Response of Asthmatics to Isoprenaline and Salbutamol Aerosols Administered by Intermittent Positive-pressure Ventilation

The bronchodilator and cardiac effects produced by aerosols of 0·5% isoprenaline and of 0·25, 0·5, and 1% salbutamol administered in 40% oxygen by intermittent positive-pressure ventilation were compared in 24 asthmatic patients. Isoprenaline and salbutamol in concentrations of 0·5% were equipotent in peak bronchodilator effect; salbutamol was superior in total bronchodilator effect and duration of average effect, but the peak bronchodilator effect occurred earlier after isoprenaline. Significantly greater tachycardia was produced by 0·5% isoprenaline than by the same concentration of salbutamol. The 0·25, 0·5, and 1% concentrations of salbutamol had about the same peak bronchodilator effect, but there was a stepwise increase in total effect and duration of average effect in relation to the concentration used. A similar stepwise increase in heart rate was also noted, but with all concentrations this was significantly less than with 0·5% isoprenaline. It was concluded that a 0·5% solution of salbutamol, which provided maximal bronchodilatation without important tachycardia, was therapeutically superior to the other three treatments.     

Synergistic effects of a combined salbutamol-nitroprusside regimen in acute myocardial infarction and severe left ventricular failure.

The haemodynamic effects of a simultaneous infusion of salbutamol and nitroprusside were measured in 20 patients with acute myocardial infarction and severe left ventricular failure. Six patients also had clinical manifestations of cardiogenic shock. Ten patients received salbutamol first with the subsequent addition of nitroprusside; in the other 10 patients nitroprusside was infused first. Salbutamol was infused at a constant rate of 20 micrograms/min in all patients, while the dose of nitroprusside, which averaged 51.25 micrograms/min, was adjusted to reduce left ventricular filling pressure (measured as pulmonary artery end-diastolic pressure) to approximately 15 mm Hg with reference to sternal angle. Cardiac index increased in all patients from a mean of 1.8 to 2.6 l/min/m2 while pulmonary artery end-diastolic pressure fell significantly from 24 to 16 mm Hg. The adverse effects were small in most patients: heart rate did not increase significantly and systolic arterial pressure fell on average from 112 to 96 mm Hg. Ten of the 20 patients survived to leave hospital. Nitroprusside accounted for most of the fall in filling pressure irrespective of treatment sequence, whereas both drugs contributed to the augmented cardiac output. The haemodynamic benefits of this combined regimen were considerably greater than those achieved by either drug alone. Thus salbutamol and nitroprusside have synergistic effects which influence favourably the two principal manifestations of left ventricular dysfunction after extensive myocardial infarction.     

Haemodynamic Effects of Salbutamol in Patients Needing Circulatory Support after Open-heart Surgery

The effects of substituting an infusion of salbutamol for isoprenaline were studied in 12 patients needing circulatory support after valve replacement surgery. The cardiac output rose while the heart rate remained unaltered. There was a reduction in systemic vascular resistance, and though the oxygen uptake tended to rise the increase in cardiac output was proportionately greater so that the arteriovenous oxygen difference fell.It is suggested that the drug is of value for two reasons. It causes a selective reduction in peripheral arteriolar resistance, which avoids peripheral pooling, but permits limited myocardial work to be used to generate flow rather than pressure, and the increase in cardiac output is not accompanied by a corresponding rise in oxygen uptake.     

Comparison of Effect of Salbutamol and Isoprenaline on Spirometry and Blood-gas Tensions in Bronchial Asthma

The effect of the aerosol inhalation of 200 μg. of salbutamol and 1,000 μg. of isoprenaline on spirometry and blood-gas tensions was compared in the same 11 asthmatic subjects. Both drugs significantly reduced airway obstruction, and the extent of the reduction did not differ for periods of up to 30 minutes. After isoprenaline tachycardia and a small significant fall in arterial oxygen tension occurred, whereas after salbutamol there was no change in pulse rate and the arterial oxygen tension did not fall.     

Salivary secretion during selective β-adrenoreceptor stimulation and blockade in the parotid gland of red kangaroos,<Emphasis Type="Italic"> Macropus rufus</Emphasis>

Intracarotid infusions of noradrenaline (0.3 nmol.kg(-1) x min(-1)) stimulated salivary fluid secretion and caused increases in salivary concentrations of protein, potassium. magnesium. chloride and phosphate, and decreases in bicarbonate. These effects of intracarotid noradrenaline were not reduced by simultaneous intracarotid infusion of phentolamine (3.0 nmol.kg(-1) x min(-1)) but were significantly greater than the responses accompanying intravenous noradrenaline infusion. Concomitant administration of the beta-antagonist, CGP20712A, were much more effective in blocking the noradrenaline-induced changes in salivary composition than equimolar infusions of the beta2-antagonist, ICI118551, thereby confirming the presence of beta1-adrenoreceptors. Intracarotid infusion of salbutamol at 0.6 nmol x kg(-1) x min(-1) and 6.0 nmol x kg(-1) x min(-1) caused increasing but qualitatively similar changes in salivary composition to intracarotid noradrenaline but was less effective than noradrenaline in augmenting salivary protein release. Equimolar intravenous infusions of salbutamol and noradrenaline were equally potent in altering salivary electrolyte concentrations but salbutamol by this route had less effect on protein release and fluid secretion. Concurrent intravenous and intracarotid infusions of beta1-(CGP) and beta2-(ICI) antagonists with intracarotid salbutamol showed that the beta2-antagonist was more potent than the beta1-antagonist by the intracarotid route thereby demonstrating the presence of glandular beta2-receptors and eliminating the possibility that the response to salbutamol was due totally by reflex increases in general sympathetic tone triggered by lowered blood pressure. It was concluded that the kangaroo parotid has functional beta1- and beta2-adrenoreceptor subtypes in endpieces whereas the data provide little support for either adrenoreceptor subtype being present in the excurrent duct system.     

The inotropic and chronotropic responses of the guinea pig and dog myocardium to isoprenaline and salbutamol.

The relative effects of isoprenaline and salbutamol on the inotropic and chronotropic responses of the denervated myocardium of the chloralose anesthetized dog and of the isolated guinea pig atrium, and the inotropic response of the isolated dog papillary muscle were studied. Both the in vivo dog heart and the in vitro guinea pig atrium displayed a similar relative response pattern to isoprenaline and salbutamol with regard to their inotropic and chronotropic responses. However, a comparison of the relative inotropic responses of the dog heart in vivo and in vitro showed that in vitro, salbutamol has a much lower affinity and efficacy for the adrenergic receptors than isoprenaline.     

Different Effects of Adrenergic Beta-receptor Blockade on Heart Rate Response to Mental Stress,Catecholamines, and Exercise

The magnitude and duration of effect of a single 40-mg oral tablet of oxprenolol on the tachycardias associated with motor-car driving, isoprenaline infusion, and walking were compared against placebo in six normal people by a double-blind study. The tachycardias due to driving and isoprenaline were both conspicuousy reduced for over eight hours; the magnitude and duration of the reduction in exercise tachycardia was substantially less. Thus relatively small doses of beta-receptor antagonists will suppress the increase in heart rate induced by mental stress or catecholamines with relatively little effect on the response to everyday exercise. Possibly smaller doses of these drugs would relieve emotionally-induced anginal pain and tachycardia.     

Mechanism of tachycardia caused by intracarotid PGE2 in conscious ewes

Conscious adult ewes prepared with nonocclusive indwelling vascular catheters were used to determine the mechanism by which heart rate increases during central administration of prostaglandin E2 (PGE2). Heart rate increased 14 bpm during steady-state intracarotid infusion of PGE2, 10 ng/kg/min (P less than 0.05). Intravenous atropine methyl bromide, 1 mg/kg, increased heart rate 26 bpm (P less than 0.05) 5 min after injection. Heart rate remained elevated 30 min after injection. The heart rate response to PGE2 plus atropine was greater than the heart rate response to either atropine or PGE2 alone (P less than 0.05). Propranolol, 1 mg/kg bolus plus intravenous infusion, 0.025 mg/kg/min, did not change resting heart rate. Propranolol attenuated but did not abolish the increase in heart rate caused by intracarotid PGE2. Although heart rate increased in response to PGE2 after administration of either propranolol or atropine alone, the combination of propranolol and atropine prevented any further increase in heart rate during subsequent PGE2 infusion. The increase in heart rate when all three drugs were given together was not different from the increase observed during atropine alone. Thus, both beta-adrenergic activation and muscarinic deactivation contribute to the PGE2-induced tachycardia.     

The acute effects of capsaicin on the cardiovascular system

Arterial blood pressure and heart rate were recorded from male Wistar rats anaesthetized with urethane. Intravenous injection of capsaicin, 1 microgram, produced a reproducible triphasic effect on blood pressure, comprising an initial fall in blood pressure and heart rate, followed by a transient and then a sustained pressor response. The depressor response and bradycardia were abolished by vagal section. The transient pressor response was altered in shape by hexamethonium. Slow intravenous infusion of capsaicin, 50 micrograms over 12 min, produced only a sustained pressor response accompanied by tachycardia, which was resistant to hexamethonium but abolished by morphine and pithing. Responses to both 1 microgram injection and 50 micrograms infusion of capsaicin were unaffected by the SP antagonist, spantide, but were abolished by capsaicin pretreatment of the rats. Capsaicin induces complex effects on the cardiovascular system, the nature of which varies with the dose and speed of administration.     

Effect of intravenous infusion of salbutamol on ventilatory response to carbon dioxide and hypoxia and on heart rate and plasma potassium in normal men.

Intravenous infusion of salbutamol 10 mug/min in seven healthy subjects significantly increased their ventilatory responses to inhaled CO2 in both hypoxia and hyperoxia. These changes in chemical control of breathing are unlikely to be significant when the drug is used in severe asthma but may benefit patients with acute exacerbations of chronic ventilatory failure. The infusion also increased heart rate, which was most pronounced when hypoxia was combined with hypercapnia. The infusion produced an average fall in plasma potassium from 3-99 to 3-10 mmol/l, which was associated with an increase in plasma glucose and serum insulin, suggesting that this arose from a shift of potassium from the extracellular to the intracellular space. Routine monitoring of plasma potassium and the electrocardiogram is indicated when an intravenous salbutamol infusion is used to treat severe asthma as the drug may predispose to cardiac dysrhythmias.     

Effects of Salbutamol and Isoprenaline Phenylephrine in Reversible Airways Obstruction

Ventolin (salbutamol) and Medihaler-Duo (isoprenaline/phenylephrine combination) standard pressurized inhalers were used to administer doses of two or six “puffs” to 16 patients with known reversible airways obstruction. The doses were administered in random order over two days. Both the Ventolin and Medihaler-Duo inhalers substantially increased FEV₁, but in the doses used salbutamol was more effective than isoprenaline/phenylephrine (P < 0·01). There was no significant difference between two and six puffs of salbutamol, though there seemed to be an advantage of six puffs of isoprenaline/phenylephrine over two puffs (P < 0·05). Adrenaline (1/1,000) 0·5 ml and atropine 0·6 mg produced similar increases in FEV₁ to those produced by salbutamol.The Pao₂ fell more than 5 mm Hg in three patients after salbutamol and in three after isoprenaline/phenylephrine. There was no significant fall in mean Pao₂ in any of the treatment groups. It is concluded that the Ventolin inhalant, administered in the conventional dose of two puffs, is as effective a bronchodilator as subcutaneous adrenaline and atropine, is more effective than the Medihaler-Duo, and is without detectable side effects.     

Intravenous beta agonist in severe acute asthma.

STUDY OBJECTIVE--To determine whether salbutamol is more effective in treating severe asthma when given intravenously or by inhalation. DESIGN--Randomised trial of short term response to intravenous versus nebulised salbutamol in acute severe asthma. SETTING--District general hospital (secondary care centre). PARTICIPANTS--76 patients aged 16-70 admitted to hospital with acute severe asthma (peak expiratory flow rate less than 50% of predicted) during study period. Five withdrawn because of adverse effects of treatment or non-response. Of remaining 71, 34 allocated to nebuliser group and 37 to intravenous treatment group. Patients with history of cardiovascular disease or recent corticosteroid or intravenous bronchodilator treatment excluded. Admission characteristics similar in the two groups. INTERVENTIONS--All patients given 5 mg nebulised salbutamol on admission before randomisation plus 200 mg hydrocortisone bolus intravenously and 35% inspired oxygen throughout. Nebuliser group received two more 5 mg doses of nebuliser salbutamol at 30 minutes and 2 hours; intravenous group received 4 hours'' continuous salbutamol infusion (12 micrograms/min) starting at 30 minutes plus supplementary intravenous potassium chloride. No other bronchodilators used. ENDPOINT--Change in peak expiratory flow rate over 4 hours. MEASUREMENTS and MAIN RESULTS--Peak expiratory flow rate improved more in intravenous group (25.2%) than in nebuliser group (14.3%) (p less than 0.01, 95% confidence interval 2.4 to 19.1%). Tachycardia caused two withdrawals from intravenous group; non-response caused three withdrawals from nebuliser group. CONCLUSIONS--Intravenous salbutamol is more effective than nebulised salbutamol in acute severe asthma but may have unacceptable cardiovascular effects.     

Comparison of phenylephrine bolus and infusion methods in baroreflex measurements

Phenylephrine (PE) bolus and infusion methods have both been used to measure baroreflex sensitivity in humans. To determine whether the two methods produce the same values of baroreceptor sensitivity, we administered intravenous PE by both bolus injection and graded infusion methods to 17 normal subjects. Baroreflex sensitivity was determined from the slope of the linear relationship between the cardiac cycle length (R-R interval) and systolic arterial pressure. Both methods produced similar peak increases in arterial pressure and reproducible results of baroreflex sensitivity in the same subjects, but baroreflex slopes measured by the infusion method (9.9 +/- 0.7 ms/mmHg) were significantly lower than those measured by the bolus method (22.5 +/- 1.8 ms/mmHg, P less than 0.0001). Pretreatment with atropine abolished the heart rate response to PE given by both methods, whereas plasma catecholamines were affected by neither method of PE administration. Naloxone pretreatment exaggerated the pressor response to PE and increased plasma beta-endorphin response to PE infusion but had no effect on baroreflex sensitivity. Thus our results indicate that 1) activation of the baroreflex by the PE bolus and infusion methods, although reproducible, is not equivalent, 2) baroreflex-induced heart rate response to a gradual increase in pressure is less than that seen with a rapid rise, 3) in both methods, heart rate response is mediated by the vagus nerves, and 4) neither the sympathetic nervous system nor the endogenous opiate system has a significant role in mediating the baroreflex control of heart rate to a hypertensive stimulus in normal subjects.     

Effect of misoprostol, a synthetic equivalent of prostaglandin E1, on bronchodilation in bronchial spasm]

A effect of a single dose 400 micrograms misoprostol (Cytotec-Searle) on a degree of the bronchospasm relief has been investigated in 8 patients, and the results have been compared with those produced by aminophylline i.v. infusion in the rate of 500 mg/hour. Prior to and 10, 20, 30, 60, 90, 120, 150 and 180 minutes after administration of both drugs, the following parameters of pulmonary ventilation have been determined: VC, VC%, FEV1, FEV1%, MVV, and MEFR. The results have shown that misoprostol given in a single oral dose of 400 micrograms to patients with bronchospasm has the bronchodilating activity which is statistically significant. However, this activity is rather weak and significantly lower than that of intravenous aminophylline infusion.     

Potent effects of aerosol compared with intravenous treprostinil on the pulmonary circulation.

Inhaled vasodilator therapy for pulmonary hypertension may decrease the systemic side effects commonly observed with systemic administration. Inhaled medications only reach ventilated areas of the lung, so local vasodilation may improve ventilation-perfusion matching and oxygenation. We compared the effects of intravenous vs. aerosolized treprostinil on pulmonary and systemic hemodynamics in an unanesthetized sheep model of sustained acute pulmonary hypertension. Acute, stable pulmonary hypertension was induced in instrumented unanesthetized sheep by infusing a PGH(2) analog, U-44069. The sheep were then administered identical doses of treprostinil either intravenously or by aerosol. Systemic and pulmonary hemodynamics were recorded during each administration. Both intravenous and aerosol delivery of treprostinil reduced pulmonary vascular resistance and pulmonary arterial pressure, but the effect was significantly greater with aerosol delivery (P < 0.05). Aerosol delivery of treprostinil had minimal effects on systemic hemodynamics, whereas intravenous delivery increased heart rate and cardiac output and decreased left atrial pressure and systemic blood pressure. Aerosol delivery of the prostacyclin analog treprostinil has a greater vasodilatory effect in the lung with minimal alterations in systemic hemodynamics compared with intravenous delivery of the drug. We speculate that this may result from treprostinil stimulated production of vasodilatory mediators from pulmonary epithelium.     

Comparison of aerosol ipratropium bromide and salbutamol in chronic bronchitis and asthma.

The effects of inhaling 200 mu g of salbutamol were compared with those of inhaling 40 mu g of ipratropium bromide singly and in combination with salbutamol in eight patients with bronchitis and eight asthmatic patients in a double-blind controlled trial. Changes in airways resistance were assessed by measuring the forced expiratory volume in 1 second and specific airways conductance. Both drugs were significantly better in relieving airways obstruction than placebo. Salbutamol was significantly more effective than ipratropium bromide in patients with asthma, but in the patients with bronchitis there was no significant difference between salbutamol and ipratropium bromide. The combination of the two drugs produced a slightly greater and longer response than either drug alone but this was not significant.     

Comparative metabolic and cardiovascular effects of carbuterol, isoproterenol, metaproterenol and salbutamol in the baboon

The metabolic and cardiovascular responses to two bronchiolar selective beta-adrenergic drugs, carbuterol (CAR) and salbutamol (SAL), were compared with isoproterenol (ISO) and metaproterenol (MET) in fasted, anesthetized baboons. ISO was more active than the selective beta-adrenergic drugs in elevating plasma levels of glucose, lactate, free fatty acids, insulin, and glucagon. Moreover, ISO was more active in increasing heart rate and respiratory rate and in depressing diastolic blood pressure. Although ISO was shown to have greater activity than CAR, MET, and SAL, the bronchiolar selective drugs (CAR and SAL) did produce significant changes in plasma levels of metabolic substrates and pancreatic hormones and in cardiovascular measurements at higher dose rates.     

Effect on beta adrenergic receptors of tachyphylaxis on the sensitivity of smooth muscle in the bronchi to beta adrenergic receptor agonists in bronchial asthma

The study involved 30 subjects: 15 healthy individuals and 15 patients with atopic bronchial asthma of the moderate degree. Salbutamol was administered to asthmatic patients in the intravenous infusion for 7 days. beta-adrenergic receptor density in the lymphocytes and FEV1 were evaluated before and after therapy. Moreover, isoprenaline test was carried out to evaluate the sensitivity of the bronchial smooth muscle to beta-agonist. The test was performed prior to and after salbutamol therapy. It was found that beta-receptor agonist statistically significantly decreases beta-adrenergic receptor density. Equivalently, bronchial smooth muscle is less sensitive to beta-agonist in the same degree as a decrease in beta-adrenergic receptor density in the peripheral blood lymphocytes.     

Comparison between ibuterol hydrochloride and terbutaline in asthma.

The bronchodilating effect, circulatory effects, and subjective side effects of ibuterol hydrochloride, the di-isobutyric acid ester of terbutaline, at two dose levels (2 and 4 mg) were compared with those of 5 mg terbutaline sulphate in a double-blind cross-over study on 12 patients with asthma. Both drugs were given by mouth. The 2-mg dose of ibuterol had the same bronchodilating effect during the first three hours as 5 mg terbutaline. The 4-mg dose, however, produced a significantly greater increase in the peak expiratory flow rate between the 30th and 120th minutes than terbutaline. No significant changes in heart rate or pulse amplitude were noted, and there was no difference in the incidence of subjective side effects between ibuterol at either dose level and terbutaline.     

Cardiorespiratory responses to HCl vs. lactic acid infusion

Previous reports indicate that intravenous infusion of HCl can alter breathing and blood pressure even if reductions in systemic arterial pH are prevented. To extend these findings, as well as to determine whether other acids elicit comparable results, this report compares the cardiopulmonary response between right atrial infusion of lactic acid and HCl in awake ponies. Lactic acid, infused at a dose of 1.5 mmol/kg over 18 min, lowered systemic and pulmonary arterial pH 0.062 and 0.092 U, respectively, and increased pulmonary arterial pressure (delta Ppa, 4 mmHg), heart rate (HR, 4/min), and tidal volume (delta VT, 190 ml/m2). HCl, infused at a reduced dose of 0.5 mmol/kg over 18 min, lowered systemic and pulmonary arterial pH 0.024 and 0.047 U, respectively, but produced increases in Ppa (delta 23 mmHg), HR (delta 42/min), and VT (delta 321 ml/m2) that were significantly greater than from the larger dose of lactic acid. These results indicate that cardiopulmonary responses to infusion acidosis differ between the type of acid infused. It is suggested that, in the unanesthetized pony, HCl-induced infusion acidosis has a unique cardiopulmonary-stimulating action unrelated to the pH changes imparted to the circulating arterial blood and that this response is absent during the infusion of lactic acid.