Comparative plasma catecholamine and hemodynamic responses to handgrip, cold pressor and supine bicycle exercise testing in normal subjects

Serial hemodynamic and plasma catecholamine responses were compared among 10 healthy men (27 +/- 3 years) (+/- 1 standard deviation) during symptom-limited handgrip (33% maximal voluntary contraction for 4.4 +/- 1.8 minutes), cold pressor testing (6 minutes) and symptom-limited supine bicycle exercise (22 +/- 5 minutes). Plasma catecholamine concentrations were measured by radioenzymatic assays: ejection fraction and changes in cardiac volumes were assessed by equilibrium radionuclide angiography. During maximal supine exercise, plasma norepinephrine and epinephrine concentrations increased three to six times more than during either symptom-limited handgrip or cold pressor testing. Additionally, increases in heart rate, systolic blood pressure, rate-pressure product, stroke volume, ejection fraction and cardiac output were significantly greater during bicycle exercise than during the other two tests. A decrease in ejection fraction of 0.05 units or more was common in young normal subjects during the first 2 minutes of cold pressor testing (6 of 10 subjects) or at symptom-limited handgrip (3 of 10), but never occurred during maximal supine bicycle exercise. The magnitude of hemodynamic changes with maximal supine bicycle exercise was greater, more consistent and associated with much higher sympathetic nervous system activation, making this a potentially more useful diagnostic stress than either handgrip exercise or cold pressor testing.     

Effects of beta 1-selective and nonselective beta-adrenoceptor blockade during exercise conditioning in healthy adults

The interaction of beta 1-selective (cardioselective) and nonselective beta-adrenoceptor blockade with exercise conditioning was investigated in 30 healthy adult persons. A double-blind protocol was used and the effects of atenolol (100 mg/day), propranolol (80 mg twice daily), and placebo were studied by treadmill testing (Bruce protocol) before and after a 2-month supervised program of dynamic exercise. Exercise tolerance was assessed by time and work performed to exhaustion. Subjects who received propranolol, but not those who received atenolol or placebo, showed an acutely impaired exercise tolerance after drug administration but before training (-8 +/- 4%, p less than 0.05). All 3 groups showed significantly improved exercise capacity following training after drug treatment had been discontinued (atenolol, 22 +/- 6% improvement; propranolol, 13 +/- 6%; placebo, 10 +/- 3%). However, when tested while still receiving medication, subjects who received propranolol failed to show significant improvement in exercise capacity. In contrast, patients who received atenolol and placebo improved significantly. The data indicate that enhancement of maximal work capacity by exercise conditioning can occur despite administration of either beta 1-selective or nonselective beta-adrenoceptor antagonists. However, the fatiguing effects of propranolol that were evident when work performance during propranolol therapy was compared with work performance while not receiving propranolol before the training program persists after training and may limit the net improvement in work capacity induced by exercise conditioning compared with the pretraining state.     

Rest and exercise hemodynamic effects of sequential alpha-1-adrenoceptor (trimazosin) and beta-adrenoceptor (propranolol) antagonism in essential hypertension

The efficacy of acute beta blockade in essential hypertension is limited by reflex vasoconstriction. The aim of this study was to determine whether the latter response was modified by prior selective alpha-1-adrenoceptor blockade. A single-blind, within-patient, placebo-controlled evaluation of the immediate hemodynamic effects of sequential alpha-1 (trimazosin)- and beta (propranolol)-adrenoceptor blockade was undertaken in 10 men (34 to 58 years) with previously untreated essential hypertension. The study commenced with a 4-minute control period of constant-load (600 to 900 kpm/min) upright bicycle exercise, and measurements were made before (control) and 30 minutes after intravenous trimazosin (2 mg/kg) and exercise was then repeated; measurements at rest were again made 4 minutes after intravenous propranolol (0.2 mg/kg) before a final exercise period. Trimazosin at rest reduced systolic and diastolic arterial pressure and systemic vascular resistance without change in heart rate, cardiac output, or left ventricular (LV) filling pressure. During upright bicycle exercise the reductions in blood pressure were sustained without change in their rest-to-exercise increments. Other circulatory variables did not differ from control values. At rest the addition of propranolol further reduced systolic arterial pressure. Heart rate and cardiac output fell and systemic vascular resistance increased to its pretreatment control value. During exercise the changes at rest were sustained and the rest-to-exercise increments in blood pressure, heart rate, and cardiac output were reduced. LV filling pressure was significantly increased. In conclusion, alpha-1-adrenoceptor blockade modified the adverse effects of acute beta blockade at rest but not during exercise.     

Electrical and contractile consequences of Na+ or Ca2+ gradient reduction in cultured heart cells

The normal electrical and contractile activity of cultured neonatal rat ventricular cells is characterized and compared to activity seen in low [Ca²⁺]₀ and low [Na⁺]₀ solutions. In 0 Ca²⁺/0.5 mm EGTA solutions electrical activity is altered: the maximum diastolic potential (m.d.p.), maximum rate of rise ($\text{+}\text{V}\text{?}{}_{\mathrm{<mtext>max</mtext>}}$), and overshoot (o.s.) are reduced, while duration is increased. Low [Ca²⁺]₀ activity is insensitive to TTX and blocked by La³⁺. In low [Na⁺]₀ solutions electrical activity is generally absent; when present $\text{+}\text{V}\text{?}{}_{\mathrm{<mtext>max</mtext>}}$ and o.s. are decreased while duration is increased. Low [Na⁺]₀ activity is blocked by La³⁺. These data suggest the presence of one La³⁺-sensitive slow inward current channel. The absence of spontaneous electrical activity in low [Na⁺]₀ solutions suggests an inhibition of automaticity. To determine if this inhibition is due to a reduction of the Na⁺ gradient, drugs which raise [Na⁺]_i were examined. Both monensin (a Na⁺ ionophore) and ouabain inhibit the occurrence of spontaneous action potentials (cells respond to stimulation) indicating a dependence of pacemaker activity on a normal Na⁺ gradient. During Na⁺ gradient reduction, asynchronous subcellular contractile activity occurs independent of membrane potential fluctuation. This asynchronous activity is inhibited by La³⁺ or when Ca²⁺₀ is absent, but continues in the presence of verapamil (normal activity is blocked by all three conditions). The Na⁺Ca²⁺ exchange system is unaffected by verapamil but blocked by La³⁺, while both these drugs block the slow inward current. These data indicate that the Na⁺Ca²⁺ exchange system can directly supply Ca²⁺ (independent of electrical activity at the membrane) to intracellular sites that support contractile activity.     

Effect of manganese chloride and Verapamil on automaticity of digitalized Purkinje fibers.

The effects of manganese chloride (MnCl2) and verapamil on automaticity of digitlazied Purkinje fibers were studied using conventional microelectrode techniques. The stduied wer made in isolated, spontaneously beating Purkinje prearations. Quabain alone consistently increased the automatic rate, whereas no such increase was observed when the preparations were superfused with a mixture of ouabain adn MnCl2. MnCl2 was also shown to be effective is suppressing the enhanced automaticity induced by ouabain. Mncl2 alone did not have a significant effect on the spontaneous rate of Purkinje fibers. The effect of verapamil was similar to that of MnCl2 in preventing and suppressing the ouabain-induced increase in automaticity. MnCl2 and verapamil have been shown to inhibt tha slow inward calcium current of cardiac fibers. The results therefore suggest that an inward calcium ion current may play a role in the development of digitalis-induced increase in the stope of phase 4 depolarization in Purkinje fibers.     

Low-dose colestipol plus probucol for hypercholesterolemia

The hypocholesterolemic and adverse effects of colestipol, 20 g/day, and colestipol, 10 g/day combined with probucol, 1 g/day, were compared. A double-placebo, diet-controlled, crossover trial that lasted 19 months was undertaken on 22 hypercholesterolemic patients who had low-density lipoprotein (LDL) cholesterol levels greater than 180 mg/dl after 3 months of diet and placebo treatment. Uniformity of diet and physical activity were monitored throughout the study. Compared with baseline values after 3 months on diet-placebo treatment, "combined" therapy reduced LDL cholesterol by more than 20% in 15 patients, more than 25% in 9 patients and more than 45% in 2 patients. Treatment with "half-dose" colestipol and probucol resulted in the greatest mean LDL cholesterol reduction, from 239 mg/dl during diet-placebo period to 170 mg/dl; the difference was not statistically significantly different from the reduction to 180 mg/dl with 20 g of colestipol alone. Fifteen patients showed the greatest reduction in LDL cholesterol after combined therapy. Probucol produced statistically significant reductions in very low density lipoprotein and high-density lipoprotein cholesterol. The major gastrointestinal side effects of single therapy with colestipol (constipation) and probucol (diarrhea) were ameliorated or abolished by concomitant administration. Probucol-colestipol co-administration allowed a 50% reduction in the colestipol dosage, with similar efficacy and improved tolerability and reduced mean serum LDL cholesterol with a frequency and magnitude rarely seen with other hypocholesterolemic treatments. Hypercholesterolemic persons who cannot tolerate full doses of resins may receive equal benefit by half the dose if probucol is added to the regimen.