Effect of beta-adrenoceptor blockade on thermoregulation during prolonged exercise

The effect of clinically used equipotent doses of nonselective (beta 1/beta 2; propranolol) and selective (beta 1; atenolol) beta-adrenoceptor blockers on thermoregulation was studied during prolonged exercise in the heat. Oral propranolol (160 mg/day), atenolol (100 mg/day) or matching placebo were taken for 6 days each by 11 healthy young adult caucasian males. Subjects participated in 2 h of block-stepping at a work rate of 54 W in an environmental chamber with a temperature of 33.2 +/- 0.3 degree C dry bulb and 31.7 /+- 0.3 degree C wet bulb, 2 h after ingestion of the final dose of each drug. Both active agents produced similar marked (P less than 0.001) increases in subjective perception of effort, the mechanism of which was not immediately evident from changes in serum electrolytes, blood glucose, blood lactate, or ventilatory parameters. Propranolol did, however, cause a greater rise in serum K+ than placebo (P less than 0.02) and atenolol (P = NS) after exercise. Although rectal and mean skin temperatures were insignificantly altered by beta-adrenoceptor blockade, an increased total sweat production was noted with propranolol (P less than 0.01 vs. placebo) and to a lesser degree atenolol (P = NS vs. placebo) therapy. Analysis of the time course of sweat production showed the propranolol-mediated enhancement of sweating to ensue largely during the initial hour of block-stepping and to be transient in nature. The scientific and clinical implications of this observation will be dependent upon the precise underlying mechanism, a factor not identified by the present study.     

Effect of beta-adrenoceptor blockade on renin-aldosterone and alpha-ANF during exercise at altitude

The renin-aldosterone system may be depressed in subjects exercising at high altitude, thereby preventing excessive angiotensin I (ANG I) and aldosterone levels, which could favor the onset of acute mountain sickness. The role of beta-adrenoceptors in hormonal responses to hypoxia was investigated in 12 subjects treated with a nonselective beta-blocker, pindolol. The subjects performed a standardized maximal bicycle ergometer exercise with (P) and without (C) acute pindolol treatment (15 mg/day) at sea level, as well as during a 5-day period at high altitude (4,350 m, barometric pressure 450 mmHg). During sea-level exercise, pindolol caused a reduction in plasma renin activity (PRA, 2.83 +/- 0.35 vs. 5.13 +/- 0.7 ng ANG I.ml-1.h-1, P less than 0.01), an increase in plasma alpha-atrial natriuretic factor (alpha-ANF) level (23.1 +/- 2.9 (P) vs. 10.4 +/- 1.5 (C) pmol/1, P less than 0.01), and no change in plasma aldosterone concentration [0.50 +/- 0.04 (P) vs. 0.53 +/- 0.03 (C) nmol/1]. Compared with sea-level values, PRA (3.45 +/- 0.7 ng ANG I.ml-1.h-1) and PA (0.39 +/- 0.03 nmol/1) were significantly lower (P less than 0.05) during exercise at high altitude. alpha-ANF was not affected by hypoxia. When beta-blockade was achieved at high altitude, exercise-induced elevation in PRA was completely abolished, but no additional decline in PA occurred. Plasma norepinephrine and epinephrine concentrations tended to be lower during maximal exercise at altitude; however, these differences were not statistically significant. Our results provide further evidence that hypoxia has a suppressive effect on the renin-aldosterone system. However, beta-adrenergic mechanisms do not appear to be responsible for inhibition of renin secretion at high altitude.     

Effect of preliminary blockade of alpha- and beta-adrenoreceptors on stress-induced disorders of myocardial relaxation and contractile functions

Effect of preliminary administration of the alpha-adrenoblocker phentolamine and the beta-adrenoblocker inderal on stress-induced disturbances of myocardial extensibility, contractile function and myocardial resistance to hypoxia and excess Ca2+ was studied on an isometrically contracting isolated right atrium of the rat. Inderal substantially prevented the post-stress decrease in atrial extensibility and almost completely prevented the stress-induced decline in the developed tension and the Frank-Starling mechanism efficiency. At the same time inderal prevented the post-stress increase in hypoxic and hypercalcium contracture of the atrium. Phentolamine did not produce any such protective effects. It is suggested that the damaging action of catecholamine excess occurring under stress is mediated via beta-adrenoreceptors but not via alpha-adrenoreceptors of the heart.     

Effect of calcium channel blockade and beta-adrenoceptor blockade on short graded and single-level endurance exercises in normal men

The effect of verapamil (240 mg) on exercise capacity was studied during a short graded and a single-level endurance exercise test in 12 normal volunteers; it was compared to the effects of atenolol (100 mg x day-1). Intake of verapamil, atenolol and placebo, administered according to a randomized, double-blind cross-over design, was started 3 days before the exercise tests. Compared to placebo, verapamil did not affect peak oxygen uptake in the graded test or exercise duration in the endurance test. Heart rate, systolic blood pressure, rating of perceived exertion and respiratory data at submaximal and peak exercise were unaffected in either test. On the other hand atenolol reduced maximal oxygen uptake by 5% (p less than 0.001) and endurance exercise duration by 17% (p less than 0.05). Besides marked decreases in heart rate and systolic blood pressure during the two types of exercise, atenolol also reduced oxygen uptake at submaximal exercise levels and it increased the rating of perceived exertion (p less than 0.05), the latter only during the endurance exercise test.     

Left ventricular rupture threshold during the healing phase after myocardial infarction in the dog

The mechanical resistance of the infarcted left ventricle to rupture, or rupture threshold, was measured by the balloon technique 1-42 days after left anterior descending coronary artery ligation in 70 dogs: 26 without infarction (18 sham, 8 with ligation) and 44 with infarction. Rupture threshold in noninfarcted hearts was higher than in infarcted hearts (1168 +/- 165 (SD) vs. 754 +/- 223 mmHg (1 mmHg = 133.32 Pa), p less than 0.001) and did not change over 6 weeks. In contrast, rupture threshold in infarcted hearts decreased (p less than or equal to 0.05) after 14 days, the average value for 21-42 days being less than that for 1-14 days: 577 +/- 140 vs. 867 +/- 191 mmHg, p less than 0.001. Passive left ventricular stiffness in infarcted hearts was higher than for noninfarcted hearts throughout the 6 weeks during early filling (11.1 +/- 3.9 vs. 7.1 +/- 1.4 mmHg/mL, p less than 0.001) but decreased (p less than or equal to 0.05) after 14 days during the prerupture phase (11.3 +/- 5.3 vs. 6.2 +/- 3.0 mmHg/mL, p less than 0.005). Between 7 and 42 days, the infarct zone showed marked increase in hydroxyproline (10.0 +/- 2.0 vs. 48.8 +/- 19.7 mg/g dry weight, p less than 0.001), shrinkage (infarct size, 25 +/- 9 vs. 9 +/- 5% of the left ventricle, p less than 0.005), and thinning (infarct to normal wall thickness ratio, 0.83 +/- 0.11 vs. 0.51 +/- 0.09, p less than 0.001) but little further stretching (expansion index or the ratio of lengths of infarcted and noninfarcted segments, 1.14 +/- 0.10 vs. 1.28 +/- 0.17, p less than 0.2). A mild decrease (p less than 0.05) in left atrial pressure and increase (p less than 0.05) in diastolic area and fractional change in area (two-dimensional echocardiography) were detected at 6 weeks. The late decrease in rupture threshold and prerupture stiffness of the infarcted left ventricle and thinning of the scar suggest a late decrease in mechanical strength and resistance of the infarcted left ventricle to distension.     

Myocardial dysfunction in diabetic rats: influence of beta-adrenoceptor blockade (propranolol)

The effects of a beta-blocker, propranolol, on the enzyme and isoenzyme activities in the heart muscle in vitro and concomitant histopathology of the component cells of the islets of Langerhans were studied in the Wistar rats after treatment with streptozotocin and isoproterenol. The biochemical data indicated that the isoproterenol induced myocardial infarction (MI) precipitates an acute diabetic response in the rat heart. The superimposition of MI in diabetes mellitus caused significant inhibition of phosphofructokinase and hexokinase in the heart muscle. The lactate dehydrogenase depicted shifting of H-type to M-type in diabetes with or without MI. The drugs, when administered in combination, brought distinctive histopathological changes in beta-cells of the pancreatic islets including degranulation, hyalinosis and a near-total destruction; however A and D cells remained more or less unaffected. The effect of propranolol in diabetes mellitus was uncertain but in MI with or without prior diabetes, the drug inversely altered the activities of all the cardiac enzymes, besides stimulating a mild recuperation of the cells of the endocrine parenchyma.     

Effect of NO synthase inhibition on myocardial metabolism during moderate ischemia

Nitric oxide (NO) is involved in the control of myocardial metabolism. In normoperfused myocardium, NO synthase inhibition shifts myocardial metabolism from free fatty acid (FFA) toward carbohydrate utilization. Ischemic myocardium is characterized by a similar shift toward preferential carbohydrate utilization, although NO synthesis is increased. The importance of NO for myocardial metabolism during ischemia has not been analyzed in detail. We therefore assessed the influence of NO synthase inhibition with N(G)-nitro-l-arginine (l-NNA) on myocardial metabolism during moderate ischemia in anesthetized pigs. In control animals, the increase in left ventricular pressure with l-NNA was mimicked by aortic constriction. Before ischemia, l-NNA decreased myocardial FFA consumption (MV(FFA); P < 0.05), while consumption of carbohydrate and O(2) (MVo(2)) remained constant. ATP equivalents [calculated with the assumption of complete oxidative substrate decomposition (ATP(eq))] decreased with l-NNA (P < 0.05), associated with a decrease of regional myocardial function (P < 0.05). In contrast, aortic constriction had no effect on MV(FFA), while MVo(2) increased (P < 0.05) and ATP(eq) and regional myocardial function remained constant. During ischemia, alterations in myocardial metabolism were similar in control and l-NNA-treated animals: MV(FFA) decreased (P < 0.05) and net lactate consumption was reversed to net lactate production (P < 0.05). Regional myocardial function was decreased (P < 0.05), although more markedly in animals receiving l-NNA (P < 0.05). We conclude that the efficiency of oxidative metabolism was impaired by l-NNA per se, paralleled by impaired regional myocardial function. During ischemia, l-NNA had no effect on myocardial substrate consumption, indicating that NO synthases were no longer effectively involved in the control of myocardial metabolism.     

Effect of beta-adrenoceptor blockade on H+ and K+ flux in exercising humans

The effect of beta-adrenoceptor blockade (beta B) on muscle release and uptake of H+ and K+ in humans during maximal exercise has been investigated. Eight volunteers cycled intermittently at power outputs corresponding to 100% of maximal O2 uptake. Prior to exercise either propranolol (beta B) or saline (control) was infused into the femoral vein. Arterial and femoral venous blood samples were drawn at rest, during exercise, and during 30-min recovery. Peak arterial blood values for K+, lactic acid (LA), and base deficit (BD) (mean +/- SE) were respectively 5.5 +/- 0.1, 9.5 +/- 0.6, and 11.7 +/- 0.9 mmol/l during beta B and 5.1 +/- 0.1, 8.3 +/- 0.6, and 10.3 +/- 1.0 for control (P less than 0.05). The release of K+ from the working leg did not differ between treatments during exercise, but K+ uptake during late recovery (5-30 min) was slightly lower during beta B. Thus the higher arterial K+ levels during exercise (beta B) cannot be attributed to greater release by active muscle but are likely due to decreased K+ uptake by noncontracting muscle. Arterial-femoral venous differences for LA and BD did not differ significantly between treatments. Additionally LA exchange across the leg was similar to H+ exchange (arterial-femoral venous differences for BD) under all conditions. During early recovery (1-5 min), regardless of experimental treatment, BD levels iin arterial blood were higher than LA (P less than 0.05). These elevated BD levels may be due to unequal removal rates between LA and H+ equivalents by nonexercised tissue.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inflammation in the course of early myocardial ischemia

Experimental models of acute ischemic myocardial injury indicate that the inflammatory response after the ischemic event contributes to tissue damage. This is especially apparent with reperfusion of the ischemic tissue. In such models some therapeutic strategies designed to reduce neutrophil accumulation or function have resulted in apparently beneficial effects. Although such findings are encouraging, interventions into these pathological processes using specific molecular targets will require greater understanding of specific mechanisms. Current evidence indicates that potential sites of therapeutic intervention will be found in pathways leading to complement activation, generation of lipid-derived mediators, adhesion of neutrophils to endothelial cells and cardiac myocytes, and activation of neutrophil secretory processes releasing, for example, proteolytic enzymes and reactive oxygen. Understanding the dynamic interplay between the mediators, adhesion pathways, and secretory processes that results in myocardial damage will allow a rational approach to controlling the detrimental inflammatory consequences of ischemia and reperfusion.     

Effect of superoxide dismutase and catalase on myocardial energy metabolism during ischemia and reperfusion

Survival of cardiac patients undergoing heart surgery depends critically upon the recovery of myocardial energy metabolism during reperfusion of ischemic myocardium. The present study compares various parameters of myocardial energy metabolism using an isolated in situ pig heart. The left anterior descending (LAD) coronary artery was occluded for 60 min, followed by 60 min of global hypothermic cardioplegic arrest and 60 min of reperfusion. Free radical scavengers [superoxide dismutase SOD and catalase] were used to protect the ischemic heart from reperfusion injury. In both control and SOD plus catalase-treated groups, ATP, creatine phosphate (CP), ATP/ADP ratio, energy charge and phosphorylation potential dropped significantly during ischemic insult. After reperfusion, CP, ATP/ADP ratio and phosphorylation potential improved significantly, but they were restored to control level only in treated animals. In either case, free energy of ATP hydrolysis (delta G) lowered only by 5% during ischemia, but recovered promptly upon reperfusion. SOD and catalase also improved coronary blood flow and reduced creatine kinase release compared to those of untreated animals, suggesting improved myocardial recovery upon reperfusion. Our results suggest that SOD and catalase significantly improve the myocardial recovery during reperfusion by enhancing rephosphorylation steps, and the value of delta G is more critical compared to those of ATP and CP for myocardial recovery.     

Metabolic and EEG alterations during the early phase of triethyltinsulphate (TET) intoxication

EEG changes as well as the mechanisms of the hyperglycaemic effect of triethyltinsulphate (TET), a compound known to induce brain oedema, were investigated in cats and rabbits, respectively. Considerable EEG alterations characterized by slow waves appeared in some minutes after TET administration. The hyperglycaemic effect of TET like that of epinephrine could be prevented by the administration of 1 mg/kg of the beta blocker, pindolol. It is suggested that the hyperglycaemic effect of TET is brought about by sympathetic activation.     

Effect of angiotensin II type 2 receptor blockade on mitogen activated protein kinases during myocardial ischemia-reperfusion

Mitogen-activated protein kinases (MAPKs) have been implicated during ischemia-reperfusion (IR) and angiotensin II (AngII) type 2 receptor (AT2R) blockade has been shown to induce cardioprotection involving protein kinase Cepsilon (PKCepsilon) signaling after IR. We examined whether the 3 major MAPKs, p38, c-Jun NH2-terminal kinase (JNK-1 and JNK-2), and extracellular signal regulated kinases (ERK-1 and ERK-2) are activated after IR and whether treatment with the AT2R antagonist PD123,319 (PD) alters their expression. Isolated rat hearts were randomized to control (aerobic perfusion, 80 min), IR (no drug; 50 min of perfusion, 30 min global ischemia and 30 min reperfusion; working mode), and IR + PD (0.3 micromol/l) and left ventricular (LV) work was measured. We measured LV tissue content of p38, p-p38, p-JNK-1 (54 kDa), p-JNK-2 (46 kDa), p-ERK-1 (44 kDa), p-ERK-2 (42 kDa) and PKCepsilon proteins by immunoblotting and cGMP by enzyme immunoassay. IR resulted in significant LV dysfunction, increase in p-p38 and p-JNK-1/-2, no change in p-ERK-1/-2 or PKCepsilon, and decrease in cGMP. PD improved LV recovery after IR, induced a slight increase in p-p38 (p < 0.01 vs. control), normalized p-JNK-1, did not change p-ERK-1/-2, and increased PKCepsilon and cGMP. The overall results suggest that p38 and JNK might play a significant role in acute IR injury and the cardioprotective effect of AT2R blockade independent of ERK. The activation of p38 and JNKs during IR may be linked, in part, to AT2R stimulation.     

Effect of myocardial ischemia on uridine incorporation and histone acetylation

The influence of transient myocardial ischemia on recovery uridine incorporation into RNA and histone acetylation was investigated in an isolated perfused rat heart. Hemodynamically, hearts recovered from 15 min of ischemic arrest and were stable for at least 60 min of perfusion. Uridine incorporation was reduced (P less than 0.05) in ischemic hearts by 24 and 26% after 30 and 60 min of recovery perfusion. The incorporation of uridine into RNA from purified myocytes was decreased by 50% in the ischemic muscle cells. The covalent acetylation of total nucleohistones was diminished by 37%. Histone fractionation by urea polyacrylamide gel electrophoresis clearly indicated that histones H3 and H4 preferentially incorporated less acetate during ischemic recovery. However, histone acetylation for proteins H2A + H2B was not effected. These data suggest that a brief period of ischemia disrupts nucleotide incorporation during the recovery phase, with marked decrease associated with the muscle cell. The similar change in histone acetylation indicates a possible link between nucleoproteins and chromatin function during ischemic insult to the heart.     

Effect of duration of ischemia on myocardial proteome in ischemia/reperfusion injury

Ischemia/reperfusion (I/R) injury is a serious problem resulting from clinical setting of coronary revascularization. Despite extensive studies on I/R injury, the molecular bases of cardiac dysfunction caused by I/R are still unknown, but are likely to result from alterations in protein expression. Isolated rat hearts were subjected to 15-30 min of no-flow ischemia without (Ischemia protocol) or with 30 min of reperfusion (I/R protocol). 2-DE analysis of heart proteins from both experimental protocols showed wide-ranging changes in protein levels. In the Ischemia protocol, 39 protein spots were changed in ischemic groups and those changes correlated with duration of ischemia. Ninety percent of the affected proteins were increased. In contrast to increased protein levels, the total messenger RNA (mRNA) level decreased approximately two fold. Compared to the Ischemia protocol, changes in protein levels in the I/R protocol did not correlate with the duration of ischemia and the degree of recovery of mechanical function. The decrease of affected protein from I/R protocol was associated with the increase in total protein level in reperfusate. Our studies show that the protein increase is correlated with the mechanical function of the I/R hearts and the increase is not likely associated with an increase in protein synthesis.     

Effect of beta-adrenergic blockade on thermoregulation during exercise

To resolve conflicting reports concerning the effects of beta-blockade (BB) on thermoregulatory reflexes during exercise, we studied six fit men during 40 min of cycle ergometer exercise at 60% maximum O2 consumption at ambient temperatures of 22 and 32 degrees C. Two hours before exercise, each subject ingested a capsule containing either 80 mg of propranolol or placebo in single-blind fashion. Heart rate at 40 min of exercise was reduced (P less than 0.01) from 125 to 103 beats min at 22 degrees C and 137 to 104 beats min at 32 degrees C, demonstrating effective BB. After 40 min of exercise, esophageal temperature (Tes) was elevated with BB (P less than 0.05) from 37.66 +/- 0.04 to 38.14 +/- 0.03 and 38.13 +/- 0.04 to 38.41 +/- 0.04 degrees C at 22 and 32 degrees C, respectively. The elevated Tes resulted from a reduced core-to-skin heat flux at both temperatures, indicated by a reduction in the slope of the forearm blood flow (FBF)-Tes relationship, and a decrease in maximal FBF. Systolic blood pressure was decreased 20 mmHg with BB (P less than 0.01), whereas diastolic blood pressure was unchanged, reducing arterial pulse pressure (PP). Because PP was decreased and cardiac filling pressure was presumably not reduced (since cardiac stroke volume was elevated), we suggest that at least a part of the relative increase in peripheral vasomotor tone during BB was the consequence of reduced sinoaortic baroreceptor stimulation.     

Effect of ischemic preconditioning on free radical centers of the isolated rat heart during ischemia and early reperfusion

The effect of ischemic preconditioning on the free-radical state of isolated rat myocardium fixed by rapid freezing at the 25th min of normothermic total ischemia and the 3rd min of reperfusion was studied by the EPR method. It was shown that EPR spectra registered at -40 degrees C consist of two free-radical signals: of the semireduced forms of ubiquinone and flavine coynzymes. It was found that during ischemia and at the beginning of reperfusion, the preconditioning results in a narrowing of the spectra (as compared with control) due to an increase in the narrow ubisemiquinone EPR signal portion, and a decrease in the total concentration of free-radical centers: by 16% in the case of ischemia, and 23% in the case of reperfusion. It was concluded that in both cases the changes were due to a decrease in the concentration of myocardial flavosemiquinones as a result of ischemic preconditioning. We registered the microvawe power saturation curves for these two stages, which corresponded to control and ischemic preconditioning. In the case of ischemia these dependences had similar shapes; however, in the case of reperfusion they differ from each other due to changes in the relative intensities of the EPR signals from ubisemiquinone and flavosemiquinones in the integral myocardial free-radical spectra.