Restoration of myocardial contractile function during gradual reperfusion after total ischemia

Isolated guinea pig hearts subjected to 25-min total normothermic ischemia and 30-min reperfusion with the initial rate exhibited a great rise in isovolumic diastolic pressure while the contractile function recovered to 34 +/- 4% of initial value. Reperfusion with gradually increased rate from 13% of initial rate to 100% resulted in better recovery of the contractile function--to 54 +/- 3% and markedly less rise in the diastolic pressure. This coincided with 28% less inosine loss. More better recovery of the myocardial contractile function (to 80 +/- 5%) was observed in experiments in which gradual reperfusion was combined with recirculation. In both gradual reperfusion series, the recovery of the heart rate and the contractile function were much delayed during first 5 min reperfusion and were associated with a rise in coronary resistance.     

Inhibition of ischemia/reperfusion-induced damage by dexamethasone in isolated working rat hearts: the role of cytochrome c release

We investigated the contribution of dexamethasone treatment on the recovery of postischemic cardiac function and the development of reperfusion-induced arrhythmias in ischemic/reperfused isolated rat hearts. Rats were treated with 2 mg/kg of intraperitoneal injection of dexamethasone, and 24 hours later, hearts were isolated according to the 'working' mode, perfused, and subjected to 30 min global ischemia followed by 120 min reperfusion. Cardiac function including heart rate, coronary flow, aortic flow, and left ventricular developed pressure were recorded. After 60 min and 120 min reperfusion, 2 mg/kg of dexamethasone significantly improved the postischemic recovery of aortic flow and left ventricular developed pressure from their control values of 10.7 +/- 0.3 ml/min and 10.5 +/- 0.3 kPa to 22.2 +/- 0.3 ml/min (p < 0.05) and 14.3 +/- 0.5 kPa (p < 0.05), 19.3 +/- 0.3 ml/min (p < 0.05) and 12.3 +/- 0.5 kPa (p < 0.05), respectively. Heart rate and coronary flow did not show a significant change in postischemic recovery after 60 or 120 min reperfusion. In rats treated with 0.5 mg/kg of actinomycin D injected i.v., one hour before the dexamethasone injection, suppressed the dexamethasone-induced cardiac protection. Electrocardiograms were monitored to determine the incidence of reperfusion-induced ventricular fibrillation. Dexamethasone pretreatment significantly reduces the occurrence of ventricular fibrillation. Cytochrome c release was also observed in the cytoplasm. The results suggest that the inhibition of cytochrome c release is involved in the dexamethasone-induced cardiac protection.     

Triiodothyronine concomitantly inhibits calcium overload and postischemic myocardial stunning in diabetic rats.

Acute effects of triiodothyronine (T3) on postischemic myocardial stunning and intracellular Ca2+ contents were studied in the isolated working hearts of streptozotocin-induced diabetic rats and age-matched controls. After two weeks of diabetes, serum T3 and T4 levels were decreased to 62.5% and 33.9% of control values. Basal preischemic cardiac performance did not differ between diabetic and control rats. In contrast, during reperfusion after 20-min ischemia, diabetic rats exhibited an impaired recovery of heart rate (at 30-min reperfusion 57.5% of baseline vs. control 88.5%), left ventricular (LV) systolic pressure (44.1% vs. 89.5%), and cardiac work (23.1% vs. 66.0%). When 1 and 100 nM T3 was added before ischemia, heart rate was recovered to 77.2% and 81.8% of baseline, LV systolic pressure to 68.3% and 81.9%, and cardiac work to 50.8% and 59.0%, respectively. Diabetic rat hearts showed a higher Ca2+ content in the basal state and a further increase after reperfusion (4.96+/-1.17 vs. control 3.78+/-0.48 micromol/g, p<0.01). In diabetic hearts, H+ release was decreased after reperfusion (5.24+/-2.21 vs. 8.70+/-1.41 mmol/min/g, p<0.05). T3 administration caused a decrease in the postischemic Ca2+ accumulation (lnM T3 4.66+/-0.41 and 100 nM T3 3.58+/-0.36) and recovered the H+ release (lnM T3 16.2+/-3.9 and 100 nM T3 11.6+/-0.9). T3 did not alter myocardial O2 consumption. Results suggest that diabetic rat hearts are vulnerable to postischemic stunning, and T3 protects the myocardial stunning possibly via inhibiting Ca2+ overload.     

Rapid blunting of sympathetic vasoconstriction in the human forearm at the onset of exercise.

The purpose of this study was to test the hypothesis that sympathetic vasoconstriction is rapidly blunted at the onset of forearm exercise. Nine healthy subjects performed 5 min of moderate dynamic forearm handgrip exercise during -60 mmHg lower body negative pressure (LBNP) vs. without (control). Beat-by-beat forearm blood flow (Doppler ultrasound), arterial blood pressure (finger photoplethysmograph), and heart rate were collected. LBNP elevated resting heart rate by approximately 45%. Mean arterial blood pressure was not significantly changed (P = 0.196), but diastolic blood pressure was elevated by approximately 10% and pulse pressure was reduced by approximately 20%. At rest, there was a 30% reduction in forearm vascular conductance (FVC) during LBNP (P = 0.004). The initial rapid increase in FVC with exercise onset reached a plateau between 10 and 20 s of 126.6 +/- 4.1 ml. min(-1). 100 mmHg(-1) in control vs. only 101.6 +/- 4.1 ml. min(-1). 100 mmHg(-1) in LBNP (main effect of condition, P = 0.003). This difference was quickly abolished during the second, slower phase of adaptation in forearm vascular tone to steady state. These data are consistent with a rapid onset of functional sympatholysis, in which local substances released with the onset of muscle contractions impair sympathetic neural vasoconstrictor effectiveness.     

Transduction of anti-cell death protein FNK protects isolated rat hearts from myocardial infarction induced by ischemia/reperfusion

Artificial anti-cell death protein FNK, a Bcl-x(L) derivative with three amino acid-substitutions (Y22F, Q26N, and R165K) has enhanced anti-apoptotic and anti-necrotic activity and facilitates cell survival in many species and cell types. The objectives of this study were (i) to investigate whether the protein conjugated with a protein transduction domain (PTD-FNK) reduces myocardial infarct size and improves post-ischemic cardiac function in ischemic/reperfused rat hearts, and (ii) to understand the mechanism(s) by which PTD-FNK exerts a protective effect. Isolated rat hearts were subjected to 35-min global ischemia, followed by 120-min reperfusion using the Langendorff methods. PTD-FNK (a total of 30 microl) was injected intramuscularly into the anterior wall of the left ventricle either at 1 min after induction of global ischemia (group A) or at 30 min after induction of global ischemia (at 5 min before reperfusion) (group B). In group A, infarct size was significantly reduced from 47.8+/-6.8% in the control to 30.4+/-5.2, 28.7+/-3.8, and 30.4+/-6.8% with PTD-FNK at 5, 50, and 500 nmol/l, respectively (p<0.05). Temporal recovery of left ventricular developed pressure at 60 min and 120 min after reperfusion was significantly better in PTD-FNK (50 and 500 nmol/l)-treated groups than in the control (p<0.05). In contrast, PTD-FNK treatment had no effect on group B. Western blot analysis showed that PTD-FNK markedly inhibited procaspase-3 cleavage (activation of caspase-3) and reduced the number of nuclei stained by a terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphoshate nick-end labeling (TUNEL) assay. These findings suggest that PTD-FNK reduces the volume of myocardial infarction with corresponding functional recovery, at least in part, through the suppression of myocardial apoptosis following ischemia/reperfusion.     

NO produced by endothelial NO synthase is a mediator of delayed preconditioning-induced endothelial protection

Preconditioning with brief periods of ischemia-reperfusion (I/R) induces a delayed protection of coronary endothelial cells against reperfusion injury. We assessed the possible role of nitric oxide (NO) produced during prolonged I/R as a mediator of this endothelial protection. Anesthetized rats were subjected to 20-min cardiac ischemia/60-min reperfusion, 24 h after sham surgery or cardiac preconditioning (1 x 2-min ischemia/5-min reperfusion and 2 x 5-min ischemia/5-min reperfusion). The nonselective NO synthase (NOS) inhibitor l-NAME, the selective inhibitors of neuronal (7-nitroindazole) or inducible (1400W) NOS, or the peroxynitrite scavenger seleno-l-methionine were administered 10 min before prolonged ischemia. Preconditioning prevented the reperfusion-induced impairment of coronary endothelium-dependent relaxations to acetylcholine (maximal relaxation: sham 77 +/- 3; I/R 44 +/- 6; PC 74 +/- 5%). This protective effect was abolished by l-NAME (41 +/- 7%), whereas 7-NI, 1400W or seleno-l-methionine had no effect. The abolition of preconditioning by l-NAME, but not by selective nNOS or iNOS inhibition, suggests that NO produced by eNOS is a mediator of delayed endothelial preconditioning.     

Poly(ADP-ribose) polymerase inhibitor PJ-34 reduces mesenteric vascular injury induced by experimental cardiopulmonary bypass with cardiac arrest

The aim of this study was to investigate effects of poly(ADP-ribose) polymerase (PARP) inhibition on mesenteric vascular function and metabolism in an experimental model of cardiopulmonary bypass (CPB) with cardiac arrest. Twelve anesthetized dogs underwent 90-min hypothermic CPB. After 60 min of cardiac arrest, reperfusion was started for 40 min following application of either saline vehicle (control, n = 6) or a potent PARP inhibitor, PJ-34 (10 mg/kg iv bolus and 0.5 mg.kg(-1).min(-1) infusion for 20 min, n = 6). PJ-34 led to better recovery of cardiac output (2.2 +/- 0.1 vs. 1.8 +/- 0.2 l/min in control) and mesenteric blood flow (175 +/- 38 vs. 83 +/- 4 ml/min, P < 0.05 vs. control) after reperfusion. The impaired vasodilator response of the superior mesenteric artery to acetylcholine, assessed in the control group after CPB (-32.8 +/- 3.3 vs. -57.6 +/- 6.6% at baseline, P < 0.05), was improved by PJ-34 (-50.3 +/- 3.6 vs. -54.3 +/- 4.1% at baseline, P < 0.05 vs. control). Although plasma nitrate/nitrite concentrations were not significantly different between groups, mesenteric nitric oxide synthase activity was increased in the PJ-34 group (P < 0.05). Moreover, the treated group showed a marked attenuation of mesenteric venous plasma myeloperoxidase levels after CPB compared with the control group (75 +/- 1 vs. 135 +/- 9 ng/ml, P < 0.05). Pharmacological PARP inhibition protects against development of post-CPB mesenteric vascular dysfunction by improving hemodynamics, restoring nitric oxide production, and reducing neutrophil adhesion.     

Core temperature "null zone".

An experimental protocol was designed to investigate whether human core temperature is regulated at a "set point" or whether there is a neutral zone between the core thresholds for shivering thermogenesis and sweating. Nine male subjects exercised on an underwater cycle ergometer at a work rate equivalent to 50% of their maximum work rate. Throughout an initial 2-min rest period, the 20-min exercise protocol, and the 100-min recovery period, subjects remained immersed to the chin in water maintained at 28 degrees C. On completion of the exercise, the rate of forehead sweating (Esw) decayed from a mean peak value of 7.7 +/- 4.2 (SD) to 0.6 +/- 0.3 g.m-2.min-1, which corresponds to the rate of passive transpiration, at core temperatures of 37.42 +/- 0.29 and 37.39 +/- 0.48 degrees C, as measured in the esophagus (Tes) and rectum (Tre), respectively. Oxygen uptake (VO2) decreased rapidly from an exercising level of 2.11 +/- 0.25 to 0.46 +/- 0.09 l/min within 4 min of the recovery period. Thereafter, VO2 remained stable for approximately 20 min, eventually increased with progressive cooling of the core region, and was elevated above the median resting values determined between 15 and 20 min at Tes = 36.84 +/- 0.38 degrees C and Tre = 36.80 +/- 0.39 degrees C. These results indicate that the core temperatures at which sweating ceases and shivering commences are significantly different (P less than 0.001) regardless of whether core temperature is measured within the esophagus or rectum.(ABSTRACT TRUNCATED AT 250 WORDS)     

Separate hemodynamic roles for chloride and sodium in deoxycorticosterone acetate-salt hypertension

It has been reported that both sodium and chloride ions must be ingested to induce the elevated blood pressure of deoxycorticosterone acetate (DOCA)-salt-sensitive hypertension. This study was designed to determine the separate roles of the sodium and chloride ions in the altered hemodynamics underlying the high blood pressure. DOCA pellets (75 mg) were implanted in uninephrectomized rats and the animals were then fed one of four diets: (i) high sodium chloride, (ii) high sodium-low chloride, (iii) high chloride-low sodium, or (iv) low sodium chloride. Blood pressures were measured weekly by tail-cuff plethysmography for 5 weeks and the animals were then subjected to a terminal experiment to measure cardiac output by thermodilution technique, renal blood flow by electromagnetic flow probe, and direct arterial pressure. Blood pressure in the DOCA-high NaCl group was significantly greater (P less than 0.05) compared with that of the DOCA-low NaCl group (160 +/- 3 mm Hg vs 124 +/- 2 mm Hg, respectively) at 5 weeks after treatment; all other groups were not significantly different from the DOCA-low NaCl group. Cardiac output was significantly greater in DOCA-treated rats consuming diets high in sodium (44 +/- 2 ml/min/100 g) or sodium chloride (40 +/- 2 ml/min/100 g) compared with animals consuming low sodium chloride (31 +/- 2 ml/min/100 g; P less than 0.01 for each comparison). Direct intraarterial blood pressure and renal blood flow were used to calculate renal vascular resistance. Renal vascular resistance was increased in those DOCA-treated rats consuming diets high in chloride (42 +/- 3 mm Hg/ml/min/100 g) and high sodium chloride (54 +/- 3 mm Hg/ml/min/100 g) compared with rats consuming low sodium chloride (30 +/- 3 mm Hg/ml/min/100 g; P less than 0.01 for each). It appears that elevations in cardiac output are associated with increased dietary sodium and act in synergy with the elevations in renal vascular resistance associated with increased dietary chloride. Increases in both cardiac output and renal vascular resistance are involved in the maintenance of elevated blood pressure in the DOCA-salt-sensitive model of hypertension.     

Role of endogenous opioids in ischemic preconditioning but not in short-term hibernation in pigs

Endogenous opioids are involved in ischemic preconditioning (IP) in several species. Whether or not opioids are important for IP and short-term myocardial hibernation (STMH) in pigs is currently unknown. In 34 enflurane-anesthetized pigs, the left anterior descending coronary artery was flow constantly perfused. Subendocardial blood flow (Endo), infarct size (IS; percent area at risk), and the free energy change of ATP hydrolysis (DeltaG) were determined. After 90-min severe ischemia and 120-min reperfusion, IS averaged 28.3 +/- 5.4% (means +/- SE) (n = 8; Endo: 0.047 +/- 0.009 ml. min(-1) x g(-1)). IP by 10-min ischemia and 15-min reperfusion reduced IS to 9.9 +/- 3.8% (P < 0.05, n = 8; Endo: 0.044 +/- 0.009 ml. min(-1) x g(-1)). After naloxone (1 mg/kg iv followed by 2 microg x kg(-1) x min(-1)), IS averaged 25.8 +/- 7.0% (n = 6; Endo: 0.039 +/- 0.008 ml x min(-1) x g(-1)) without and 24.7 +/- 4.7% (n = 6; Endo: 0.044 +/- 0.006 ml x min(-1) x g(-1)) with IP. At 5-min moderate ischemia in the presence of naloxone, Endo decreased from 0.90 +/- 0.07 to 0.28 +/- 0.03 ml x min(-1) x g(-1)and DeltaG decreased from -58.6 +/- 1.0 to -52.6 +/- 0.4 kJ/mol. Prolongation of ischemia to 90 min did not alter Endo, but DeltaG recovered toward control values (57.7 +/- 1.1 kJ/mol), and the myocardium remained viable. These responses are identical to those of nonnaloxone-treated pigs. Endogenous opioids are involved in IP but not in STMH in pigs.     

Stroke volume and cardiac output decrease at termination of obstructive apneas.

Patients with obstructive sleep apnea (OSA) experience repetitive nocturnal oscillations of systemic arterial pressure that occur in association with changes in respiration and changes in sleep state. To investigate cardiac function during the cycle of obstruction (apnea) and resumption of ventilation (recovery), we continuously measured left ventricular stroke volume (LVSV) and mean arterial blood pressure (MAP) during non-rapid-eye-movement sleep in six males with severe OSA (apnea/hypopnea index > or = 30 events/h associated with oxygen saturation < 82%). LVSV was assessed continuously using an ambulatory ventricular function monitor (VEST; Capintec). The apnea-recovery cycle was divided into three phases: 1) early apnea (EA), 2) late apnea (LA), and 3) recovery (Rec). In all subjects recovery was associated with an abrupt decrease in LVSV [54.0 +/- 14.5 (SD) ml] compared with either EA (91.4 +/- 14.7 ml; P < 0.001) or LA (77.1 +/- 15.2 ml; P < 0.005). Although heart rate increased with recovery, the increase was not sufficient to compensate for the decrease in LVSV so that cardiac output (CO) fell (EA: 6,247 +/- 739 ml/min; LA: 5,741 +/- 1,094 ml/min; Rec: 4,601 +/- 1,249 ml/min; EA vs. Rec, P < 0.01; LA vs. Rec, P < 0.025). Recovery was also associated with a significant increase in MAP. We speculate that such abrupt decreases in LVSV and CO at apnea termination, occurring coincident with the nadir of oxygen saturation, may further compromise tissue oxygen delivery.     

Ischemic and anesthetic preconditioning reduces cytosolic [Ca2+] and improves Ca(2+) responses in intact hearts

Ca(+) loading during reperfusion after myocardial ischemia is linked to reduced cardiac function. Like ischemic preconditioning (IPC), a volatile anesthetic given briefly before ischemia can reduce reperfusion injury. We determined whether IPC and sevoflurane preconditioning (SPC) before ischemia equivalently improve mechanical and metabolic function, reduce cytosolic Ca(2+) loading, and improve myocardial Ca(2+) responsiveness. Four groups of guinea pig isolated hearts were perfused: no ischemia, no treatment before 30-min global ischemia and 60-min reperfusion (control), IPC (two 2-min occlusions) before ischemia, and SPC (3.5 vol%, two 2-min exposures) before ischemia. Intracellular Ca(2+) concentration ([Ca(2+)](i)) was measured at the left ventricular (LV) free wall with the fluorescent probe indo 1. Ca(2+) responsiveness was assessed by changing extracellular [Ca(2+)]. In control hearts, initial reperfusion increased diastolic [Ca(2+)] and diastolic LV pressure (LVP), and the maximal and minimal derivatives of LVP (dLVP/dt(max) and dLVP/dt(min), respectively), O(2) consumption, and cardiac efficiency (CE). Throughout reperfusion, IPC and SPC similarly reduced ischemic contracture, ventricular fibrillation, and enzyme release, attenuated rises in systolic and diastolic [Ca(2+)], improved contractile and relaxation indexes, O(2) consumption, and CE, and reduced infarct size. Diastolic [Ca(2+)] at 50% dLVP/dt(min) was right shifted by 32-53 +/- 8 nM after 30-min reperfusion for all groups. Phasic [Ca(2+)] at 50% dLVP/dt(max) was not altered in control but was left shifted by -235 +/- 40 nM [Ca(2+)] after IPC and by -135 +/- 20 nM [Ca(2+)] after SPC. Both SPC and IPC similarly reduce Ca(2+) loading, while augmenting contractile responsiveness to Ca(2+), improving postischemia cardiac function and attenuating permanent damage.     

Effective protection by NHE-1 inhibition in ischemic and reperfused heart under preconditioning blockade

We compared the protective effects of ischemic preconditioning (IPC) and the Na(+)/H(+) exchanger-1 (NHE-1) inhibitor cariporide in isolated rat hearts subjected to global ischemia (45 or 90 min) and 30-min reperfusion and determined the protective effects of cariporide under IPC blockade with the mitochondrial ATP-sensitive K(+) channel blocker 5-hydroxydecanoate (5-HD). With 45-min ischemia, both IPC and cariporide equally increased maximum recovery of left ventricular developed pressure twofold (P < 0.05), although recovery was significantly greater with cariporide for the first 15 min of reperfusion. 5-HD almost completely blocked the protective effects of IPC on recovery but had no influence on the salutary effects of cariporide. With 90-min ischemic control, recovery was only 3% of preischemia and was unaffected by IPC, although cariporide increased recovery to approximately 30% (P < 0.05). This was associated with a 37% preservation of viable cardiac cells, whereas no structurally intact cells were found in either IPC or control hearts. Our study shows that NHE-1 inhibition is a more effective cardioprotective strategy than IPC in this model, possibly because of enhanced myocyte salvage, and because protection by NHE-1 inhibition is completely unaffected by IPC blockade with 5-HD.     

Atrial distension, arterial pulsation, and vasopressin release during negative pressure breathing in humans

During an antiorthostatic posture change, left atrial (LA) diameter and arterial pulse pressure (PP) increase, and plasma arginine vasopressin (AVP) is suppressed. By comparing the effects of a 15-min posture change from seated to supine with those of 15-min seated negative pressure breathing in eight healthy males, we tested the hypothesis that with similar increases in LA diameter, suppression of AVP release is dependent on the degree of increase in PP. LA diameter increased similarly during the posture change and negative pressure breathing (-9 to -24 mmHg) from between 30 and 31 +/- 1 to 34 +/- 1 mm (P < 0.05). The increase in PP from 38 +/- 2 to 44 +/- 2 mmHg (P < 0.05) was sustained during the posture change but only increased during the initial 5 min of negative pressure breathing from 36 +/- 3 to 42 +/- 3 mmHg (P < 0.05). Aortic transmural pressure decreased during the posture change and increased during negative pressure breathing. Plasma AVP was suppressed to a lower value during the posture change (from 1.5 +/- 0.3 to 1.2 +/- 0.2 pg/ml, P < 0.05) than during negative pressure breathing (from 1.5 +/- 0.3 to 1.4 +/- 0.3 pg/ml). Plasma norepinephrine was decreased similarly during the posture change and negative pressure breathing compared with seated control. In conclusion, the results are in compliance with the hypothesis that during maneuvers with similar cardiac distension, suppression of AVP release is dependent on the increase in PP and, furthermore, probably unaffected by static aortic baroreceptor stimulation.     

Glycogen turnover and anaplerosis in preconditioned rat hearts

Using (13)C NMR, we tested the hypothesis that protection by preconditioning is associated with reduced glycogenolysis during ischemia. Preconditioned rat hearts showed improved postischemic function and reduced ischemic damage relative to ischemic controls after 30 min stop-flow ischemia and 30 min reperfusion (contractility: 30+/-10 vs. 2+/-2%; creatine kinase release: 41+/-4 vs. 83+/-15 U/g; both P<0.05). Preconditioning decreased preischemic [(13)C]glycogen by 24% (a 10% decrease in total glycogen), and delayed ischemic [(13)C]glycogen consumption by 5-10 min, reducing ischemic glycogenolysis without changing acidosis relative to controls. Upon reperfusion, glycogen synthesis resumed only after preconditioning. Glutamate (13)C-isotopomer analysis showed recovery of Krebs cycle activity with higher anaplerosis than before ischemia (23+/-4 vs. 11+/-3%, P<0.05), but in controls reperfusion failed to restore flux. Compared to control, preconditioning before 20 min ischemia increased contractility (86+/-10 vs. 29+/-14%, P<0.05) and restored preischemic anaplerosis (13+/-3 vs. 39+/-9%, P<0.05). Preconditioning is associated with reduced glycogenolysis early during ischemia. However, protection does not rely on major variations in intracellular pH, as proposed earlier. Our isotopomer data suggest that preconditioning accelerates metabolic and functional recovery during reperfusion by more efficient/active replenishment of the depleted Krebs cycle.     

Evidence of sustained forearm vasodilatation after brief isocapnic hypoxia.

Healthy subjects exposed to 20 min of hypoxia increase ventilation and muscle sympathetic nerve activity (MSNA). After return to normoxia, although ventilation returns to baseline, MSNA remains elevated for up to an hour. Because forearm vascular resistance is not elevated after hypoxic exposure, we speculated that the increased MSNA might be a compensatory response to sustained release of endogenous vasodilators. We studied the effect of isocapnic hypoxia (mean arterial oxygen saturation 81.6 +/- 4.1%, end-tidal Pco2 44.7 +/- 6.3 Torr) on plethysmographic forearm blood flow (FBF) in eight healthy volunteers while infusing intra-arterial phentolamine to block local alpha-receptors. The dominant arm served as control. Forearm arterial vascular resistance (FVR) was calculated as the mean arterial pressure (MAP)-to-FBF ratio. MAP, heart rate (HR), and FVR were reported at 5-min intervals at baseline, then while infusing phentolamine during room air, isocapnic hypoxia, and recovery. Despite increases in HR during hypoxia, there was no change in MAP throughout the study. By design, FVR decreased during phentolamine infusion. Hypoxia further decreased FVR in both forearms. With continued phentolamine infusion, FVR after termination of the exposure (17.47 +/- 6.3 mmHg x min x ml(-1) x 100 ml of tissue) remained lower than preexposure baseline value (23.05 +/- 8.51 mmHg x min x ml(-1) x 100 ml of tissue; P < 0.05). We conclude that, unmasked by phentolamine, the vasodilation occurring during hypoxia persists for at least 30 min after the stimulus. This vasodilation may contribute to the sustained MSNA rise observed after hypoxia.     

Sex-specific influence of aging on exercising leg blood flow.

Our previous work suggests that healthy human aging is associated with sex-specific differences in leg vascular responses during large muscle mass exercise (2-legged cycling) (Proctor DN, Parker BA. Microcirculation 13: 315-327, 2006). The present study determined whether age x sex interactions in exercising leg hemodynamics persist during small muscle mass exercise that is not limited by cardiac output. Thirty-one young (20-30 yr; 15 men/16 women) and 31 older (60-79 yr; 13 men/18 women) healthy, normally active adults performed graded single-leg knee extensions to maximal exertion. Femoral artery blood velocity and diameter (Doppler ultrasound), heart rate (ECG), and beat-to-beat arterial blood pressure (mean arterial pressure, radial artery tonometry) were measured during each 3-min work rate (4.8 and 8 W/stage for women and men, respectively). The results (means +/- SE) were as follows. Despite reduced resting leg blood flow and vascular conductance, older men exhibited relatively preserved exercising leg hemodynamic responses. Older women, by contrast, exhibited attenuated hyperemic (young: 52 +/- 3 ml.min(-1).W(-1); vs. older: 40 +/- 4 ml.min(-1).W(-1); P = 0.02) and vasodilatory responses (young: 0.56 +/- 0.06 ml.min(-1).mmHg(-1).W(-1) vs. older: 0.37 +/- 0.04 ml.min(-1).mmHg(-1) W(-1); P < 0.01) to exercise compared with young women. Relative (percentage of maximal) work rate comparisons of all groups combined also revealed attenuated vasodilator responses in older women (P < 0.01 for age x sex x work rate interaction). These sex-specific age differences were not abolished by consideration of hemoglobin, quadriceps muscle, muscle recruitment, and mechanical influences on muscle perfusion. Collectively, these findings suggest that local factors contribute to the sex-specific effects of aging on exercising leg hemodynamics in healthy adults.     

Pulmonary neutrophil kinetics in sheep: effects of altered hemodynamics

We investigated the effect of elevated left atrial pressure and reduced cardiac output on pulmonary neutrophil kinetics in the sheep. Sheep neutrophils were isolated, labeled with 111In-oxine, and reinfused. Erythrocytes were labeled with [99mTc]pertechnetate. A gamma camera measured the lung activities of the labeled neutrophils and erythrocytes. The results indicated that 38.5% of the total injected neutrophils marginated in the lung. Pulmonary hemodynamics were altered by inflating a left atrial balloon three times in each sheep for 15-30 min to achieve 5- to 25-mmHg increments in pulmonary arterial wedge pressure. At least a 30-min recovery period was allowed between inflations. After each left atrial balloon inflation, neutrophil uptake remained unchanged from base line, despite decreased mean cardiac output to 0.67 +/- 0.24 (+/- SD) 1/min and increased pulmonary blood volume. The absence of pulmonary neutrophil uptake was confirmed by arterial-venous measurements. Increased pulmonary blood volume had little effect on lung neutrophil uptake, suggesting that most of the pulmonary neutrophils are marginated. We conclude that the lungs have a large marginated neutrophil pool compared with the circulating pool and that reduced cardiac output and elevated left atrial pressure have no effect on pulmonary neutrophil kinetics in the sheep.     

Distribution of respiratory muscle and organ blood flow during endotoxic shock in dogs

Respiratory muscle blood flow and organ blood flow during endotoxic shock were studied in spontaneously breathing dogs (SB, n = 6) and mechanically ventilated dogs (MV, n = 5) with radiolabeled microspheres. Shock was produced by a 5-min intravenous injection of Escherichia coli endotoxin (0.55:B5, Difco, 10 mg/kg) suspended in saline. Mean arterial blood pressure and cardiac output in the SB group dropped to 59 and 45% of control values, respectively. There was a similar reduction in arterial blood pressure and cardiac output in the MV group. Total respiratory muscle blood flow in the SB group increased significantly from the control value of 51 +/- 4 ml/min (mean +/- SE) to 101 +/- 22 ml/min at 60 min of shock. In the MV group, respiratory muscle perfusion fell from control values of 43 +/- 12 ml/min to 25 +/- 3 ml/min at 60 min of shock. In the SB group, 8.8% of the cardiac output was received by the respiratory muscle during shock in comparison with 1.9% in the MV group. In both groups of dogs, blood flow to most organs was compromised during shock; however, blood flow to the brain, gut, and skeletal muscles was higher in the MV group than in the SB group. Thus by mechanical ventilation a fraction of the cardiac output used by the working respiratory muscles can be made available for perfusion of other organs during endotoxic shock.     

Anesthetic preconditioning: triggering role of reactive oxygen and nitrogen species in isolated hearts

We postulated that anesthetic preconditioning (APC) is triggered by reactive oxygen/nitrogen species (ROS/RNS). We used the isolated guinea pig heart perfused with L-tyrosine, which reacts with ROS and RNS to form strong oxidants, principally peroxynitrite (ONOO(-)), and then forms fluorescent dityrosine. ROS scavengers superoxide dismutase, catalase, and glutathione (SCG) and NO. synthesis inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) were given 5 min before and after sevoflurane preconditioning stimuli. Drugs were washed out before 30 min of ischemia and 120 min of reperfusion. Groups were control (nontreated ischemia control), APC (two, 2-min periods of perfusion with 0.32 +/- 0.02 mM of sevoflurane; separated by a 6-min period of perfusion without sevoflurane), SCG, APC + SCG, L-NAME, and APC + L-NAME. Effluent dityrosine at 1 min reperfusion was 56 +/- 6 (SE), 15 +/- 5, 40 +/- 5(++), 39 +/- 4(++), 35 +/- 4(++) , and 33 +/- 5(++) units ((++)P< 0.05 vs. APC), respectively; left ventricular pressure (%baseline) at 60 min of reperfusion was 30 +/- 5(++), 60 +/- 4, 35 +/- 5(++), 37 +/- 5(++), 44 +/- 4, and 47 +/- 4; and infarct size (%total heart weight) was 50 +/- 5(++), 19 +/- 2, 48 +/- 3(++), 46 +/- 4(++), 42 +/- 4(++), and 45 +/- 2(++). Thus APC is initiated by ROS as shown by improved function, reduced infarct size, and reduced dityrosine on reperfusion; protective and ROS/RNS-reducing effect of APC were attenuated when bracketed by ROS scavengers or NO* inhibition.