Charles A. Chidsey

Combined Therapy with Vasodilator Drugs and Beta-Adrenergic Blockade in Hypertension: A Comparative Study of Minoxidil and Hydralazine

The hypotensive efficacies of two vasodilators, hydralazine and minoxidil, were assessed as these drugs were used individually in combination with beta-adrenergic blockade and diuretics in 11 hypertensive patients in whom elevated blood pressure had not been adequately controlled previously by other antihypertensive therapy.Control supine blood pressure fell from 191/128 mm Hg on propranolol and hydrochlorothiazide to 169/108 mm Hg on hydralazine, with a significantly greater reduction to 142/92 mm Hg on minoxidil. Although sodium retention and tachycardia were controlled by the use of concomitant diuretics and beta-blockade, an increment in each of these drugs was occasionally required to prevent these complications. Renal function was changed little with the decrease in blood pressure. Plasma renin increased from a standing control of 14.5 mμg/ml/hr to 35.9 and 31.1 mμg/ml/hr, respectively, on hydralazine and minoxidil. These data suggest the role of vasodilators used in combination with beta-blockers and diuretics and indicate the greater therapeutic efficacy of minoxidil.

Inhibition of theophylline clearance by troleandomycin

The effect of troleandomycin, a macrolide antibiotic, on theophylline elimination was examined in eight patients with chronic asthma. Clearance from serum was reduced by 50 +/- 6% (mean +/- SD) during administration of 250 mg troleandomycin four times daily. Reduction of clearance persisted to a lesser degree in one of these patients examined while receiving 250 mg troleandomycin daily. An increase in serum theophylline concentration can thus result from initiating troleandomycin in asthmatic patients receiving continuous treatment with theophylline. This may be at least a partial explanation for the apparent benefit of troleandomycin in chronic asthma and also suggests that possibility of inducing theophylline toxicity, including seizures, as was observed in one of the patients in this study.

Effects of Propranolol and Isosorbide Dinitrate on Exercise Performance and Adrenergic Activity in Patients with Angina Pectoris

Twelve patients with angina pectoris were evaluated in a single blind crossover study with respect to objective changes in exercise performance on the treadmill and subjective, clinical improvement on oral administration of propranolol, isosorbide dinitrate (ISD), and a combination of propranolol and ISD. Combined objective and subjective evaluations showed that nine of 12 patients improved on propranolol, seven of 10 on ISD, and all 10 on the combination of drugs. The differences in objective improvement between the various drug regimens were not significant. However, subjectively all patients on the combination of drugs improved markedly. The patients on propranolol or the combination had a decrease in pressure-rate index of about 30% both at rest and during exercise, while these values did not change on ISD. A significant reduction in exercise-induced S-T depression was observed with propranolol alone and in combination with ISD at grade 3+ pain. Adrenergic activity, estimated from plasma and urinary catecholamines, appeared to be increased in these patients before drug treatment and was not altered during treatment. It is concluded that propranolol, ISD, and the combination of these drugs all improve exercise performance in patients with angina. Although the combination of drugs could not be shown to produce a greater increase in exercise performance than either drug alone, the combination effected a greater overall clinical improvement.

Plasma Volume Expansion Resulting from Interference with Adrenergic Function in Normal Man

Guanethidine was administered to 10 normal subjects in order to examine the effects of reduced adrenergic function on plasma volume. An increase in the plasma volume was observed averaging 21.4% after 1 week, and 12.1% and 13.1% after 2 and 3 weeks of drug administration. A similar change in plasma volume resulted when alphaadrenergic blockade was produced with phenoxybenzamine. These changes occurred in the absence of sodium retention and were associated with attenuation of forearm venous sympathetic reflexes and a rise in forearm venous compliance. The increase in venous compliance which was observed was proportional to the changes in plasma volume in these subjects. Thus, the sympathetic nervous system through its control of venous resistance may provide a means whereby the blood volume can be regulated.

Intracellular Calcium and Myocardial Contractility

The function of the sarcoplasmic reticulum of the failing myocardiums was studied in vitro by comparing calcium uptake and calcium-activated ATPase in microsomes prepared from hearts of control calves and calves in which right ventricular failure developed during experimentally induced pulmonary hypertension. The rate of calcium uptake averaged .147 μmole·mg−1·min−1 at 25°C in the presence of oxalate in control preparations and was significantly reduced in preparations from failing right ventricles (avg .086 μmoles·mg−1·min−1). Calcium-activated ATPase was also diminished significantly in failure (avg .184 compared to .073 μmoles·mg−1·min−1). Although two preparations also showed diminished calcium activities in the nonfailing left ventricle, group these activities were not significantly depressed in preparations from ventricle in calves with failure. A similar reduction in calcium activities observed at 37°C with preparations further purified by sucrose gradient centrifugation. The uptake capacity of microsomes, measured as calcium uptake in the absence of oxalate, was not diminished in the preparations from failing hearts. Mitochondrial contamination did not appear to be a factor since azide inhibited calcium activity almost completely in mitochondria, whereas inhibition was less than 10% in microsomes of both control and failing hearts. Ouabain had no effect on the microsomes from failing hearts. These studies indicate that there is a defect in calcium transport in microsomes and a functional abnormality of the sarcoplasmic reticulum in the intact myocardial cell in heart failure which could lead to changes in the excitation-contraction coupling mechanisms of clinical importance.

Intracellular calcium and myocardial contractility V. Calcium uptake of sarcoplasmic reticulum fractions in hypertrophied and failing rabbit hearts

To evaluate calcium uptake in the sarcoplasmic reticulum (SRF) in the hypertrophied and failing myocardium, SRF was prepared from hearts of rabbits with experimentally produced aortic insufficiency (AI). In SRF preparations from the hypertrophied hearts of animals killed shortly (2 weeks) after AI production calcium uptake was normal, 0.146 ± 0.001 compared to control values of 0.137 ± 0.010 μmol×mg−1×min−1. However, calcium uptake was reduced in SRF preparations from hypertrophied hearts removed from animals later (4 to 7 weeks) after AI production. In this latter group, some of the animals had no pathologic evidence of left ventricular failure but a significant reduction of calcium uptake was observed, 0.086 ± 0.002 μmol×mg−1×min−1 (P < 0.01). In other animals, with clear pathologic findings of failure, further reduction of calcium uptake was observed, 0.058 ± 0.006 μmol×mg−1×min−1. Ouabain was not effective in reversing these depressed activities, either when given in vivo or in vitro. These findings indicate that the decrease in SRF function is not a necessary accompaniment of ventricular hypertrophy, but may develop later as hypertrophy becomes more extensive and/or heart failure occurs. It remains to be demonstrated whether or not the abnormality of SRF uptake of calcium initiates the onset of heart failure or is in fact the result of the development of such depressed cardiac function.

A sensitive gas chromatographic method for the determination of propranolol in human plasma

Abstract A gas chromatographic method for the determination of propranolol in plasma has been developed. After solvent extraction, a difluorobutyrate derivative is formed, which is measured by an electron capture detector. The quantification is controlled by using an internal standard, pronethalol, which is added to all samples. The electron capture detector response was linear between 5 and 80 ng/ml. No interference from common cardiovascular drugs was found. Concentrations of propranolol in the plasma determined by this method were directly related to the administered dose of the drug.

Pharmacokinetic studies of practolol, a beta adrenergic antagonist, in man.

The disposition of practolol after oral and intravenous administration was studied in hypertensive patients. The plasma half‐life was 13.2 hours. After intravenous administration practolol was recovered quantitively in the urine. Its volume of distribution was larger than that of body water, 1.6 L. per kilogram, and its clearance from this volume, 135 ml. per minute, was equal to renal clearance of the drug; both were slightly higher than the creatinine clearance. Despite its weakly basic character, this aromatic alkylamine was not affected by changes in urinary pH from 5.4 to 8.0. These studies indicate that practolol is slowly removed from the body and that it is excreted entirely by the kidneys.

The pharmacologic basis of antihypertensive therapy: The role of vasodilator drugs☆

N I RECENT YEARS, the drug therapy of hypertension has centered around pharmacologic methods for inhibition of adrenergic nervous activity. The rationale of this approach has been that the removal or attenuation of the adrenergic outflow will lower blood pressure regardless of the arterial pressor mechanisms responsible for the hypertension, since these nerves are still active and contributing vasoconstrictive stimuli despite the elevated blood pressure. The presence of a normal functional level of activity of the adrenergic nerves in the hypertensive patient has been shown by the excretion of catecholamines in the urine, which is at least equivalent to the excretion in nonhypertensive subjects.’ Indeed, in some of these patients, there may even be an increase of adrenergic activity as shown either by blood catecholamines2 or by an alteration of the pattern of firing of peripheral sympathetic nerves.3 As adrenergic influences on the vascular resistance are reduced by pharmacologic inhibition of neuronal function, there will also be a reduced cardiac output resulting from diminished myocardial contractility and venous pooling,4 and these factors will also contribute to a vasodepressor esponse. In some patients, the therapeutic approach with adrenergicinhibiting drugs is successful, and a hypotensive effect can be achieved with only a moderate disruption of the overall control function of the adrenergic nervous system. However, in others, either the desired vasodepressor effect is not achieved, or it is obtained only at the expense of an unacceptable degree of disruption of adrenergic function such that homeostatic control of the circulation is severely compromised. In these latter patients, it becomes necessary to utilize other mechanisms for blood pressure reduction, and in

Intracellular calcium and myocardial contractility. IV. Distribution of calcium in the failing heart.

Abstract Myocardial calcium and its distribution in intracellular fractions were measured in chronic heart failure occurring in rabbits with experimental aortic insufficiency. In these animals heart failure was characterized by the presence of pulmonary congestion and edema and the development of diminished myocardial contractility. Hearts were analyzed for calcium contents either after perfusion in vitro or immediately after removal from the animals. Total myocardial calcium was similar in control and failing hearts after in vitro perfusion and was only minimally increased in those failing hearts which were not perfused. However, calcium was elevated in intracellular fractions prepared from failing hearts. An increase of calcium was found in mitochondria of hearts perfused in vitro from a control of 10.9 ± 0.5 to 16.3 ± 1.6 nmol/mg. Similar increments in mitochondrial calcium were seen in the failing hearts which were not perfused but analyzed immediately after removal from the animal. Changes of calcium in the microsomal fractions were more difficult to interpret because of the greater heterogeneity of these fractions. These findings indicate that, although the total amount of calcium available to the myocardial cell is not diminished in the failing heart, a change of intracellular calcium metabolism is present, leading to an altered distribution of this cation with greater amounts accumulated in mitochondria. These changes may be causally related to the reduced contractility of the failing heart by limiting the amount of calcium available to initiate contraction.