Effects of nonspecific beta-adrenergic stimulation and blockade on blood coagulation in hypertension.

A hypercoagulable state might contribute to increased atherothrombotic risk in hypertension. The sympathetic nervous system is hyperactive in hypertension, and it regulates hemostatic function. We investigated the effect of nonspecific beta-adrenergic stimulation (isoproterenol) and blockade (propranolol) on clotting diathesis in hypertension. Fifteen hypertensive and 21 normotensive subjects underwent isoproterenol infusion in two sequential, fixed-order doses of 20 and then 40 ng. kg(-1). min(-1) for 15 min/dose. Thirteen subjects were double-blind studied after receiving placebo or propranolol (100 mg/day) for 5 days each. In hypertensive subjects, isoproterenol elicited a dose-dependent increase in plasma von Willebrand factor (vWF) antigen [F(2,34) = 5.02; P = 0.032] and a decrease in D-dimer [F(2,34) = 4.57; P = 0.040], whereas soluble tissue factor remained unchanged. Propranolol completely abolished the increase in vWF elicited by isoproterenol [F(1,12) = 10.25; P = 0.008] but had no significant effect on tissue factor and D-dimer. In hypertension, vWF is readily released from endothelial cells by beta-adrenergic stimulation, which might contribute to increased cardiovascular risk. However, beta-adrenergic stimulation alone may not be sufficient to trigger fibrin formation in vivo.     

Effects of beta-adrenergic receptor stimulation and blockade on substrate metabolism during submaximal exercise

We used beta-adrenergic receptor stimulation and blockade as a tool to study substrate metabolism during exercise. Eight moderately trained subjects cycled for 60 min at 45% of VO(2 peak) 1) during a control trial (CON); 2) while epinephrine was intravenously infused at 0.015 microg. kg(-1) x min(-1) (beta-STIM); 3) after ingesting 80 mg of propranolol (beta-BLOCK); and 4) combining beta-BLOCK with intravenous infusion of Intralipid-heparin to restore plasma fatty acid (FFA) levels (beta-BLOCK+LIPID). beta-BLOCK suppressed lipolysis (i.e., glycerol rate of appearance) and fat oxidation while elevating carbohydrate oxidation above CON (135 +/- 11 vs. 113 +/- 10 micromol x kg(-1) x min(-1); P < 0.05) primarily by increasing rate of disappearance (R(d)) of glucose (36 +/- 2 vs. 22 +/- 2 micromol x kg(-1) x min(-1); P < 0.05). Plasma FFA restoration (beta-BLOCK+LIPID) attenuated the increase in R(d) glucose by more than one-half (28 +/- 3 micromol x kg(-1) x min(-1); P < 0.05), suggesting that part of the compensatory increase in muscle glucose uptake is due to reduced energy from fatty acids. On the other hand, beta-STIM markedly increased glycogen oxidation and reduced glucose clearance and fat oxidation despite elevating plasma FFA. Therefore, reduced plasma FFA availability with beta-BLOCK increased R(d) glucose, whereas beta-STIM increased glycogen oxidation, which reduced fat oxidation and glucose clearance. In summary, compared with control exercise at 45% VO(2 peak) (CON), both beta-BLOCK and beta-STIM reduced fat and increased carbohydrate oxidation, albeit through different mechanisms.     

Effects of chronic beta-adrenergic blockade on exercise training in dogs

To assess the role of beta-adrenergic stimulation in cardiovascular conditioning we examined the effects of a beta-adrenergic blocker, propranolol, in mongrel dogs during an 8-wk treadmill-training program. Seven dogs were trained without a drug (NP), six were trained on propranolol 10 mg.kg-1.day-1 (P), and five served as caged controls (C). Effective beta-adrenergic blockade was documented by a decrease in peak exercise heart rate of 54 +/- 11 (SE) beats/min (P less than 0.05) and a one-log magnitude of increase in the isoproterenol-heart rate dose-response curve. Testing was performed before drug treatment or training and again after training without the drug for 5 days. Submaximal exercise heart rate decreased similarly in both NP and P (-26 +/- 4 NP vs. -25 +/- 9 beats/min P, P less than 0.05 for both) but peak heart rate decreased only with NP (-33 +/- 9 beats/min, P less than 0.05). Treadmill exercise time increased similarly in both groups: 3.4 +/- 0.6 min in NP and 3.0 +/- 0.2 min in P (both P less than 0.05). Blood volume also increased after training in both groups: 605 +/- 250 ml (26%) in NP and 377 +/- 140 ml (17%) in P (both P less than 0.05). Submaximal exercise arterial lactates were reduced similarly in both groups but peak exercise lactate was reduced more in NP (-1.4 +/- 0.3 NP vs -0.3 +/- 0.12 mmol/l P, P less than 0.05). Lactate threshold increased in both groups but the increase was greater in NP (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of beta-adrenergic blockade on training-induced structural adaptations in rat left ventricle

The study was designed to evaluate the effects of eight weeks of exercise training or training-beta-adrenergic blockade combination on gross and microscopic alterations of rat cardiac muscle and microvascular bed. Rats were randomly assigned to either sedentary control (C), trained (T), metoprolol-trained (MT), or propranolol-trained (PT) groups. The training protocol involved treadmill running for 8 weeks at 0.5 ms-1, 20% grade. Earlier experiments by us showed this training protocol to be effective in producing significant changes in selected skeletal muscle enzyme activities in all trained groups. In the current study an absolute reduction in left ventricular (LV) weight was observed in the PT compared to the C group (0.91 +/- 0.02 vs. 1.04 +/- 0.04 g, P less than 0.05). LV weight in the T and MT groups was no different from C so that LV to BW ratio (mg.g-1) was significantly increased (P less than 0.05) due to a similar reduction in body weight (BW) in all three training groups. Morphometric analysis of LV myocardium revealed no significant differences in myocyte mean cross-sectional area (micron 2) in any of the groups (289 +/- 16-C, 332 +/- 20-T, 281 +/- 44-MT, and 273 +/- 12-PT). Capillary density independently calculated by light and electron microscopy was unchanged by training or training-beta-blockade combination. It was concluded that training of sufficient intensity and duration to produce skeletal muscle enzyme adaptations does not necessarily produce myocyte hypertrophy or alter LV capillarity. Additionally functioning beta-adrenergic receptors appear to play a role in both the central and peripheral adaptations to endurance exercise training.     

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.     

Effects of changes in osmolarity on isolated human airways

The effects of hypo- and hyperosmolarity on the function of isolated human airways were studied. Changes in osmolarity induced an increasing bronchoconstriction that was proportional to the magnitude of the change in osmolarity. Hypertonicity-induced airway narrowing resulted when buffer was made hypertonic with sodium chloride or mannitol but not with urea. The airways showed no tachyphylaxis to repetitive exposure to hypo- and hypertonic buffer of 200 and 600 mosM, respectively. The bronchoconstriction was not secondary to stimulation of H1 or leukotriene C4/D4 receptors or the release of prostaglandins in the preparation. The bronchoconstriction in hypotonic buffer was totally dependent on extracellular calcium, whereas in hypertonic buffer the bronchoconstriction seemed partially dependent on intracellular calcium release. Isoprenaline prevented the bronchoconstriction in hyper- or hypotonic buffer of 450 and 250 mosM but not in buffer of 600 and 150 mosM. It is concluded that hypo- and hypertonic buffers lead to bronchoconstriction via different mechanisms, which relate to influx of extracellular calcium in hyposmolar buffer and probably to release of calcium from intracellular stores in hypertonic buffer. In strongly hypertonic buffer, part of the bronchoconstriction may be due to osmotic shrinkage. The relevance of our data for the mechanism of bronchoconstriction after inhalation of hypo- or hypertonic saline depends on whether changes in osmolarity around the airway smooth muscle occur in asthmatics but not in normal subjects, and this has not yet been established.     

Effects of β-bungarotoxin and taipoxin on contractions of canine airways caused by nerve stimulation

β-Bungarotoxin and taipoxin are snake venoms that have been reported to induce neuromuscular blockade exclusively in somatic motor neurons by a presynaptic mechanism. Taipoxin (1 μg/ml), but not β-bungarotoxin (1 μg/ml), depressed the contractile response of canine airway smooth muscle to electrical stimulation. Taipoxin (1 μg/ml) also slightly depressed the contractile activity of canine airways to two concentrations (5 × 10^?6M and 10^?5M) of exogenously administered acetylcholine. We conclude that taipoxin, but not β-bungarotoxin, induces a weak neuromuscular blockade in the parasympathetic fibers innervating canine airways. The sites of this inhibition are believed to be both presynaptic and postsynaptic.     

Effect of beta-adrenergic blockade on hyperventilation and exercise tolerance in emphysema

Ventilation, heart rate, and arterial blood gas tensions were measured at rest and during incremental exercise in 10 patients with emphysema after intravenous placebo or 7 mg metoprolol. Metoprolol reduced heart rate by 14% (P less than 0.001) and ventilation by 11% (P less than 0.01), but there was no significant difference in arterial O2 or CO2 tension (Pao2 and PaCO2, respectively). Metoprolol increased the time to exhaustion on a cycle ergometer (P less than 0.05) but did not improve the 12-min walking distance. A double-blind randomized crossover comparison of 4 wk treatment with atenolol (100 mg/day), metoprolol (100 mg/day), or matched placebo was performed in 12 patients with emphysema. Both beta-adrenoceptor antagonists reduced resting heart rate by 33% (P less than 0.001) and resting minute ventilation by 11% (P less than 0.025). There was no change in resting or exercise Pao2 or Paco2. During steady-state exercise on a cycle ergometer, atenolol and metoprolol reduced ventilation by 14 and 4%, respectively. This was accompanied by 11 and 5% reductions in O2 consumption (P less than 0.05) and 13 and 6% falls in CO2 production (P less than 0.05). There were no significant changes in tests of exercise tolerance, but forced expiratory volume in 1 s and forced vital capacity were reduced during beta 1-adrenergic blockade. beta 1-Blocking drugs reduce hyperventilation in emphysema by reducing pulmonary gas exchange without a change in arterial blood gas tensions. Increased airflow obstruction prevents this reduction being of therapeutic value.