Propranolol enhances adenine nucleotide degradation in human muscle during exercise

Eight healthy men cycled to exhaustion [4.1 +/- 0.3 (SE) min] during beta-adrenoceptor blockade (beta B) with propranolol. The exercise was repeated on another day with the same power output and duration but without propranolol (control). The total adenine nucleotide (TAN) content in muscle (quadriceps femoris) decreased during exercise, and the decrease was more pronounced during beta B (delta TAN = 4.8 +/- 1.0 mmol/kg dry wt) than during control (delta TAN = 2.8 +/- 0.9; P less than 0.01, beta B vs. control). The decrease in TAN corresponded with a similar increase in inosine 5'-monophosphate (IMP). The increase in IMP was more pronounced during beta B (delta IMP = 5.1 +/- 1.2 mmol/kg dry wt) than during control (delta IMP = 2.8 +/- 0.7; P less than 0.05, beta B vs. control). Similarly, the increase in the content of NH3 in muscle was twice as high during beta B vs. control (P less than 0.01). The increase in muscle lactate and the decrease in phosphocreatine during exercise were similar between treatments, but postexercise hexose phosphates were approximately twofold higher (P less than 0.05) during control than during beta B. It is concluded that beta B enhances the degradation of TAN and the production of NH3 and IMP in muscle during intense exercise. This indicates that the imbalance between the rates of utilization and resynthesis of ATP is more pronounced during beta B possibly because of a decreased O2 transport to the contracting muscle and a diminished activation of glycolysis by the hexose phosphates.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oxygen uptake/heart rate relationship in leg and arm exercise, sitting and standing.

The effect of leg exercise and of arm exercise in sitting and standing body positions on energy output and on some cardiorespiratory parameters was studied in seven male subjects. Oxygen uptake (VO2), heart rate (fH), pulmonary ventilation (VE) and respiratory frequency were measured at rest, in the 7-8th min of submaximal work (300, 600, 900 kpm/min), and at maximal effort. Significantly higher Vo2, fH, and VE in arm cranking than in cycling were found at submaximal work loads above 300 kpm/min. Though the maximal work load in arm exercise was 50-60% of that in cycling, Vo2 in arm work was at maximal effort only 22% lower than in leg exercise while the difference in fH was insignificant. No differences were found in arm work between the results obtained at any work level in sitting and standing body positions. The only postural difference in arm work was a 13% higher work load achieved at maximal effort when standing than when sitting. Differences in fH between arm and leg exercise were much smaller for the same Vo2 than for the same work load and were time dependent. While fH quickly leveled off in leg exercise, fH in arm cranking rose steadily during the first 6 min of work which created the fH differences observed in the 7-8 min of submaximal arm arm and leg exercise. At submaximal work levels a tendency to synchronize the respiratory frequency with the frequency of the rotatory movements was more apparent in arm cranking than in cycling.     

Leg vasoconstriction during dynamic exercise with reduced cardiac output.

We evaluated whether a reduction in cardiac output during dynamic exercise results in vasoconstriction of active skeletal muscle vasculature. Nine subjects performed four 8-min bouts of cycling exercise at 71 +/- 12 to 145 +/- 13 W (40-84% maximal oxygen uptake). Exercise was repeated after cardioselective (beta 1) adrenergic blockade (0.2 mg/kg metoprolol iv). Leg blood flow and cardiac output were determined with bolus injections of indocyanine green. Femoral arterial and venous pressures were monitored for measurement of heart rate, mean arterial pressure, and calculation of systemic and leg vascular conductance. Leg norepinephrine spillover was used as an index of regional sympathetic activity. During control, the highest heart rate and cardiac output were 171 +/- 3 beats/min and 18.9 +/- 0.9 l/min, respectively. beta 1-Blockade reduced these values to 147 +/- 6 beats/min and 15.3 +/- 0.9 l/min, respectively (P < 0.001). Mean arterial pressure was lower than control during light exercise with beta 1-blockade but did not differ from control with greater exercise intensities. At the highest work rate in the control condition, leg blood flow and vascular conductance were 5.4 +/- 0.3 l/min and 5.2 +/- 0.3 cl.min-1.mmHg-1, respectively, and were reduced during beta 1-blockade to 4.8 +/- 0.4 l/min (P < 0.01) and 4.6 +/- 0.4 cl.min-1.mmHg-1 (P < 0.05). During the same exercise condition leg norepinephrine spillover increased from a control value of 2.64 +/- 1.16 to 5.62 +/- 2.13 nM/min with beta 1-blockade (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Factorial aerobic scope is independent of temperature and primarily modulated by heart rate in exercising Murray cod (Maccullochella peelii peelii)

Several previous reports, often from studies utilising heavily instrumented animals, have indicated that for teleosts, the increase in cardiac output (Vb) during exercise is mainly the result of an increase in cardiac stroke volume (V(S)) rather than in heart rate (fH). More recently, this contention has been questioned following studies on animals carrying less instrumentation, though the debate continues. In an attempt to shed more light on the situation, we examined the heart rates and oxygen consumption rates (Mo2; normalised to a mass of 1 kg, given as Mo2kg) of six Murray cod (Maccullochella peelii peelii; mean mass+/-SE = 1.81+/-0.14 kg) equipped with implanted fH and body temperature data loggers. Data were determined during exposure to varying temperatures and swimming speeds to encompass the majority of the biological scope of this species. An increase in body temperature (Tb) from 14 degrees C to 29 degrees C resulted in linear increases in Mo2kg (26.67-41.78 micromol min(-1) kg(-1)) and fH (22.3-60.8 beats min(-1)) during routine exercise but a decrease in the oxygen pulse (the amount of oxygen extracted per heartbeat; 1.28-0.74 micromol beat(-1) kg(-1)). During maximum exercise, the factorial increase in Mo2kg was calculated to be 3.7 at all temperatures and was the result of temperature-independent 2.2- and 1.7-fold increases in fH and oxygen pulse, respectively. The constant factorial increases in fH and oxygen pulse suggest that the cardiovascular variables of the Murray cod have temperature-independent maximum gains that contribute to maximal oxygen transport during exercise. At the expense of a larger factorial aerobic scope at an optimal temperature, as has been reported for species of salmon and trout, it is possible that the Murray cod has evolved a lower, but temperature-independent, factorial aerobic scope as an adaptation to the largely fluctuating and unpredictable thermal climate of southeastern Australia.     

Effect of partial agonist activity in beta blockers in severe angina pectoris: a double blind comparison of pindolol and atenolol.

The use of beta adrenoceptor blockade in the treatment of rest angina is controversial, and the effects on severe angina of partial agonist activity in beta blockers are unknown. Eight patients with effort angina and seven with effort and nocturnal angina and severe coronary artery disease were studied initially when they were not taking any antianginal drugs. Pindolol 5 mg thrice daily (with partial agonist activity) and atenolol 100 mg daily (without partial agonist activity) were given for five days each in a double blind randomised manner. Diaries of angina were kept and treadmill exercise testing and ambulatory ST monitoring performed during the last 48 hours of each period of treatment. Daytime and nocturnal resting heart rates and the frequency of angina were significantly reduced by atenolol compared with pindolol (p less than 0.01). The duration of exercise was significantly increased and the frequency, duration, and magnitude of daytime and nocturnal episodes of ST segment depression on ambulatory monitoring were reduced by atenolol. Reduction in resting heart rate is important in the treatment of both effort and nocturnal angina. Partial agonist activity in beta adrenoceptor antagonists may be deleterious in patients with severe angina pectoris.     

Effect of propranolol on thyroxine-induced changes in body temperature and metabolism during exercise in dogs.

Effects of thyroxine on temperature and metabolism during exercise were studied in dogs after beta-adrenergic blockade. Dogs performed 60 min treadmill exercise of moderate intensity 5 and 72 h following thyroxine injected s.c. in a single dose of 0.1 mg/kg b.w. Thyroxine increased significantly the lipolytic response to exercise as well as blood lactate (LA) concentrations and rectal temperature (Tre) during exercise as early as 5h following the hormone administration. The changes became more pronounced 72 h after the injection. At rest Tre, blood FFA and LA levels in the thyroxine-treated dogs did not differ from the control values, and blood glucose was slightly, but significantly higher. Propranolol given intravenously in a dose of 0.25 mg/kg at 30 min of the exercise performed 72 h following thyroxine injection abolished the plasma FFA rise, and inhibited to a certain extent increases in Tre and blood LA concentrations during the next 30 min of exercise.     

Role of beta 2-adrenergic receptors on coronary resistance during exercise

The effects of regional alpha- and specific beta 2-adrenergic receptor blockade on measurements of late diastolic coronary resistance (LDCR) and mean coronary blood flow velocity (CBFV) during exercise were examined in 14 conscious adult mongrel dogs. Specific beta 2-adrenergic receptor blockade (ICI 118.551) significantly decreased CBFV and increased LDCR by blockade of beta 2-vasodilator tone independent of alpha-adrenergic receptor-mediated tone and independent of altering myocardial metabolism. alpha-Adrenergic receptor blockade (phentolamine, 1 mg) significantly increased CBFV and decreased LDCR by blocking sympathetically mediated vasoconstrictor tone. There was no significant difference in the magnitude of response between alpha- and beta 2-adrenergic receptor blockade. These results demonstrate that alpha- and beta 2-adrenergic receptors have a significant and evidently equal influence on CBFV and LDCR during exercise. Four weeks of daily exercise and left stellate ganglionectomy (LSGx) prevented phentolamine-induced vasodilation but not ICI 118.551-induced vasoconstriction. This suggests that daily exercise and LSGx significantly decreased the alpha-adrenergic receptor-mediated vasoconstrictor tone on the coronary circulation, resulting in an apparently greater role for the coronary vascular beta 2-adrenergic receptor on the control of CBFV and LDCR during exercise.     

Effect of hematocrit reduction on hormonal and metabolic responses to exercise

We wished to determine the effect of a 25% hematocrit reduction on glucoregulatory hormone release and glucose fluxes during exercise. In five anemic dogs, plasma glucose fell by 21 mg/dl and in five controls by 7 mg/dl by the end of the 90-min exercise period. After 50 min of exercise, hepatic glucose production (Ra) and glucose metabolic clearance rate (MCR) began to rise disproportionately in anemics compared with controls. By the end of exercise, the increase in Ra was almost threefold higher (delta 15.1 +/- 3.4 vs. delta 5.2 +/- 1.3 mg X kg-1 X min-1) and MCR nearly fourfold (delta 24.6 +/- 8.8 vs. delta 6.5 +/- 1.3 ml X kg-1 X min-1). Exercise with anemia, in relation to controls resulted in elevated levels of glucagon [immunoreactive glucagon (IRG) delta 1,283 +/- 507 vs delta 514 +/- 99 pg/ml], norepinephrine (delta 1,592 +/- 280 vs. delta 590 +/- 155 pg/ml), epinephrine (delta 2,293 +/- 994 vs. delta 385 +/- 186 pg/ml), cortisol (delta 6.7 +/- 2.2 vs. delta 2.1 +/- 1.0 micrograms/dl) and lactate (delta 12.1 +/- 2.2 vs. delta 4.2 +/- 1.8 mg/dl) after 90 min. Immunoreactive insulin and free fatty acids were similar in both groups. In conclusion, exercise with a 25% hematocrit reduction results in 1) elevated lactate, norepinephrine, epinephrine, cortisol, and IRG levels, 2) an increased Ra which is likely related to the increased counterregulatory response, and 3) we speculate that a near fourfold increase in MCR is related to metabolic changes due to hypoxia in working muscle.(ABSTRACT TRUNCATED AT 250 WORDS)     

Physiological responses to prolonged exercise in ultramarathon athletes

The physiological responses of 10 ultramarathon athletes to prolonged exercise at the highest intensity level they could sustain for 4 h have been examined. Energy expenditure for the 4 h of exercise was 14,146 +/- 1,789 kJ, of which 63% was provided by the oxidation of fat. Plasma free fatty acids rose, but the changes in blood lactate concentration (delta 0.2 mmol/l) and exchange ratio (delta 0.05) were small, and the postexercise glycogen content (130 +/- 42 mumol/g) of the vastus lateralis muscles was estimated to be 37-53% of normal resting values. During exercise O2 intake (VO2) increased with time from the 50th to 240th min, the rise becoming significant (P less than 0.01) after 110 min of work. The change in VO2 was equivalent to a rise in relative intensity (%VO2max) of +9.1% and a change of speed of 1.49 km/h. A rise in cardiac frequency compensated for a fall in stroke volume (SV), so that cardiac output was maintained, and the increases in rectal temperature (Tre) (delta 0.63 degree C) and sweat loss (3.49 +/- 0.50 kg, equivalent to 5.5% of body wt) and the decreased mean skin temperature (Tsk) (-1.22 degree C) were within tolerable limits during exercise. Following exercise there was a loss (-25%) of ability to generate voluntary force of the quadriceps femoris, though electrically evoked mechanical properties of the muscle remained unchanged. The results suggest that neither thermal nor cardiovascular factors are limiting to prolonged (4 h) exercise, although the ability to utilize fat as a fuel may be important in ultradistance athletes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of endothelin in alpha-adrenoceptor coronary vasoconstriction

It has been proposed that alpha-adrenoceptor vasoconstriction in coronary resistance vessels results not from alpha-adrenoceptors on coronary smooth muscle but from alpha-adrenoceptors on cardiac myocytes that stimulate endothelin (ET) release. The present experiments tested the hypothesis that the alpha-adrenoceptor-mediated coronary vasoconstriction that normally occurs during exercise is due to endothelin. In conscious dogs (n = 10), the endothelin ET(A)/ET(B) receptor antagonist tezosentan (1 mg/kg iv) increased coronary venous oxygen tension at rest but not during treadmill exercise. This result indicates that basal endothelin levels produce a coronary vasoconstriction at rest that is not observed during the coronary vasodilation during exercise. In contrast, the alpha-adrenoceptor antagonist phentolamine increased coronary venous oxygen tension during exercise but not at rest. The difference between the endothelin blockade and alpha-adrenoceptor blockade results indicates that alpha-adrenoceptor coronary vasoconstriction during exercise is not due to endothelin. However, in anesthetized dogs, bolus intracoronary injections of the alpha-adrenoceptor agonist phenylephrine produced reductions in coronary blood flow that were partially antagonized by endothelin receptor blockade with tezosentan. These results are best explained if alpha-adrenoceptor-induced endothelin release requires high pharmacological concentrations of catecholamines that are not reached during exercise.     

Influence of alpha and beta adrenergic receptors blockade on the adrenolytic effect of muscular work

The changes in the response of adrenergic receptors alpha and beta in the blood vessels in the working muscles in a hindlimb in cats were studied after intra-arterial administration of noradrenaline, isoprenaline and during electric stimulation of the sympathetic trunk. The experiments were carried out during alpha-adrenergic receptors blockade with dihydroergotamine (0.3 mg/kg) beta-adrenergic receptors blockade with propranolol (1 mg/kg) and blockade of acetylcholine M receptors with atropine (0.5 mg/kg). The investigations were performed at rest, during exercise (electric stimulation of the sciatic nerve) and after the exercise. The following results deserve attention: 1) beta-adrenergic receptors blockade reduced significantly the alpha-adrenolytic effect of exercise restoring the ability of blood vessel to constriction in response to noradrenaline; 2) the vasodilator effect of isoprenaline evident in resting state and maintained to some extent during exercise was abolished completely by preceding alpha-adrenergic blockade. The changes in the reactivity of resistance vessels in working skeletal muscles to noradrenaline, with abolition of its vasoconstrictor effect, have been shown by Rein [7] and others authors [2, 5]. Similarly, it is well known that the resistance vessels contain two types of adrenergic receptors alpha and beta, and that the response of the vessels to stimulation of these receptors are different [1]. In view of the recently published observations of Jarhult and Lundvall suggesting that the beta-adrenergic receptors play an important physiological role [6] in the arterial part of the microcirculation [6] and in view of the hypothesis put forward by Kunos and Szentivanyj that alpha and beta receptors can be transformed depending on the intensity of tissue metabolism [8] it seemed worth while to study more systematically the changes of the reactivity of alpha and beta adrenergic receptors in the vascular bed of the skeletal muscles during and after muscle exercise.     

Thermoregulation during prolonged exercise in heat: alterations with beta-adrenergic blockade

Thermoregulation and cardiovascular drift were studied under conditions of prolonged exercise in a warm environment (dry bulb temperature 31.7 +/- 0.3 degrees C, rh 44.7 +/- 4.7%) during beta-adrenergic blockade. Fourteen subjects performed 90-min rides on a cycle ergometer at a work rate equivalent to 40% of their control maximal O2 uptake under each of three treatments provided in a randomized double-blind manner: atenolol (100 mg/day), propranolol (160 mg/day), and a placebo. Exercise during the propranolol trial resulted in significantly higher forearm vascular resistance values and significantly lower forearm blood flows (FBF) compared with the placebo trial. However, the significantly lower FBF during propranolol did not significantly alter the rectal temperature (Tre) response to prolonged exercise. In addition, both beta-blockers produced lower FBF for any given Tre, suggesting that beta-adrenergic blockade affects FBF through nonthermal factors. The slight differences in Tre, despite the large differences in FBF between the various treatments, are apparently the result of an enhanced sweat loss and a lower mean skin temperature during exercise with beta-blockade. The uncoupling of FBF and sweat loss provides evidence of independent regulation. The reduction in FBF at any given Tre was concomitant to lower blood pressure values during beta-blockade and suggests that baroreflexes provide significant input to the control of skin blood flow when both pressure and temperature maintenance are simultaneously challenged.     

Physical performance and serum potassium under chronic beta-blockade

Various publications have described a beta 2-receptor regulated potassium transport system in the cellular membrane of human skeletal muscle. To examine the suggestion that serum potassium alterations are among the causes of premature muscular fatigue during physical exercise under pharmacological blockade of beta-receptors, we have compared the influence of sustained blockade with a beta 1-selective blocker and a nonselective beta-blocker on the levels of serum potassium before, during and after a physical exercise test. 63 healthy physical education students received in random order and under double blind conditions either 100 mg Metoprolol (beta 1-selective) or 80 mg Propranolol (non-selective), or placebo daily for 3 months. Serum potassium was measured before, during (at 150 Watt and at the end of exercise) and after a bicycle exercise with a stepwise increase in work loads. After three months of beta-blocker treatment serum potassium levels during exercise were significantly higher than in control subjects receiving the placebo, and it took longer for the serum potassium levels to return to the resting level in the beta-blocker treated subjects. At rest, however, the levels were not found to be statistically different. In the subjects receiving Propranolol the post-exercise serum potassium levels were higher than in the subjects receiving Metoprolol. Three days after cessation of the medication these differences were no longer perceptible. Our findings confirm the existence of a beta-receptor regulated potassium transport system in human skeletal muscle and indicate that the transmembranous potassium transport in human skeletal muscle is predominantly regulated via beta 2-receptors, although beta 1-receptors seem also to be involved.(ABSTRACT TRUNCATED AT 250 WORDS)     

Beta-blockade reduces tidal volume during heavy exercise in trained and untrained men

The effects of beta-blockade on tidal volume (VT), breath cycle timing, and respiratory drive were evaluated in 14 endurance-trained [maximum O2 uptake (VO2max) approximately 65 ml X kg-1 X min-1] and 14 untrained (VO2max approximately 50 ml X kg-1 X min-1) male subjects at 45, 60, and 75% of unblocked VO2max and at VO2max. Propranolol (PROP, 80 mg twice daily), atenolol (ATEN, 100 mg once a day) and placebo (PLAC) were administered in a randomized double-blind design. In both subject groups both drugs attenuated the increases in VT associated with increasing work rate. CO2 production (VCO2) was not changed by either drug during submaximal exercise but was reduced in both subject groups by both drugs during maximal exercise. The relationship between minute ventilation (VE) and VCO2 was unaltered by either drug in both subject groups due to increases in breathing frequency. In trained subjects VT was reduced during maximal exercise from 2.58 l/breath on PLAC to 2.21 l/breath on PROP and to 2.44 l/breath on ATEN. In untrained subjects VT at maximal exercise was reduced from 2.30 l/breath on PLAC to 1.99 on PROP and 2.12 on ATEN. These observations indicate that 1) since VE vs. VCO2 was not altered by beta-adrenergic blockade, the changes in VT and f did not result from a general blunting of the ventilatory response to exercise during beta-adrenergic blockade; and 2) blockade of beta 1- and beta 2-receptors with PROP caused larger reductions in VT compared with blockade of beta 1-receptors only (ATEN), suggesting that beta 2-mediated bronchodilation plays a role in the VT response to heavy exercise.     

Venous responses during exercise in rainbow trout, Oncorhynchus mykiss: alpha-adrenergic control and the antihypotensive function of the renin-angiotensin system

The role of the alpha-adrenergic system in the control of cardiac preload (central venous blood pressure; P(ven)) and venous capacitance during exercise was investigated in rainbow trout (Oncorhynchus mykiss). In addition, the antihypotensive effect of the renin-angiotesin system (RAS) was investigated during exercise after alpha-adrenoceptor blockade. Fish were subjected to a 20-min exercise challenge at 0.66 body lengths s(-1) (BL s(-1)) while P(ven), dorsal aortic blood pressure (P(da)) and relative cardiac output (Q) was recorded continuously. Heart rate (f(H)), cardiac stroke volume (SV) and total systemic resistance (R(sys)) were derived from these variables. The mean circulatory filling pressure (MCFP) was measured at rest and at the end of the exercise challenge, to investigate potential exercise-mediated changes in venous capacitance. The protocol was repeated after alpha-adrenoceptor blockade with prazosin (1 mg kg(-1)M(b)) and again after additional blockade of angiotensin converting enzyme (ACE) with enalapril (1 mg kg(-1)M(b)). In untreated fish, exercise was associated with a rapid (within approx. 1-2 min) and sustained increase in Q and P(ven) associated with a significant increase in MCFP (0.17+/-0.02 kPa at rest to 0.27+/-0.02 kPa at the end of exercise). Prazosin treatment did not block the exercise-mediated increase in MCFP (0.25+/-0.04 kPa to 0.33+/-0.04 kPa at the end of exercise), but delayed the other cardiovascular responses to swimming such that Q and P(ven) did not increase significantly until around 10-13 min of exercise, suggesting that an endogenous humoral control mechanism had been activated. Subsequent enalapril treatment revealed that these delayed responses were in fact due to activation of the RAS, because resting P(da) and R(sys) were decreased further and essentially all cardiovascular changes during exercise were abolished. This study shows that the alpha-adrenergic system normally plays an important role in the control of venous function during exercise in rainbow trout. It is also the first study to suggest that the RAS may be an important modulator of venous pressure and capacitance in fish.     

Hepatic alpha- and beta-adrenergic receptors are not essential for the increase in R(a) during exercise in diabetes

The purpose of this study was to determine the role of direct hepatic adrenergic stimulation in the control of endogenous glucose production (R(a)) during moderate exercise in poorly controlled alloxan-diabetic dogs. Chronically catheterized and instrumented (flow probes on hepatic artery and portal vein) dogs were made diabetic by administration of alloxan. Each study consisted of a 120-min equilibration, 30-min basal, 150-min moderate exercise, 30-min recovery, and 30-min blockade test period. Either vehicle (control; n = 6) or alpha (phentolamine)- and beta (propranolol)-adrenergic blockers (HAB; n = 6) were infused in the portal vein. In both groups, epinephrine (Epi) and norepinephrine (NE) were infused in the portal vein during the blockade test period to create suprapharmacological levels at the liver. Isotopic ([3-(3)H]glucose, [U-(14)C]alanine) and arteriovenous difference methods were used to assess hepatic function. Arterial plasma glucose was similar in controls (345 +/- 24 mg/dl) and HAB (336 +/- 23 mg/dl) and was unchanged by exercise. Basal arterial insulin was 5 +/- 1 mU/ml in controls and 4 +/- 1 mU/ml in HAB and fell by approximately 50% during exercise in both groups. Basal arterial glucagon was similar in controls (56 +/- 10 pg/ml) and HAB (55 +/- 7 pg/ml) and rose similarly, by approximately 1.4-fold, with exercise in both groups. Despite greater arterial Epi and NE levels in HAB compared with controls during the basal and exercise periods, exercise-induced increases in catecholamines from basal were similar in both groups. Gluconeogenic conversion from alanine and lactate and the intrahepatic efficiency of this process were increased by twofold during exercise in both groups. R(a) rose similarly by 2.9 +/- 0.7 and 2.7 +/- 1.0 mg. kg(-1). min(-1) at time = 150 min during exercise in controls and HAB. During the blockade test period, arterial plasma glucose and R(a) rose to 454 +/- 43 mg/dl and 11.3 mg. kg(-1). min(-1) in controls, respectively, but were essentially unchanged in HAB. The attenuated response to the blockade test in HAB substantiates the effectiveness of the hepatic adrenergic blockade. In conclusion, these results demonstrate that direct hepatic adrenergic stimulation does not play a role in the stimulation of R(a) during exercise in poorly controlled diabetes.     

Activation of CaMKIIdeltaC is a common intermediate of diverse death stimuli-induced heart muscle cell apoptosis

Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) is expressed in many mammalian cells, with the delta isoform predominantly expressed in cardiomyocytes. Previous studies have shown that inhibition of CaMKII protects cardiomyocytes against beta(1)-adrenergic receptor-mediated apoptosis. However, it is unclear whether activation of CaMKII is sufficient to cause cardiomyocyte apoptosis and whether CaMKII signaling is important in heart muscle cell apoptosis mediated by other stimuli. Here, we specifically enhanced or suppressed CaMKII activity using adenoviral gene transfer of constitutively active (CA-CaMKII(deltaC)) or dominant negative (DN-CaMKII(deltaC)) mutants of CaMKII(deltaC) in cultured adult rat cardiomyocytes. Expression of CA-CaMKII(deltaC) promoted cardiomyocyte apoptosis that was associated with increased mitochondrial cytochrome c release and attenuated by co-expression of Bcl-X(L). Importantly, isoform-specific suppression of CaMKII(deltaC) with the DN-CaMKII(deltaC) mutant similar to nonselective CaMKII inhibition by the pharmacological inhibitors (KN-93 or AIP) not only prevented CA-CaMKII(deltaC)-mediated apoptosis but also protected cells from multiple death-inducing stimuli. Thus, activation of CaMKII(deltaC) constitutes a common intermediate by which various death-inducing stimuli trigger cardiomyocyte apoptosis via the primary mitochondrial death pathway.     

Effects of somatostatin and adrenergic blockade on glucagon, insulin and glucose in exercising sheep

This study was conducted to characterize the mechanisms of hyperglycaemia in exercising sheep. Sheep were run on a treadmill for 45 min (5.5 km h-1, 8% incline) during adrenergic blockade (propranolol or phentolamine mesylate infusions) and during suppression of the rise in glucagon by infusion of somatostatin (SRIF). Propranolol did not alter the glucagon, insulin or glucose responses, except it tended to increase the metabolic clearance of glucose, presumably as a result of blocking the beta-adrenergic inhibition of glucose uptake. Phentolamine mesylate administration was associated with a suppression of the rise in glucagon concentrations, a reversal of alpha-adrenergic inhibition of insulin release and a reduction in glucose appearance during exercise. SRIF prevented the rise in glucagon and reduced insulin concentrations to below resting values. Propranolol and phentolamine mesylate did not alter the glucagon, insulin or glucose response to SRIF. However, SRIF prevented the insulin rise that occurred during phentolamine administration. The increment in glucose appearance produced in response to exercise was the same for SRIF, plus phentolamine mesylate and phentolamine mesylate in the first 25 min of exercise, but was significantly less than in the controls. During the last 20 min of exercise, glucose appearance was not significantly different from the control for any of the groups. The depression by SRIF and alpha-adrenergic blockade of the increment in glucose appearance due to exercise was associated with an impairment of the glucagon response. It appears, therefore, that glucagon may stimulate glucose production early in exercise in sheep directly, as well as by having a permissive effect.     

Autonomic effects on QT-RR interval dynamics after exercise

This study was designed to assess autonomic effects on the QT interval during recovery from exercise. Exercise is associated with an acute increased risk of sudden cardiac death. Evidence of impaired parasympathetic activity, such as low heart rate variability and heart rate recovery, and an increased QT interval are also associated with increased mortality. However, there is no clear pathophysiological link among these findings. Bicycle exercise testing was performed serially in 33 healthy volunteers (19 men; ages, 54 +/- 7 yr) under four conditions: 1) baseline, 2) beta-adrenergic blockade-intravenous propranolol (0.2 mg/kg) administered during exercise, 3) parasympathetic blockade-intravenous atropine (0.04 mg/kg) administered during exercise, and 4) double blockade with propranolol and atropine. ECGs were obtained every minute in recovery for 10 min and then at the 15th and 20th min, from which the QT and RR intervals were measured. Linear regression analyses were used to assess the individual QT-RR relationships for each subject for each condition. Relative to baseline, the QT-RR relationship with parasympathetic blockade was shifted to the left and had a steeper slope. In contrast, the QT-RR relationship with beta-adrenergic blockade was shifted to the right and had a less steep slope. The baseline and double-blockade QT-RR relationships were in the middle and essentially superimposable. There was a negative relationship between QT-RR slope and heart rate or RR interval recoveries, but it was significant only for the 1- and 2-min RR interval recoveries with low R(2) values of 0.124 and 0.114. The main parasympathetic effect in the postexercise recovery period is to counteract the sympathetically mediated QT prolongation. These data support the concept that parasympathetic tone may provide a natural antiarrhythmic effect during this time.     

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.