78.1 +/- 8.7 Torr (P < 0.05) with Hex] and blunted the reduction in CO [from 2.09 +/- 0.15 to 1.78 +/- 0.18 l/ml for O2 and from 2.91 +/- 0.43 to 2.50 +/- 0.35 l/ml for Hex (both P < 0.05)] and SV. However, the reduction in LVEDL and LV end-diastolic pressure was the same as with RA. There was no change in systemic vascular resistance and LVEDL during O2 and Hex relative to baseline. In the CHF pigs during apnea, there was an exaggerated reduction in CO and SV relative to our previously published data from normal sedated pigs under similar conditions. The primary difference between CHF (present study) and the normal animals is that, in addition to increased LV afterload, there was a decrease in LV preload in CHF contributing to SV depression not seen in normal animals. The decrease in LV preload during apneas in CHF may be related to effects of ventricular interdependence.     

Cardiac sympathetic activation in patients with pulmonary arterial hypertension

Patients with congestive heart failure (CHF) due to left ventricular (LV) dysfunction have sympathetic activation specifically directed to the myocardium. Although pulmonary arterial hypertension (PAH) is associated with increased systemic sympathetic activity, its impact on sympathetic drive to ventricular myocardium is unknown. Fifteen patients with PAH (9 women; 54 ± 12 years) were studied: 10 with idiopathic PAH and 5 with a connective tissue disorder. We measured hemodynamics, as well as radiolabeled and endogenous concentrations of arterial and coronary sinus norepinephrine (NE). These measures were repeated after inhaled nitric oxide (NO). Measurement of transcardiac NE concentrations and the cardiac extraction of radiolabeled NE allowed calculation of the corrected transcardiac gradient of NE (CTCG of NE). Comparative data were collected from 15 patients (9 women: 55 ± 12 yr) with normal LV function and 15 patients with CHF (10 women; 53 ± 12 yr). PAH patients had elevated arterial NE concentrations compared with those with normal LV function but were similar to those with CHF. The CTCG of NE was higher in those with PAH than in the normal LV group (3.6 ± 2.2 vs. 1.5 ± 0.9 pmol/ml; P < 0.01) but similar to that seen in those with CHF (3.3 ± 1.4; P = NS). Inhaled NO, which reduced pulmonary artery pressure and increased cardiac output, had no effect on cardiac sympathetic activity. Therefore, cardiac sympathetic activation occurs in PAH. The mechanism of this activation remains uncertain but does not involve elevations in left heart filling pressure.     

Cardiac sympathetic neuroprotective effect of desipramine in tachycardia-induced cardiomyopathy

Cardiac sympathetic transmitter stores are reduced in the failing heart. In this study, we proposed to investigate whether the reduction of cardiac sympathetic neurotransmitters was associated with increased interstitial norepinephrine (NE) and reactive oxygen species in congestive heart failure (CHF), using a microdialysis technique and salicylate to detect .OH generation. Rabbits with and without rapid ventricular pacing (340 beats/min) were randomized to receive desipramine (10 mg/day) or placebo for 8 wk. Rapid pacing produced left ventricular dilation and systolic dysfunction. The failing myocardium also showed reduced tissue contents of NE and tyrosine hydroxylase protein and activity. In contrast, myocardial interstitial NE was increased in CHF (0.89 +/- 0.11 ng/ml) compared with the sham-operated animals (0.26 +/- 0.03 ng/ml). In addition, cardiac oxidative stress was increased in CHF animals as measured by myocardial interstitial .OH radical, tissue oxidized glutathione, and oxidized mitochondrial DNA. Desipramine treatment produced significant NE uptake inhibition as evidence by an exaggerated pressor response and a greater increase of myocardial interstitial NE in response to intravenous NE infusion but no significant effects on cardiac function or hemodynamics in sham-operated or CHF animals. However, desipramine treatment attenuated the reductions of tissue NE and tyrosine hydroxylase protein and activity in CHF. Desipramine also prevented the reduction of tyrosine hydroxylase produced by NE in PC12 cells. Thus the reduction of cardiac sympathetic neurotransmitters is related to the increased interstitial NE and tissue oxidative stress in CHF. Also, normal neuronal uptake of NE is required for NE or its oxidized metabolites to exert their neurotoxic effects.     

Catecholamine release and ventricular arrhythmias during coronary occlusion and reperfusion in the dog

In anesthetized dogs, 60-min occlusions of either the proximal (n = 14), distal (n = 8) left circumflex (LCX), or left anterior descending (LAD, n = 10) arteries were followed by reperfusion. Coronary sinus and aortic norepinephrine and epinephrine plasma concentrations were measured. The ventricular arrhythmias were ventricular premature depolarizations (VPDs), unsustained ventricular tachycardia (VT) (greater than or equal to 3 and less than 20 VPDs), sustained VT (greater than or equal to 20 VPDs), and ventricular fibrillation (VF). A gradual twofold increase (p less than 0.05) in myocardial norepinephrine overflow followed occlusion in all three groups. The increases in the amounts of norepinephrine released in the coronary sinus blood during reperfusion were significant and proportional to the size of the occluded area: proximal LCX, from 0.236 +/- 0.038 to 1.528 +/- 0.490 ng/mL of plasma (p less than 0.001); LAD, from 0.180 +/- 0.027 to 0.795 +/- 0.286 ng/mL (p less than 0.05); distal LCX, from 0.215 +/- 0.039 to 0.404 +/- 0.110 ng/mL (p less than 0.05). Aortic epinephrine concentrations were significantly increased only by LAD occlusion; at 15 min, the value had increased to 0.187 +/- 0.053 ng/mL from an initial value of 0.069 +/- 0.029 ng/mL (p less than 0.001). Two phases of ventricular arrhythmias followed both occlusion and reperfusion. Phase 1 postocclusion was characterized by VPDs and phase 2 by VPDs and unsustained VT. Sustained VT was seen only in phase 1 postreperfusion, whereas unsustained VT was seen in phase 2. VF was seen in 50, 35, and 25% of the dogs with proximal LCX, LAD, and distal LCX occlusion and reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Involvement of endogenous ouabain-like compound in the cardiac hypertrophic process in vivo

The Na(+)/K(+)-ATPase inhibitor ouabain has been shown to trigger hypertrophic growth of cultured cardiomyocytes; however, the significance of endogenous ouabain-like compound (OLC) in the hypertrophic process in vivo is unknown. Here we characterized the involvement of OLC in left ventricular (LV) hypertrophy induced by norepinephrine (NE) and angiotensin II (Ang II) infusions in rats. Administration of NE (300 microg/kg/h) via subcutanously implanted osmotic minipumps for 72 h resulted in a significant increase in left ventricular weight to body weight (LVW/BW) ratio (P<0.001) and a substantial up-regulation of atrial natriuretic peptide (ANP) gene expression (13.2-fold, P<0.001). NE infusion induced a transient increase in plasma OLC levels at 12 h (P<0.05), which returned to control levels by 72 h. Adrenalectomy markedly reduced both basal and NE-induced increase in plasma OLC levels. LVW/BW ratio was not modulated by adrenalectomy; however, ANP gene expression was blunted by 44% (P<0.01) and 47% (P<0.05) at 12 and 72 h, respectively. In agreement, adrenalectomy reduced up-regulation of ANP without affecting LV mass in rats infused with Ang II (33 microg/kg/h). Administration of exogenous ouabain (1 nM to 100 microM) for 24 h had no effect on ANP gene expression in cultured neonatal rat ventricular myocytes. However, the up-regulation of ANP mRNA levels induced by the alpha-adrenergic agonist phenylephrine (1 microM) was markedly enhanced by ouabain (100 microM) (5.6-fold vs. 9.6-fold, P<0.01). These data show that OLC as an adrenal-derived factor may be required for the induction LV ANP gene expression during the hypertrophic process.     

Dialysate dihydroxyphenylglycol as a window for in situ axoplasmic norepinephrine disposition

To examine basal axoplasmic norepinephrine (NE) kinetics at the in situ cardiac sympathetic nerve ending, we applied a dialysis technique to the heart of anesthetized cats and performed the dialysate sampling with local administration of a pharmacological tool through a dialysis probe. The dialysis probe was implanted in the left ventricular wall, and dihydroxyphenylglycol (DHPG, an index of axoplasmic NE) levels were measured by liquid chromatogram-electrochemical detection. Control dialysate DHPG levels were 161+/-19 pg/ml. Pargyline (monoamine oxidase inhibitor, 1 mM) decreased the dialysate DHPG levels to 38+/-10 pg/ml. Further alpha-methyl-para-tyrosine, omega-conotoxin GVIA, desipramine (NE synthesis, release and uptake blockers) decreased the dialysate DHPG levels to 64+/-19, 106+/-15, 110+/-22 pg/ml, respectively. In contrast, reserpine (vesicle NE transport inhibitor, 10 microM) increased the dialysate DHPG levels to 690+/-42 pg/ml. Thus, NE synthesis, metabolism and recycling (release, uptake and vesicle transport) affected basal intraneuronal NE disposition at the nerve endings. Measurement of DHPG levels through a dialysis probe provides information about basal intraneuronal NE disposition at the cardiac sympathetic nerve endings. Yohimbine (alpha(2)-adrenoreceptor blocker, 10 microM) and U-521 (catechol-O-methyltransferase blocker, 100 microM) did not alter the dialysate DHPG levels. Furthermore, there were no significant differences in the reserpine induced DHPG increment between the presence and absence of desipramine (10 microM) or alpha-methyl-para-tyrosine (100 mg/kg i.p.). These results may be explained by the presence of two axoplasmic pools of NE, filled by NE taken up and synthesized, and by NE overflow from vesicle. The latter pool of NE may be closed to the monoamine oxidase system in the axoplasma.     

Endogenous beta3-adrenoreceptor activation contributes to left ventricular and cardiomyocyte dysfunction in heart failure

The objective of the present study was to test the hypothesis that endogenous beta(3)-adrenoreceptor (AR) activation contributes to left ventricular (LV) and cardiomyocyte dysfunction in heart failure (CHF). Stimulation of the beta(3)-AR inhibits cardiac contraction. In the failing myocardium, beta(3)-ARs are upregulated, suggesting that stimulation of beta(3)-ARs may contribute to depressed cardiac performance in CHF. We assessed the functional significance of endogenous beta(3)-AR activation in 10 conscious dogs before and after pacing-induced CHF. Under normal conditions, L-748,337, a specific beta(3)-AR antagonist, produced a mild increase in LV contractile performance assessed by the slope (E(es)) of the LV pressure-volume relation (18%, 6.2 +/- 0.9 vs. 7.3 +/- 1.2 mmHg/ml, P < 0.05) and the improved LV relaxation time constant (tau; 28.4 +/- 1.9 vs. 26.8 +/- 1.0 ms, P < 0.05). After CHF, the plasma norepinephrine concentration increased eightfold, and L-748,337 produced a larger increase in E(es) (34%, 3.8 +/- 0.7 vs. 5.1 +/- 0.8 mmHg/ml, P < 0.05) and a greater decrease in tau (46.4 +/- 4.2 vs. 41.0 +/- 3.9 ms, P < 0.05). Similar responses were observed in isolated myocytes harvested from LV biopsies before and after CHF. In the normal myocyte, L-748,337 did not cause significant changes in contraction or relengthening. In contrast, in CHF myocytes, L-748,337 produced significant increases in contraction (5.8 +/- 0.9 vs. 6.8 +/- 0.9%, P < 0.05) and relengthening (33.5 +/- 4.2 vs. 39.7 +/- 4.0 microm/s, P < 0.05). The L-748,337-induced myocyte response was associated with improved intracellular Ca(2+) concentration regulation. In CHF myocytes, nadolol caused a decrease in contraction and relengthening, and adding isoproterenol to nadolol caused a further depression of myocyte function. Stimulation of beta(3)-AR by endogenous catecholamine contributes to the depression of LV contraction and relaxation in CHF.     

Indomethacin does not potentiate renovascular constriction during hypercapnia in unanesthetized rabbits

The role of prostanoids in regulation of the renal circulation during hypercapnia was examined in unanesthetized rabbits. Renal blood flow (RBF) was determined with 15 micron radioactive microspheres during normocapnia (PaCO2 congruent to 30 mmHg) and hypercapnia (PaCO2 congruent to 60 mmHg), before and after intravenous administration of indomethacin (10 mg/kg) or vehicle (n = 6 for each group). Arterial blood pressure was not different among the 4 conditions in each group. RBF was 438 +/- 61 and 326 +/- 69 (P less than 0.05) ml/min per 100 g during normocapnia and hypercapnia, respectively, before indomethacin, and following administration of indomethacin, RBF was 426 +/- 59 ml/min per 100 g during normocapnia and 295 +/- 60 ml/min per 100 g during hypercapnia (P less than 0.05). In the vehicle group, RBF was 409 +/- 74 and 226 +/- 45 (P less than 0.05) ml/min per 100 g during normocapnia and hypercapnia, respectively, before vehicle; and following administration of vehicle, RBF was 371 +/- 46 ml/min per 100 g during normocapnia and 219 +/- 50 (P less than 0.05) ml/min per 100 g during hypercapnia. RBF during normocapnia was not affected by administration of indomethacin or vehicle. The successive responses to hypercapnia were not different within the indomethacin and vehicle groups, and the second responses to hypercapnia were not different between the two groups. These findings suggest that prostanoids do not contribute significantly to regulation of the renal circulation during normocapnia and hypercapnia in unanesthetized rabbits.     

Endocardial activation during ventricular fibrillation in normal and failing canine hearts

Because congestive heart failure (CHF) promotes ventricular fibrillation (VF), we compared VF in seven dogs with CHF induced by combined myocardial infarction and rapid ventricular pacing to VF in six normal dogs. A noncontact, multielectrode array balloon catheter provided full-surface real-time left ventricular (LV) endocardial electrograms and a dynamic color-coded display of endocardial activation projected onto a three-dimensional model of the LV. Fast Fourier transform (FFT) analysis of virtual electrograms showed no difference in peak or centroid frequency in CHF dogs compared with normals. The average number of simultaneous noncontiguous wavefronts present during VF was higher in normals (2.4 +/- 1.0 at 10 s of VF) than in CHF dogs (1.3 +/- 1.0, P < 0.005) and decreased in both over time. The wavefront "turnover" rate, estimated using FFT of the noncontiguous wavefront data, did not differ between normals and CHF and did not change over 5 min of VF. Thus the fundamental frequency characteristics of VF are unaltered by CHF, but dilated abnormal ventricles sustain fewer active wavefronts than do normal ventricles.     

Cardiac-specific norepinephrine mass transport and its relationship to left ventricular size and systolic performance

Objectives of this study were to develop a technique for quantifying cardiac-specific norepinephrine (NE) mass transport and determine whether cardiac NE kinetic modeling parameters were related to physiological variables of left ventricular (LV) size and systolic performance in nine patients with chronic mitral regurgitation. Biplane contrast cineventriculograms were used to determine LV size and ejection fraction (EF), micromanometer LV pressures and radionuclide LV volumes from a range of loading conditions to calculate LV end-systolic elastance, and [(3)H]NE infusions with LV and coronary sinus sampling for [(3)H]NE and endogenous NE during and after termination of infusions to model NE mass transport. Total NE release rate into cardiac interstitial fluid (M(IF)(R)) averaged 859 +/- 214 and NE released de novo into cardiac interstitial fluid (M(IF)(u,r,en)) averaged 546 +/- 174 pmol/min. Both M(IF)(R) and M(IF)(u,r,en)correlated directly with LV end-systolic volume (r = 0.84, P = 0.005; r = 0.86, P = 0.003); inversely with LV EFs (r = -0.75, P = 0.02; r = -0.81, P = 0.008); and inversely with LV end-systolic elastance values, optimally fit by a nonlinear function (r = 0.89, P = 0.04; r = 0.96, P = 0.01). We conclude that total and newly released NE into interstitial fluid of the heart, determined by regional mass transport kinetic model, are specific measures of regional cardiac-specific sympathetic nervous system activity and are strongly related to measures of LV size and systolic performance. These data support the concept that this new model of organ-specific NE kinetics has physiological relevance.     

In vivo monitoring of norepinephrine and its metabolites in skeletal muscle

Although skeletal muscle sympathetic nerve activity plays an important role in the regulation of vascular tone and glucose metabolism, relatively little is known about regional norepinephrine (NE) kinetics in the skeletal muscle. With use of the dialysis technique, we implanted dialysis probes in the adductor muscle of anesthetized rabbits and examined whether dialysate NE and its metabolites were influenced by local administration of pharmacological agents through the dialysis probes. Dialysate dihydroxyphenylglycol (DHPG) and 3-methoxy-4-hydroxyphenylglycol (MHPG) were measured as two major metabolites of NE. The skeletal muscle dialysate NE, DHPG and MHPG were 11.7+/-1.2, 38.1+/-3.2, and 266.1+/-28.7 pg/ml, respectively. Basal dialysate NE levels were suppressed by tetrodotoxin (Na(+) channel blocker, 10 microM) (5.1+/-0.6 pg/ml), and augmented by desipramine (NE uptake blocker, 100 microM) (25.8+/-3.2 pg/ml). Basal dialysate DHPG levels were suppressed by pargyline (monoamine oxidase blocker, 1mM) (24.3+/-4.6 pg/ml) and augmented by reserpine (vesicle NE transport blocker, 10 microM) (75.8+/-2.7 pg/ml). Basal dialysate MHPG levels were not affected by pargyline, reserpine, or desipramine. Addition of tyramine (sympathomimetic amine, 600 microM), KCl (100 mM), and ouabain (Na(+)-K(+) ATPase blocker, 100 microM) caused brisk increases in dialysate NE levels (200.9+/-14.2, 90.6+/-25.7, 285.3+/-46.8 pg/ml, respectively). Furthermore, increases in basal dialysate NE levels were correlated with locally administered desipramine (10, 100 microM). Thus, dialysate NE and its metabolite were affected by local administration of pharmacological agents that modified sympathetic nerve endings function in the skeletal muscle. Skeletal muscle microdialysis with local administration of a pharmacological agent provides information about NE release, uptake, vesicle uptake and degradation at skeletal muscle sympathetic nerve endings.     

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.     

Left ventricular systolic torsion correlates global cardiac performance during dyssynchrony and cardiac resynchronization therapy

Left ventricular (LV) systolic torsion is a primary mechanism contributing to stroke volume (SV). We hypothesized that change in LV torsion parallels changes in global systolic performance during dyssynchrony and cardiac resynchronization therapy (CRT). Seven anesthetized open chest dogs had LV pressure-volume relationship. Apical, basal, and mid-LV cross-sectional echocardiographic images were studied by speckle tracking analysis. Right atrial (RA) pacing served as control. Right ventricular (RV) pacing simulated left bundle branch block. Simultaneous RV-LV free wall and RV-LV apex pacing (CRTfw and CRTa, respectively) modeled CRT. Dyssynchrony was defined as the time difference in peak strain between earliest and latest segments. Torsion was calculated as the maximum difference between the apical and basal rotation. RA pacing had minimal dyssynchrony (52 ± 36 ms). RV pacing induced dyssynchrony (189 ± 61 ms, P < 0.05). CRTa decreased dyssynchrony (46 ± 36 ms, P < 0.05 vs. RV pacing), whereas CRTfw did not (110 ± 96 ms). Torsion during baseline RA was 6.6 ± 3.7°. RV pacing decreased torsion (5.1 ± 3.6°, P < 0.05 vs. control), and reduced SV, stroke work (SW), and dP/dt(max) compared with RA (21 ± 5 vs. 17 ± 5 ml, 252 ± 61 vs. 151 ± 64 mJ, and 2,063 ± 456 vs. 1,603 ± 424 mmHg/s, respectively, P < 0.05). CRTa improved torsion, SV, SW, and dP/dt(max) compared with RV pacing (7.7 ± 4.7°, 23 ± 3 ml, 240 ± 50 mJ, and 1,947 ± 647 mmHg/s, respectively, P < 0.05), whereas CRTfw did not (5.1 ± 3.6°, 18 ± 5 ml, 175 ± 48 mJ, and 1,699 ± 432 mmHg/s, respectively, P < 0.05). LV torsion changes covaried across conditions with SW (y = 0.94x+12.27, r = 0.81, P < 0.0001) and SV (y = 0.66x+0.91, r = 0.81, P < 0.0001). LV dyssynchrony changes did not correlate with SW or SV (r = -0.12, P = 0.61 and r = 0.08, P = 0.73, respectively). Thus, we conclude that LV torsion is primarily altered by dyssynchrony, and CRT that restores LV performance also restores torsion.     

Red blood cell deformability index in diabetic retinopathy

In order to investigate the relationship between haemorheological disturbances and diabetic microangiopathy we have studied the red blood cell deformability index (RBCD-index) by means of a filtration technique in 69 diabetics, aged 49-83 years, and in 40 non diabetic healthy controls (group A) of respective age and sex. The diabetics were classified into the following groups, according to the findings of a thorough clinical and laboratory investigation. Twenty patients (group B) were free of vascular complications, whereas 9 (group C) suffered from background retinopathy, 27 (group D) background retinopathy and ischaemic cardiopathy or peripheral arterial occlusive disease and 13 (group E) of proliferative retinopathy with diffuse micro- and macroangiopathy. The RBCD-index was significantly (P less than 0.001) decreased in diabetics with retinopathy compared to the diabetic and non diabetic controls. The lowest RBCD-index was observed in diabetics with proliferative retinopathy and in those with diffuse micro- and macrovascular complications (RBCD-index, means +/- SDM ml/min: A 0.68 +/- 0.15; B 0.64 +/- 0.08; C 0.60 +/- 0.08; D 0.49 +/- 0.09; E 0.48 +/- 0.09). These findings suggest that the RBCD is impaired in diabetics with retinopathy, especially in those with severe vascular complications, and that this abnormal rheological behavior of erythrocytes can be found even in the early stages of diabetic microangiopathy.     

Left ventricular catecholamines during acute myocardial infarction in the dog

To determine whether changes in left ventricular catecholamine content occur during the first 30 to 90 min of acute myocardial infarction, myocardial catecholamine (radioenzymatic assay) over the interval was studied in the dog. In nine pentobarbital-anesthetized opened-chest dogs without coronary ligation, myocardial catecholamine at 2.5 h after pentobarbital (i) consisted mainly of norepinephrine (87% total catecholamine), (ii) showed a base to apex gradient in norepinephrine (1.44 +/- 0.10 vs. 1.03 +/- 0.10 micrograms/g, p less than 0.05) and dopamine (0.20 +/- 0.03 vs. 0.12 +/- 0.02 micrograms/g, p less than 0.05) but not epinephrine (0.017 vs. 0.016 micrograms/g), and (iii) showed no difference in norepinephrine, dopamine, or epinephrine across basal, mid, and apical left ventricular transverse planes spanning the vascular territories of the two coronary arteries. In 18 pentobarbital-anesthetized dogs with coronary ligation, (i) norepinephrine, measured in 14 regions across the mid left ventricle after 90 min ischemia in four dogs, was less in the ischemic center of the occluded bed than normal myocardium (1.01 +/- 0.04 vs. 1.29 +/- 0.04 micrograms/g, p less than 0.05), and (ii) norepinephrine was unchanged in normal myocardium of 14 dogs at 30, 60, 90 min, and 48 h but decreased in ischemic myocardium by 31% at 60 min (0.89 +/- 0.10 vs. 1.29 +/- 0.08 micrograms/g, p less than 0.025) and 79% at 48 h (0.27 +/- 0.04 vs. 1.26 +/- 0.08 micrograms/g, p less than 0.001). Thus, norepinephrine depletion from ischemic but not normal myocardium is detectable by 60 min during acute myocardial infarction.     

Susceptibility to ischemia-induced arrhythmias and the effect of preconditioning in the diabetic rat heart

Diabetic heart is suggested to exhibit either increased or decreased resistance to ischemic injury. Ischemic preconditioning suppresses arrhythmias in the normal heart, whereas relatively little is known about its effects in the diseased myocardium. Our objective was to investigate whether development of diabetes mellitus modifies the susceptibility to ischemia-induced arrhythmias and affects preconditioning in the rat heart. Following 1 and 9 weeks of streptozotocin-induced (45 mg/kg, i.v.) diabetes, the hearts were Langendorff-perfused at constant pressure of 70 mm Hg and subjected to test ischemia induced by 30 min occlusion of the left anterior descending (LAD) coronary artery. Preconditioning consisted of one cycle of 5 min ischemia and 10 min reperfusion, prior to test ischemia. Susceptibility to ischemia-induced arrhythmias was lower in 1-week diabetics: only 42 % of diabetic hearts exhibited ventricular tachycardia (VT) and 16 % had short episodes of ventricular fibrillation (VF) as compared to VT 100 % and VF 70 % (including sustained VF 36 %) in the non-diabetics (P<0.05). Development of the disease was associated with an increased incidence of VT (VT 92 %, not significantly different from non-diabetics) and longer total duration of VT and VF at 9-weeks, as compared to 1-week diabetics. Preconditioning effectively suppressed arrhythmias in the normal hearts (VT 33 %, VF 0 %). However, it did not provide any additional antiarrhythmic protection in the acute diabetes. On the other hand, in the preconditioned 9-weeks diabetic hearts, the incidence of arrhythmias tended to decrease (VT 50 %, transient VF 10 %) and their severity was reduced. Diabetic rat hearts are thus less susceptible to ischemia-induced arrhythmias in the acute phase of the disease. Development of diabetes attenuates increased ischemic tolerance, however, diabetic hearts in the chronic phase can benefit more from ischemic preconditioning, due to its persisting influence.     

Effects of amiodarone on wave front dynamics during ventricular fibrillation in isolated swine right ventricle

The effects of acute amiodarone infusion on dynamics of ventricular fibrillation (VF) are unclear. Six isolated swine right ventricles (RVs) were studied in vitro. Activation patterns during VF were mapped optically, whereas action potentials were recorded with a glass microelectrode. At baseline, VF was associated with frequent spontaneous wave breaks. Amiodarone (2.5 microg/ml) reduced spontaneous wave breaks and increased the cycle length (CL) of VF from 83.3 +/- 17.8 ms at baseline to 118.4 +/- 25.8 ms during infusion (P < 0.05). Amiodarone increased the reentrant wave front CL (114.4 +/- 15.5 vs. 78.2 +/- 19.0 ms, P < 0.05) and central core area (4.1 +/- 3.8 vs. 0.9 +/- 0.3 mm2, P < 0.05). Within 30 min of infusion, VF terminated (n = 1), converted to ventricular tachycardia (VT) (n = 1) or continued at a slower rate (n = 4). Amiodarone flattened the APD restitution curves. We conclude that amiodarone reduced spontaneous wave breaks. It might terminate VF or convert VF to VT. These effects were associated with the flattening of APD restitution slope and increased core size of reentrant wave fronts.     

Effect of sustained limb ischemia on norepinephrine release from skeletal muscle sympathetic nerve endings

Acute ischemia has been reported to impair sympathetic outflow distal to the ischemic area in various organs, whereas relatively little is known about this phenomenon in skeletal muscle. We examined how acute ischemia affects norepinephrine (NE) release at skeletal muscle sympathetic nerve endings. We implanted a dialysis probe into the adductor muscle in anesthetized rabbits and measured dialysate NE levels as an index of skeletal muscle interstitial NE levels. Regional ischemia was introduced by microsphere injection and ligation of the common iliac artery. The time courses of dialysate NE levels were examined during prolonged ischemia. Ischemia induced a decrease in the dialysate NE level (from 19+/-4 to 2.0+/-0 pg/ml, mean+/-S.E.), and then a progressive increase in the dialysate NE level. The increment in the dialysate NE level was examined with local administration of desipramine (DMI, a membrane NE transport inhibitor), omega-conotoxin GVIA (CTX, an N-type Ca(2+) channel blocker), or TMB-8 (an intracellular Ca(2+) antagonist). At 4h ischemia, the increment in the dialysate NE level (vehicle group, 143+/-30 pg/ml) was suppressed by TMB-8 (25+/-5 pg/ml) but not by DMI (128+/-10 pg/ml) or CTX (122+/-18 pg/ml). At 6h ischemia, the increment in the dialysate NE level was not suppressed by the pretreatment. Ischemia induced biphasic responses in the skeletal muscle. Initial reduction of NE release may be mediated by an impairment of axonal conduction and/or NE release function, while in the later phase, the skeletal muscle ischemia-induced NE release was partly attributable to exocytosis via intracellular Ca(2+) overload rather than opening of calcium channels or carrier mediated outward transport of NE.     

Diaspirin cross-linked Hb and norepinephrine prevent the sepsis-induced increase in critical O(2) delivery

We hypothesized that support of arterial perfusion pressure with diaspirin cross-linked Hb (DCLHb) would prevent the sepsis-induced attenuation in the systemic O(2) delivery-O(2) uptake relationship. Awake septic rats were treated with a chronic infusion of DCLHb or a reference treatment [norepinephrine (NE)] to increase mean arterial pressure by 10-20% over 18 h. Septic and sham control groups received normal saline. Isovolemic hemodilution to create anemic hypoxia was then performed in a metabolic box during continuous measurement of systemic O(2) uptake. O(2) delivery was calculated from hemodynamic variables, and the critical point of O(2) delivery (DO(2 crit)) was determined using piecewise regression analysis of the O(2) delivery-O(2) uptake relationship. Sepsis increased DO(2 crit) from 4.99 +/- 0.17 to 6.69 +/- 0.42 ml x min(-1) x 100 g(-1) (P < 0.01), while O(2) extraction capacity was decreased (P < 0.05). DCLHb and NE infusion prevented the sepsis-induced increase in DO(2 crit) [4.56 +/- 0.42 ml x min(-1) x 100 g(-1) (P < 0.01) and 5.04 +/- 0.56 ml x min(-1) x 100 g(-1) (P < 0.05), respectively]. This was explained by a 59% increase in O(2) extraction capacity in the DCLHb group compared with septic controls (P < 0.05), whereas NE treatment decreased systemic O(2) uptake in anemic hypoxia (1.51 +/- 0.08 vs. 1.87 +/- 0.1 ml x min(-1) x 100 g(-1) in septic controls, P < 0.05). We conclude that DCLHb ameliorated O(2) extraction capacity in the septic microcirculation, whereas NE decreased the metabolic demands of the tissues.