Muscle metaboreflex control of coronary blood flow

We investigated the effect of muscle metaboreflex activation on left circumflex coronary blood flow (CBF) and vascular conductance (CVC) in conscious, chronically instrumented dogs during treadmill exercise ranging from mild to severe workloads. Metaboreflex responses were also observed during mild exercise with constant heart rate (HR) of 225 beats/min and beta(1)-adrenergic receptor blockade to attenuate the substantial reflex increases in cardiac work. The muscle metaboreflex was activated via graded partial occlusion of hindlimb blood flow. During mild exercise, with muscle metaboreflex activation, hindlimb ischemia elicited significant reflex increases in mean arterial pressure (MAP), HR, and cardiac output (CO) (+39.0 +/- 5.2 mmHg, +29.9 +/- 7.7 beats/min, and +2.0 +/- 0.4 l/min, respectively; all changes, P < 0.05). CBF increased from 51.9 +/- 4.3 to 88.5 +/- 6.6 ml/min, (P < 0.05), whereas no significant change in CVC occurred (0.56 +/- 0.06 vs. 0.59 +/- 0.05 ml. min(-1). mmHg(-1); P > 0.05). Similar responses were observed during moderate exercise. In contrast, with metaboreflex activation during severe exercise, no further increases in CO or HR occurred, the increases in MAP and CBF were attenuated, and a significant reduction in CVC was observed (1.00 +/- 0.12 vs. 0.90 +/- 0.13 ml. min(-1). mmHg(-1); P < 0.05). Similarly, when the metaboreflex was activated during mild exercise with the rise in cardiac work lessened (via constant HR and beta(1)-blockade), no increase in CO occurred, the MAP and CBF responses were attenuated (+15.6 +/- 4.5 mmHg, +8.3 +/- 2 ml/min), and CVC significantly decreased from 0.63 +/- 0.11 to 0.53 +/- 0.10 ml. min(-1). mmHg(-1). We conclude that the muscle metaboreflex induced increases in sympathetic nerve activity to the heart functionally vasoconstricts the coronary vasculature.     

Changes in diastolic coronary resistance during submaximal exercise in conditioned dogs

Diastolic coronary resistance (DCR) was studied in 10 conscious dogs in the untrained (UT) and partially trained (PT) condition. The PT regime consisted of treadmill running 5 days/wk for 4-5 wk. Left circumflex coronary flow, aortic pressure, and heart rate were measured, and diastolic coronary resistance (DCR) was calculated. Adrenergic blockade was achieved with propranolol (1 mg/kg, iv) (beta B) and phentolamine (1 mg/kg, iv) (alpha B). During submaximal exercise in the UT condition, DCR fell from a resting value of 3.84 +/- 0.24 Torr . ml-1 . min with increasing work load to 1.57 +/- 0.12 Torr . ml-1 . min at 6.4 km/h (speed)/16% (grade). The decrease in DCR during submaximal exercise was greater in the PT than in the UT condition. DCR following alpha-adrenergic blockade was not significantly changed in the UT and PT conditions (e.g., at 6.4 km/h (speed)/16% (grade), 1.10 +/- 0.141 vs. 1.03 +/- 0.107 Torr . ml-1 . min, whereas following beta-adrenergic blockade, DCR was larger in the UT compared with the PT condition (e.g., at 6.4 km/h (speed)/16% (grade), 2.03 +/- 0.091 vs. 1.73 +/- 0.073 Torr . ml-1 X min). Myocardial oxygen consumption was not significantly different in the PT and UT conditions, indicating no difference in metabolism with partial training. The present study suggests that during submaximal exercise in the PT condition there is a change in the neurogenic control of the coronary vasculature by a reduction in sympathetic neural activity on the coronary resistance vessels.     

Muscle metaboreflex-induced increases in cardiac sympathetic activity vasoconstrict the coronary vasculature.

Ischemia of active skeletal muscle evokes a powerful blood pressure-raising reflex termed the muscle metaboreflex (MMR). MMR activation increases cardiac sympathetic nerve activity, which increases heart rate, ventricular contractility, and cardiac output (CO). However, despite the marked increase in ventricular work, no coronary vasodilation occurs. Using conscious, chronically instrumented dogs, we observed MMR-induced changes in arterial pressure, CO, left circumflex coronary blood flow (CBF), and coronary vascular conductance (CVC) before and after alpha1-receptor blockade (prazosin, 100 microg/kg iv). MMR was activated during mild treadmill exercise by partially reducing hindlimb blood flow. In control experiments, MMR activation caused a substantial pressor response-mediated via increases in CO. Although CBF increased (+28.1 +/- 3.7 ml/min; P < 0.05), CVC did not change (0.45 +/- 0.05 vs. 0.47 +/- 0.06 ml x min(-1) x mmHg(-1), exercise vs. exercise with MMR activation, respectively; P > 0.05). Thus all of the increase in CBF was due to the increase in arterial pressure. In contrast, after prazosin, MMR activation caused a greater increase in CBF (+55.9 +/- 17.1 ml/min; P < 0.05 vs. control) and CVC rose significantly (0.59 +/- 0.08 vs. 0.81 +/- 0.17 ml x min(-1) x mmHg(-1), exercise vs. exercise with MMR activation, respectively; P < 0.05). A greater increase in CO also occurred (+2.01 +/- 0.1 vs. +3.27 +/- 1.1 l/min, control vs. prazosin, respectively; P < 0.05). We conclude that the MMR-induced increases in sympathetic activity to the heart functionally restrain coronary vasodilation, which may limit increases in ventricular function.     

Cerebral blood flow during static exercise in humans

Cerebral blood flow (CBF) was determined in humans at rest and during four consecutive unilateral static contractions of the knee extensors. Each contraction was maintained for 3 min 15 s with the subjects in a semisupine position. The contractions corresponded to 8, 16, 24, and 32% of the maximal voluntary contraction (MVC) and utilized alternate legs. CBF (measured by the 133Xe clearance technique) was expressed by a noncompartmental flow index (ISI). Heart rate and mean arterial pressure increased from resting values of 73 (55-80) beats/min and 88 (74-104) mmHg to 106 (86-138) beats/min and 124 (102-146) mmHg, respectively (P less than 0.0005), during the contraction at 32% MVC. Arterial PCO2 and central venous pressure did not change. Corrected to the average resting PCO2, CBF during control was 55 (35-73) ml.100 g-1.min-1 and remained constant during contractions. Cerebral vascular resistance increased from 1.5 (1.0-2.2) to 2.4 (1.4-3.0) mmHg. 100 g.min.ml-1 (P less than 0.025) at 32% of MVC. There was no difference in CBF between the two hemispheres at rest or during exercise. In contrast to dynamic leg exercise, static leg exercise is not associated with an increase in global CBF when measured by the 133Xe clearance technique.     

Altered muscle metaboreflex control of coronary blood flow and ventricular function in heart failure

We investigated the effect of muscle metaboreflex activation on left circumflex coronary blood flow (CBF), coronary vascular conductance (CVC), and regional left ventricular performance in conscious, chronically instrumented dogs during treadmill exercise before and after the induction of heart failure (HF). In control experiments, muscle metaboreflex activation during mild exercise elicited significant reflex increases in mean arterial pressure, heart rate, and cardiac output. CBF increased significantly, whereas no significant change in CVC occurred. There was no significant change in the minimal rate of myocardial shortening (-dl/dt(min)) with muscle metaboreflex activation during mild exercise (15.5 +/- 1.3 to 16.8 +/- 2.4 mm/s, P > 0.05); however, the maximal rate of myocardial relaxation (+dl/dt(max)) increased (from 26.3 +/- 4.0 to 33.7 +/- 5.7 mm/s, P < 0.05). Similar hemodynamic responses were observed with metaboreflex activation during moderate exercise, except there were significant changes in both -dl/dt(min) and dl/dt(max). In contrast, during mild exercise with metaboreflex activation during HF, no significant increase in cardiac output occurred, despite a significant increase in heart rate, inasmuch as a significant decrease in stroke volume occurred as well. The increases in mean arterial pressure and CBF were attenuated, and a significant reduction in CVC was observed (0.74 +/- 0.14 vs. 0.62 +/- 0.12 ml x min(-1) x mmHg(-1); P < 0.05). Similar results were observed during moderate exercise in HF. Muscle metaboreflex activation did not elicit significant changes in either -dl/dt(min) or +dl/dt(max) during mild exercise in HF. We conclude that during HF the elevated muscle metaboreflex-induced increases in sympathetic tone to the heart functionally vasoconstrict the coronary vasculature, which may limit increases in myocardial performance.     

Arterial baroreflex control of heart rate during exercise in postural tachycardia syndrome.

Patients with postural tachycardia syndrome (POTS) have excessive tachycardia without hypotension during orthostasis as well as exercise. We tested the hypothesis that excessive tachycardia during exercise in POTS is not related to abnormal baroreflex control of heart rate (HR). Patients (n = 13) and healthy controls (n = 10) performed graded cycle exercise at 25, 50, and 75 W in both supine and upright positions while arterial pressure (arterial catheter) and HR (ECG) were measured. Baroreflex sensitivity of HR was assessed by bolus intravenous infusion of phenylephrine at each workload. In both positions, HR was higher in the patients than the controls during exercise. Supine baroreflex sensitivity (HR/systolic pressure) in POTS patients was -1.3 +/- 0.1 beats.min(-1).mmHg(-1) at rest and decreased to -0.6 +/- 0.1 beats.min(-1).mmHg(-1) during 75-W exercise, neither significantly different from the controls (P > 0.6). In the upright position, baroreflex sensitivity in POTS patients at rest (-1.4 +/- 0.1 beats.min(-1).mmHg(-1)) was higher than the controls (-1.0 +/- 0.1 beats.min(-1).mmHg(-1)) (P < 0.05), and it decreased to -0.1 +/- 0.04 beats.min(-1).mmHg(-1) during 75-W exercise, lower than the controls (-0.3 +/- 0.09 beats.min(-1).mmHg(-1)) (P < 0.05). The reduced arterial baroreflex sensitivity of HR during upright exercise was accompanied by greater fluctuations in systolic and pulse pressure in the patients than in the controls with 56 and 90% higher coefficient of variations, respectively (P < 0.01). However, when baroreflex control of HR was corrected for differences in HR, it was similar between the patients and controls during upright exercise. These results suggest that the tachycardia during exercise in POTS was not due to abnormal baroreflex control of HR.     

Cardiac response to submaximal exercise in dogs susceptible to sudden cardiac death

The hemodynamic response to submaximal exercise was investigated in 38 mongrel dogs with healed anterior wall myocardial infarctions. The dogs were chronically instrumented to measure heart rate (HR), left ventricular pressure (LVP), LVP rate of change, and coronary blood flow. A 2 min coronary occlusion was initiated during the last minute of an exercise stress test and continued for 1 min after cessation of exercise. Nineteen dogs had ventricular fibrillation (susceptible) while 19 animals did not (resistant) during this test. The cardiac response to submaximal exercise was markedly different between the two groups. The susceptible dogs exhibited a significantly higher HR and left ventricular end-diastolic pressure (LVEDP) but a significantly lower left ventricular systolic pressure (LVSP) in response to exercise than did the resistant animals. (For example, response to 6.4 kph at 8% grade; HR, susceptible 201.4 +/- 5.1 beats/min vs. resistant 176.2 +/- 5.6 beats/min; LVEDP, susceptible 19.4 +/- 1.1 mmHg vs. resistant 12.3 +/- 1.7 mmHg; LVSP, susceptible 136.9 +/- 7.9 mmHg vs. resistant 154.6 +/- 9.8 mmHg.) beta-Adrenergic receptor blockade with propranolol reduced the difference noted in the HR response but exacerbated the LVP differences (response to 6.4 kph at 8% grade; HR, susceptible 163.4 +/- 4.7 mmHg vs. resistant 150.3 +/- 6.4 mmHg; LVEDP susceptible 28.4 +/- 2.1 mmHg vs. resistant 19.6 +/- 3.0 mmHg; LVSP, susceptible 122.2 +/- 8.1 mmHg vs. resistant 142.8 +/- 10.7 mmHg). These data indicate that the animals particularly vulnerable to ventricular fibrillation also exhibit a greater degree of left ventricular dysfunction and an increased sympathetic efferent activity.     

Differences in the postexercise threshold for cutaneous active vasodilation between men and women

The purpose of this study was to evaluate the possible differences in the postexercise cutaneous vasodilatory response between men and women. Fourteen subjects (7 men and 7 women) of similar age, body composition, and fitness status remained seated resting for 15 min or cycled for 15 min at 70% of peak oxygen consumption followed by 15 min of seated recovery. Subjects then donned a liquid-conditioned suit. Mean skin temperature was clamped at approximately 34 degrees C for 15 min. Mean skin temperature was then increased at a rate of 4.3 +/- 0.8 degrees C/h while local skin temperature was clamped at 34 degrees C. Skin blood flow was measured continuously at two forearm skin sites, one with (UT) and without (BT) (treated with bretylium tosylate) intact alpha-adrenergic vasoconstrictor activity. The exercise threshold for cutaneous vasodilation in women (37.51 +/- 0.08 degrees C and 37.58 +/- 0.04 degrees C for UT and BT, respectively) was greater than that measured in men (37.33 +/- 0.06 degrees C and 37.35 +/- 0.06 degrees C for UT and BT, respectively) (P < 0.05). Core temperatures were similar to baseline before the start of whole body warming for all conditions. Postexercise heart rate (HR) for the men (77 +/- 4 beats/min) and women (87 +/- 6 beats/min) were elevated above baseline (61 +/- 3 and 68 +/- 4 beats/min for men and women, respectively), whereas mean arterial pressure (MAP) for the men (84 +/- 3 mmHg) and women (79 +/- 3 mmHg) was reduced from baseline (93 +/- 3 and 93 +/- 4 mmHg for men and women, respectively) (P < 0.05). A greater increase in HR and a greater decrease in the MAP postexercise were noted in women (P < 0.05). No differences in core temperature, HR, and MAP were measured in the no-exercise trial. The postexercise threshold for cutaneous vasodilation measured at the UT and BT sites for men (37.15 +/- 0.03 degrees C and 37.16 +/- 0.04 degrees C, respectively) and women (37.36 +/- 0.05 degrees C and 37.42 +/- 0.03 degrees C, respectively) were elevated above no exercise (36.94 +/- 0.07 degrees C and 36.97 +/- 0.05 degrees C for men and 36.99 +/- 0.09 degrees C and 37.03 +/- 0.11 degrees C for women for the UT and BT sites, respectively) (P < 0.05). A difference in the magnitude of the thresholds was measured between women and men (P < 0.05). We conclude that women have a greater postexercise onset threshold for cutaneous vasodilation than do men and that the primary mechanism influencing the difference between men and women in postexercise skin blood flow is likely the result of an altered active vasodilatory response and not an increase in adrenergic vasoconstrictor tone.     

Exogenous NO administration and alpha-adrenergic vasoconstriction in human limbs.

Nitric oxide (NO) is capable of blunting alpha-adrenergic vasoconstriction in contracting skeletal muscles of experimental animals (functional sympatholysis). We therefore tested the hypothesis that exogenous NO administration can blunt alpha-adrenergic vasoconstriction in resting human limbs by measuring forearm blood flow (FBF; Doppler ultrasound) and blood pressure in eight healthy males during brachial artery infusions of three alpha-adrenergic constrictors (tyramine, which evokes endogenous norepinephrine release; phenylephrine, an alpha1-agonist; and clonidine, an alpha2-agonist). To simulate exercise hyperemia, the vasoconstriction caused by the alpha-agonists was compared during adenosine-mediated (>50% NO independent) and sodium nitroprusside-mediated (SNP; NO donor) vasodilation of the forearm. Both adenosine and SNP increased FBF from approximately 35-40 to approximately 200-250 ml/min. All three alpha-adrenergic constrictor drugs caused marked reductions in FBF and calculated forearm vascular conductance (P < 0.05). The relative reductions in forearm vascular conductance caused by the alpha-adrenergic constrictors during SNP infusion were similar (tyramine, -74 +/- 3 vs. -65 +/- 2%; clonidine, -44 +/- 6 vs. -44 +/- 6%; P > 0.05) or slightly greater (phenylephrine, -47 +/- 6 vs. -33 +/- 6%; P < 0.05) compared with the responses during adenosine. In conclusion, these results indicate that exogenous NO sufficient to raise blood flow to levels simulating those seen during exercise does not blunt alpha-adrenergic vasoconstriction in the resting human forearm.     

Altered cardiovascular responsiveness to adrenoceptor agonists in endurance-trained men

The influence of physical training on responses to intravenous infusions of phenylephrine (Phe) and isoproterenol (Iso) were investigated in 10 well-trained runners (WT) and 10 age-matched untrained controls (UT). The latter were reinvestigated after a 4-mo training period. The venous plasma Iso and Phe concentrations attained during infusions were lower in WT than in UT. Responses were related to the corresponding plasma concentrations. Phe-induced decreases and Iso-induced increases in heart rate were less pronounced (P less than 0.01) in WT than in UT. At venous plasma concentrations of 100 nM Phe and 0.8 nM Iso, the responses were -9 +/- 1 and 30 +/- 2, and -17 +/- 2 and 44 +/- 4 beats/min, respectively. Increases in blood pressures during Phe infusions were greater in WT than in UT (100 nM Phe: systolic 36 +/- 3 vs. 25 +/- 3 mmHg, P less than 0.05). The Iso-induced decrease in diastolic blood pressure was also more pronounced in WT (0.8 nM Iso: -29 +/- 3 vs. -15 +/- 2 mmHg, P less than 0.01). Iso-induced changes in systolic time intervals showed no consistent differences between training states. Increases in plasma adenosine 3',5'-cyclic monophosphate during Iso infusions were smaller (P less than 0.05) in WT than in UT, whereas increases in plasma glycerol were larger (P less than 0.05). Lymphocyte beta 2-adrenoceptor function and binding characteristics did not differ between training states. In summary, the present results indicate that beta-adrenergic vasodilator and alpha-adrenergic vasopressor responses are enhanced in endurance-trained subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sympathetic adaptations to one-legged training.

The purpose of the present study was to determine the effect of leg exercise training on sympathetic nerve responses at rest and during dynamic exercise. Six men were trained by using high-intensity interval and prolonged continuous one-legged cycling 4 day/wk, 40 min/day, for 6 wk. Heart rate, mean arterial pressure (MAP), and muscle sympathetic nerve activity (MSNA; peroneal nerve) were measured during 3 min of upright dynamic one-legged knee extensions at 40 W before and after training. After training, peak oxygen uptake in the trained leg increased 19 +/- 2% (P < 0.01). At rest, heart rate decreased from 77 +/- 3 to 71 +/- 6 beats/min (P < 0.01) with no significant changes in MAP (91 +/- 7 to 91 +/- 11 mmHg) and MSNA (29 +/- 3 to 28 +/- 1 bursts/min). During exercise, both heart rate and MAP were lower after training (108 +/- 5 to 96 +/- 5 beats/min and 132 +/- 8 to 119 +/- 4 mmHg, respectively, during the third minute of exercise; P < 0.01). MSNA decreased similarly from rest during the first 2 min of exercise both before and after training. However, MSNA was significantly less during the third minute of exercise after training (32 +/- 2 to 22 +/- 3 bursts/min; P < 0.01). This training effect on MSNA remained when MSNA was expressed as bursts per 100 heartbeats. Responses to exercise in five untrained control subjects were not different at 0 and 6 wk. These results demonstrate that exercise training prolongs the decrease in MSNA during upright leg exercise and indicates that attenuation of MSNA to exercise reported with forearm training also occurs with leg training.     

Exercise training changes autonomic cardiovascular balance in mice.

Experiments were performed to investigate the influence of exercise training on cardiovascular function in mice. Heart rate, arterial pressure, baroreflex sensitivity, and autonomic control of heart rate were measured in conscious, unrestrained male C57/6J sedentary (n = 8) and trained mice (n = 8). The exercise training protocol used a treadmill (1 h/day; 5 days/wk for 4 wk). Baroreflex sensitivity was evaluated by the tachycardic and bradycardic responses induced by sodium nitroprusside and phenylephrine, respectively. Autonomic control of heart rate and intrinsic heart rate were determined by use of methylatropine and propranolol. Resting bradycardia was observed in trained mice compared with sedentary animals [485 +/- 9 vs. 612 +/- 5 beats/min (bpm)], whereas mean arterial pressure was not different between the groups (106 +/- 2 vs. 108 +/- 3 mmHg). Baroreflex-mediated tachycardia was significantly enhanced in the trained group (6.97 +/- 0.97 vs. 1.6 +/- 0.21 bpm/mmHg, trained vs. sedentary), whereas baroreflex-mediated bradycardia was not altered by training. The tachycardia induced by methylatropine was significantly increased in trained animals (139 +/- 12 vs. 40 +/- 9 bpm, trained vs. sedentary), whereas the propranolol effect was significantly reduced in the trained group (49 +/- 11 vs. 97 +/- 11 bpm, trained vs. sedentary). Intrinsic heart rate was similar between groups. In conclusion, dynamic exercise training in mice induced a resting bradycardia and an improvement in baroreflex-mediated tachycardia. These changes are likely related to an increased vagal and decreased sympathetic tone, similar to the exercise response observed in humans.     

Central command blunts sensitivity of arterial baroreceptor-heart rate reflex at onset of voluntary static exercise

We have reported that baroreflex bradycardia by stimulation of the aortic depressor nerve is blunted at the onset of voluntary static exercise in conscious cats. Central command may contribute to the blunted bradycardia, because the most blunted bradycardia occurs immediately before exercise or when a forelimb is extended before force development. However, it remained unknown whether the blunted bradycardia is due to either reduced sensitivity of the baroreflex stimulus-response curve or resetting of the curve toward a higher blood pressure. To determine this, we examined the stimulus-response relationship between systolic (SAP) or mean arterial pressure (MAP) and heart rate (HR) at the onset of and during the later period of static exercise in seven cats (n = 348 trials) by changing arterial pressure with infusion of nitroprusside and phenylephrine or norepinephrine. The slope of the MAP-HR curve decreased at the onset of exercise to 48% of the preexercise value (2.9 +/- 0.4 beats x min(-1) x mmHg(-1)); the slope of the SAP-HR curve decreased to 59%. The threshold blood pressures of the stimulus-response curves, at which HR started to fall due to arterial baroreflex, were not affected. In contrast, the slopes of the stimulus-response curves during the later period of exercise returned near the preexercise levels, whereas the threshold blood pressures elevated 6-8 mmHg. The maximal plateau level of HR was not different before and during static exercise, denying an upward shift of the baroreflex stimulus-response curves. Thus central command is likely to attenuate sensitivity of the cardiac component of arterial baroreflex at the onset of voluntary static exercise without shifting the stimulus-response curve.     

K(ATP)(+) channels, nitric oxide, and adenosine are not required for local metabolic coronary vasodilation

The role of ATP-sensitive K(+) (K(ATP)(+)) channels, nitric oxide, and adenosine in coronary exercise hyperemia was investigated. Dogs (n = 10) were chronically instrumented with catheters in the aorta and coronary sinus and instrumented with a flow transducer on the circumflex coronary artery. Cardiac interstitial adenosine concentration was estimated from arterial and coronary venous plasma concentrations using a previously tested mathematical model. Experiments were conducted at rest and during graded treadmill exercise with and without combined inhibition of K(ATP)(+) channels (glibenclamide, 1 mg/kg iv), nitric oxide synthesis (N(omega)-nitro-L-arginine, 35 mg/kg iv), and adenosine receptors (8-phenyltheophylline, 3 mg/kg iv). During control exercise, myocardial oxygen consumption increased ~2.9-fold, coronary blood flow increased ~2.6-fold, and coronary venous oxygen tension decreased from 19.9 +/- 0.4 to 13.7 +/- 0.6 mmHg. Triple blockade did not significantly change the myocardial oxygen consumption or coronary blood flow response during exercise but lowered the resting coronary venous oxygen tension to 10.0 +/- 0.4 mmHg and during exercise to 6.2 +/- 0.5 mmHg. Cardiac adenosine levels did not increase sufficiently to overcome the adenosine receptor blockade. These results indicate that combined inhibition of K(ATP)(+) channels, nitric oxide synthesis, and adenosine receptors lowers the balance between total oxygen supply and consumption at rest but that these factors are not required for local metabolic coronary vasodilation during exercise.     

Vagal function impairment after exercise training.

The present investigation was undertaken to evaluate the vagal function of trained (T) and sedentary (S) rats by use of different approaches in the same animal. After 13 wk of exercise training (treadmill for 1 h 5 times/wk at 26.8 m/min and 15% grade), T rats had a resting heart rate (HR) slightly but significantly lower than S rats (299 +/- 3 vs. 308 +/- 3 beats/min). T rats had marked reduction of the intrinsic HR (329 +/- 4 vs. 369 +/- 5 beats/min) after blockade by methylatropine and propranolol. They also exhibited depressed vagal and sympathetic tonus. Baroreflex bradycardia (phenylephrine injections) was reduced, bradycardic responses produced by electrical stimulation of the vagus were depressed, and responses to methacholine injection were decreased in T rats. Therefore several evidences of vagal function impairment were observed in T rats. The resting bradycardia after exercise training is more likely to be dependent on alterations of the pacemaker cells, inasmuch as the intrinsic HR was markedly reduced.     

Exercise training enhances baroreflex control of heart rate by a vagal mechanism in rabbits with heart failure.

Moderate exercise training (Ex) enhances work capacity and quality of life in patients with chronic heart failure (CHF). We investigated the autonomic components of resting heart rate (HR) and the baroreflex control of HR in conscious, instrumented rabbits with pacing-induced CHF after Ex. Sham and CHF rabbits were exercise trained for 4 wk at 15-18 m/min, 6 days/wk. Arterial pressure and HR were recorded before and after metoprolol (1 mg/kg iv) or after atropine (0.2 mg/kg iv). Mean arterial pressure was altered by infusions of sodium nitroprusside and phenylephrine. The data were fit to a sigmoid (logistic) function. Baseline HRs were 266.5 +/- 8.4 and 232.1 +/- 1.6 beats/min in CHF and CHF Ex rabbits, respectively (P < 0.05). In the unblocked state, CHF rabbits had a significantly depressed peak baroreflex slope (1.7 +/- 0.3 vs. 5.6 +/- 0.7 beats. min(-1). mmHg(-1); P < 0.001) and HR range (128.6 +/- 34.5 vs. 253.2 +/- 20.3 beats/min; P < 0.05) compared with normal subjects. Ex increased baroreflex slope to 4.9 +/- 0.3 from 1.7 +/- 0.3 beats. min(-1). mmHg(-1) in unblocked rabbits (P < 0.001 compared with CHF non-Ex). Ex did not alter baroreflex function in sham animals. After metoprolol, baroreflex slope was significantly increased in CHF Ex rabbits (1.5 +/- 0.2 vs. 3.0 +/- 0.2 beats. min(-1). mmHg(-1); P < 0.05). After atropine, there was no significant change in baroreflex slope or HR range between CHF Ex and CHF rabbits. These data support the view that enhancement of baroreflex control of HR after Ex is due to an augmentation of vagal tone.     

Effect of differently induced plasma norepinephrine increments on norepinephrine sulfate formation

We investigated whether similar increments in venous plasma norepinephrine (NE) concentration caused by exercise and by intravenous NE infusion will elevate plasma norepinephrine sulfate (NES) to similar concentrations. In randomized order venous plasma NE concentration was elevated to similar concentrations by bicycle exercise (BE; 65% VO(2)max) and by intravenous NE infusion at rest (INF; 0.14 microg/min/kg). N = 11 subjects participated in the study. Increments in plasma NE and the area under curve of plasma NE were similar during BE (11.2 +/- 1.3 nM; 411 +/- 23 nM/min; means +/- S.E.) and INF (12.6 +/- 1.9 nM; 429 +/- 27 nM/min). Plasma NES was significantly elevated to similar concentrations with BE (from 5.7 +/- 1.0 to 8.5 +/- 1.3 nM) and with INF (from 5.6 +/- 0.9 to 8.9 +/- 1.0 nM). Plasma NE and NES concentration during control conditions remained unchanged. Heart rate decreased significantly to 43 +/- 1 beats/min with INF and increased significantly to 162 +/- 3 beats/min with BE. Systolic blood pressure increased with both, INF and BE (155 +/- 3 mmHg; 179 +/- 6 mmHg, respectively). Present findings firstly show that intravenously infused NE is sulfoconjugated in humans, indicating that a major part of NE is sulfoconjugated in blood or at sites easily accessible from blood. Secondly, plasma NE may be a useful additional marker for NES release.     

Hyaluronidase treatment of coronary glycocalyx increases reactive hyperemia but not adenosine hyperemia in dog hearts

Because adenosine is commonly used for inducing maximal coronary hyperemia in the clinic, it is imperative that adenosine-induced hyperemia (AH) resembles coronary hyperemia that can be attained by endogenous stimuli. In the present study we hypothesized that coronary reactive hyperemia (RH) is limited compared with AH due to the presence of the glycocalyx and that the AH response is therefore unable to detect glycocalyx modifications. In anesthetized open-chest dogs, blood flow and pressure were measured in the left circumflex artery. RH after 15-s occlusion was compared with an intracoronary infusion of adenosine (650 microg; AH) during control conditions and after intracoronary treatment of the glycocalyx with hyaluronidase (20.000 U, 2 x 20 min; n = 6) or heat-inactivated hyaluronidase (n = 5). During control, coronary conductance during RH was 1.49 +/- 0.15 ml.mmHg(-1).min(-1) and 76 +/- 7% of coronary conductance during AH (P < 0.05). After hyaluronidase, RH conductance increased (P < 0.01) by 43 +/- 13% and became 93 +/- 4% of AH conductance (P = NS). Heat-inactivated hyaluronidase had no effect on RH and AH conductance. Our results demonstrate that adenosine-induced coronary hyperemia profoundly exceeds RH and that the difference is virtually abolished on selective removal of the glycocalyx. It is concluded that, compared with RH, adenosine-induced coronary hyperemia is not affected by modification of the glycocalyx. This glycocalyx insensitivity should be taken into account when using adenosine-induced coronary hyperemia as a marker for vasodilating capacity to an ischemic stimulus.     

Changes in regional cerebral blood flow distribution during postexercise hypotension in humans.

This investigation compared patterns of regional cerebral blood flow (rCBF) during exercise recovery both with and without postexercise hypotension (PEH). Eight subjects were studied on 3 days with randomly assigned conditions: 1) after 30 min of rest; 2) after 30 min of moderate exercise (M-Ex) at 60-70% heart rate (HR) reserve during PEH; and 3) after 30 min of light exercise (L-Ex) at 20% HR reserve with no PEH. Data were collected for HR, mean blood pressure (MBP), and ratings of perceived exertion and relaxation, and rCBF was assessed by use of single-photon-emission computed tomography. With the use of ANOVA across conditions, there were differences (P < 0.05; mean +/- SD) from rest during exercise recovery from M-Ex (HR = +12 +/- 3 beats/min; MBP = -9 +/- 2 mmHg), but not from L-Ex (HR = +2 +/- 2 beats/min; MBP = -2 +/- 2 mmHg). After M-Ex, there were decreases (P < 0.05) for the anterior cingulate (-6.7 +/- 2%), right and left inferior thalamus (-10 +/- 3%), right inferior insula (-13 +/- 3%), and left inferior anterior insula (-8 +/- 3%), not observed after L-Ex. There were rCBF decreases for leg sensorimotor regions after both M-Ex (-15 +/- 4%) and L-Ex (-12 +/- 3%) and for the left superior anterior insula (-7 +/- 3% and -6 +/- 3%), respectively. Data show that there are rCBF reductions within specific regions of the insular cortex and anterior cingulate cortex coupled with a postexercise hypotensive response after M-Ex. Findings suggest that these cerebral cortical regions, previously implicated in cardiovascular regulation during exercise, may also be involved in PEH.     

Inhibition of NO production increases myocardial blood flow and oxygen consumption in congestive heart failure

Coronary blood flow (CBF) and myocardial oxygen consumption (MVO(2)) are reduced in dogs with pacing-induced congestive heart failure (CHF), which suggests that energy metabolism is downregulated. Because nitric oxide (NO) can inhibit mitochondrial respiration, we examined the effects of NO inhibition on CBF and MVO(2) in dogs with CHF. CBF and MVO(2) were measured at rest and during treadmill exercise in 10 dogs with CHF produced by rapid ventricular pacing before and after inhibition of NO production with N(G)-nitro-L-arginine (L-NNA, 10 mg/kg iv). The development of CHF was accompanied by decreases in aortic and left ventricular (LV) systolic pressure and an increase in LV end-diastolic pressure (25 +/- 2 mmHg). L-NNA increased MVO(2) at rest (from 3.07 +/- 0.61 to 4.15 +/- 0.80 ml/min) and during exercise; this was accompanied by an increase in CBF at rest (from 31 +/- 2 to 40 +/- 4 ml/min) and during exercise (both P < 0.05). Although L-NNA significantly increased LV systolic pressure, similar increases in pressure produced by phenylephrine did not increase MVO(2). The findings suggest that NO exerts tonic inhibition on respiration in the failing heart.