Regulation of sympathetic nerve activity in heart failure: a role for nitric oxide and angiotensin II.
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The mechanisms by which sympathetic function is augmented in chronic heart failure (CHF) are not well understood. A previous study from this laboratory (Circ Res. 1998;82:496-502) indicated that blockade of nitric oxide (NO) synthesis resulted in only an increase in renal sympathetic nerve activity (RSNA) when plasma angiotensin II (Ang II) levels were elevated. The present study was undertaken to determine if NO reduces RSNA in rabbits with CHF when Ang II receptors are blocked. Twenty-four New Zealand White rabbits were instrumented with cardiac dimension crystals, a left ventricular pacing lead, and a pacemaker. After pacing at 360 to 380 bpm for approximately 3 weeks, a renal sympathetic nerve electrode and arterial and venous catheters were implanted. Studies were carried out in the conscious state 3 to 7 days after electrode implantation. The effects of a 1-hour infusion of sodium nitroprusside (SNP; 3 microgram . kg-1. min-1) on RSNA and mean arterial pressure (MAP) were determined before and after Ang II blockade with losartan (5 mg/kg) in normal and CHF rabbits. Changes in MAP were readjusted to normal with phenylephrine. Before losartan, SNP evoked a decrease in MAP and an increase in RSNA in both groups that was baroreflex-mediated, because both MAP and RSNA returned to control when phenylephrine was administered. In the normal group, losartan plus SNP caused a reduction in MAP and an increase in RSNA that was 152.6+/-9.8% of control. Phenylephrine returned both MAP and RSNA back to the control levels. However, in the CHF group, losartan plus SNP evoked a smaller change in RSNA for equivalent changes in MAP (117.1+/-4.1% of control). On returning MAP to the control level with phenylephrine, RSNA was reduced to 65.2+/-2.9% of control (P<0. 0001). These data suggest that endogenous Ang II contributes to the sympathoexcitation in the CHF state and that blockade of Ang II receptors plus providing an exogenous source of NO reduces RSNA below the elevated baseline levels. We conclude that both a loss of NO and an increase in Ang II are necessary for sustained increases in sympathetic nerve activity in the CHF state. (+info)
Heart rate during exercise with leg vascular occlusion in spinal cord-injured humans.
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Feed-forward and feedback mechanisms are both important for control of the heart rate response to muscular exercise, but their origin and relative importance remain inadequately understood. To evaluate whether humoral mechanisms are of importance, the heart rate response to electrically induced cycling was studied in participants with spinal cord injury (SCI) and compared with that elicited during volitional cycling in able-bodied persons (C). During voluntary exercise at an oxygen uptake of approximately 1 l/min, heart rate increased from 66 +/- 4 to 86 +/- 4 (SE) beats/min in seven C, and during electrically induced exercise at a similar oxygen uptake in SCI it increased from 73 +/- 3 to 110 +/- 8 beats/min. In contrast, blood pressure increased only in C (from 88 +/- 3 to 99 +/- 4 mmHg), confirming that, during exercise, blood pressure control is dominated by peripheral neural feedback mechanisms. With vascular occlusion of the legs, the exercise-induced increase in heart rate was reduced or even eliminated in the electrically stimulated SCI. For C, heart rate tended to be lower than during exercise with free circulation to the legs. Release of the cuff elevated heart rate only in SCI. These data suggest that humoral feedback is of importance for the heart rate response to exercise and especially so when influence from the central nervous system and peripheral neural feedback from the working muscles are impaired or eliminated during electrically induced exercise in individuals with SCI. (+info)
Alterations of heart function and Na+-K+-ATPase activity by etomoxir in diabetic rats.
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To examine the role of changes in myocardial metabolism in cardiac dysfunction in diabetes mellitus, rats were injected with streptozotocin (65 mg/kg body wt) to induce diabetes and were treated 2 wk later with the carnitine palmitoyltransferase inhibitor (carnitine palmitoyltransferase I) etomoxir (8 mg/kg body wt) for 4 wk. Untreated diabetic rats exhibited a reduction in heart rate, left ventricular systolic pressure, and positive and negative rate of pressure development and an increase in end-diastolic pressure. The sarcolemmal Na+-K+-ATPase activity was depressed and was associated with a decrease in maximal density of binding sites (Bmax) value for high-affinity sites for [3H]ouabain, whereas Bmax for low-affinity sites was unaffected. Treatment of diabetic animals with etomoxir partially reversed the depressed cardiac function with the exception of heart rate. The high serum triglyceride and free fatty acid levels were reduced, whereas the levels of glucose, insulin, and 3,3',-5-triiodo-L-thyronine were not affected by etomoxir in diabetic animals. The activity of Na+-K+-ATPase expressed per gram heart weight, but not per milligram sarcolemmal protein, was increased by etomoxir in diabetic animals. Furthermore, Bmax (per g heart wt) for both low-affinity and high-affinity binding sites in control and diabetic animals was increased by etomoxir treatment. Etomoxir treatment also increased the depressed left ventricular weight of diabetic rats and appeared to increase the density of the sarcolemma and transverse tubular system to normalize Na+-K+-ATPase activity. Therefore, a shift in myocardial substrate utilization may represent an important signal for improving the depressed cardiac function and Na+-K+-ATPase activity in diabetic rat hearts with impaired glucose utilization. (+info)
Pulmonary capillary perfusion: intra-alveolar fractal patterns and interalveolar independence.
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Pulmonary capillary perfusion was analyzed from videomicroscopic recordings to determine flow switching characteristics among capillary segments in isolated, blood-perfused canine lungs. Within each alveolus, the rapid switching pattern was repetitive and was, therefore, nonrandom (fractal dimensions near 1.0). This self-similarity over time was unexpected in a network widely considered to be passive. Among adjacent alveoli, the relationship among the switching patterns was even more surprising, for there was virtually no relationship between the perfusion patterns (coefficients of determination approaching zero). These findings demonstrated that the perfusion patterns in individual alveolar walls were independent of their next-door neighbors. The lack of dependence among neighboring networks suggests an interesting characteristic: the failure of one alveolar-capillary bed would leave its neighbors relatively unaffected, a feature of a robust design. (+info)
Lactate kinetics at rest and during exercise in lambs with aortopulmonary shunts.
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In a previous study [G. C. M. Beaufort-Krol, J. Takens, M. C. Molenkamp, G. B. Smid, J. J. Meuzelaar, W. G. Zijlstra, and J. R. G. Kuipers. Am. J. Physiol. 275 (Heart Circ. Physiol. 44): H1503-H1512, 1998], a lower systemic O2 supply was found in lambs with aortopulmonary left-to-right shunts. To determine whether the lower systemic O2 supply results in increased anaerobic metabolism, we used [1-13C]lactate to investigate lactate kinetics in eight 7-wk-old lambs with shunts and eight control lambs, at rest and during moderate exercise [treadmill; 50% of peak O2 consumption (VO2)]. The mean left-to-right shunt fraction in the shunt lambs was 55 +/- 3% of pulmonary blood flow. Arterial lactate concentrations and the rate of appearance (Ra) and disappearance (Rd) of lactate were similar in shunt and control lambs, both at rest (lactate: 1, 201 +/- 76 vs. 1,214 +/- 151 micromol/l; Ra = Rd: 12.97 +/- 1.71 vs. 12.55 +/- 1.25 micromol. min-1. kg-1) and during a similar relative workload. We found a positive correlation between Ra and systemic blood flow, O2 supply, and VO2 in both groups of lambs. In conclusion, shunt lambs have similar lactate kinetics as do control lambs, both at rest and during moderate exercise at a similar fraction of their peak VO2, despite a lower systemic O2 supply. (+info)
Effects of muscle perfusion pressure on fatigue and systemic arterial pressure in human subjects.
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The effects of changes in arterial perfusion across the physiological range on the fatigue of a working human hand muscle were studied in seven normal subjects. With the hand above heart level, subjects made repeated isometric contractions of the adductor pollicis muscle at 50% of maximal voluntary contraction in a 6-s on, 4-s off cycle. To assess fatigue, a maximal isometric twitch was elicited in each "off" period by electrical stimulation of the ulnar nerve. The experiment was repeated at least 2 days later with the hand at heart level. Five subjects showed faster fatigue with the arm elevated, and two subjects showed little difference in fatigue for the two conditions. Central blood pressure rose in proportion to fatigue for the subjects overall and returned quickly to its initial level afterwards. We conclude that human muscle fatigue can be increased by physiological reductions in perfusion pressure. Central blood pressure increases as the muscle fatigues, a response that may partially offset declining muscle performance. (+info)
Mechanism for the posture-specific plasma volume increase after a single intense exercise protocol.
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To test the hypothesis that exercise-induced hypervolemia is a posture-dependent process, we measured plasma volume, plasma albumin content, and renal function in seven healthy subjects for 22 h after single upright (Up) or supine (Sup) intense (85% peak oxygen consumption rate) exercise. This posture was maintained for 5 h after exercise. Plasma volume decreased during exercise but returned to control levels by 5 h of recovery in both postures. By 22 h of recovery, plasma volume increased 2.4 +/- 0.8 ml/kg in Up but decreased 2.1 +/- 0.8 ml/kg in Sup. The plasma volume expansion in Up was accompanied by an increase in plasma albumin content (0.11 +/- 0.04 g/kg; P < 0.05). Plasma albumin content was unchanged in Sup. Urine volume and sodium clearance were lower in Up than Sup (P < 0.05) by 5 h of recovery. These data suggest that increased plasma albumin content contributes to the acute phase of exercise-induced hypervolemia. More importantly, the mechanism by which exercise influences the distribution of albumin between extra- and intravascular stores after exercise is altered by posture and is unknown. We speculate that factors associated with postural changes (e.g., central venous pressure) modify the increase in plasma albumin content and the plasma volume expansion after exercise. (+info)
Effects of isoproterenol on myocardial structure and function in septic rats.
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In this study we sought to determine the effect of sepsis on two sequelae of prolonged (24-h) beta-agonist administration, myocardial hypertrophy and catecholamine-induced cardiotoxicity. Sprague-Dawley rats were randomized to cecal ligation and perforation (CLP) or sham study groups and then further randomized to receive isoproterenol (2.4 mg. kg-1. day-1 iv) or placebo treatment. At 24 h, myocardial function was assessed by using the Langendorff isolated-heart technique or the heart processed for plain light microscopy. We found that 1) sepsis reduced contractile function, indicated by a rightward shift in the Starling curve (ANOVA with repeated measures, sepsis effect, P < 0.002); 2) sepsis-induced myocardial depression was reversed by isoproterenol treatment (isoproterenol effect, P < 0.0001); 3) sepsis reduced, but did not block, isoproterenol-induced myocardial hypertrophy (isoproterenol effect, P < 0.0001); 4) sepsis did not protect the heart from catecholamine-induced tissue injury; 5) the septic heart was protected against the effects of ischemiareperfusion (decreased postreperfusion resting tension, ANOVA with repeated measures, P < 0.01), an effect attenuated by isoproterenol treatment (P < 0.005); and 6) sepsis reduced the incidence of sustained asystole or ventricular fibrillation after ischemia-reperfusion (P < 0.05), an effect also attenuated by isoproterenol treatment (P < 0.01). We conclude that, in sepsis, beta-agonists induce changes in myocardial weight and function consistent with acute myocardial hypertrophy. These changes occur at the expense of significant tissue injury and increased sensitivity to ischemia-reperfusion-induced tissue injury. (+info)