Effects and mechanism of action of aminophylline on cardiac function and regional blood flow distribution in conscious dogs.

Abstract

SUMMARY The effects of aminophylline, 1 mg/kg/min infused intravenously for 10 minutes, were examined on left ventricular (LV) diameter, pressure, and indexes of myocardial contractility, as well as systemic, coronary and regional hemodynamics in conscious dogs. Aminophylline increased mean arterial pressure 12 i 2%, LV systolic pressure 8 ± 1%, LV dP/dt 20 ± 2%, velocity of myocardial fiber shortening 13 ± 2% and heart rate 5 ± 2%, and reduced LV end-diastolic diameter 2 ± 0.5%. Vascular resistance rose in the systemic bed 13 ± 5%, the coronary bed 26 ± 3%, the mesenteric bed 26 ± 5% and the iliac bed 36 ± 4%, but did not rise in the renal bed. Both 0-adrenergic receptor blockade with propranolol and chronic treatment with reserpine attentuated but did not abolish the positive inotropic response induced by aminophylline. Alphaadrenergic receptor blockade with phentolamine prevented aminophylline-induced vasoconstriction in the systemic, coronary, mesenteric and iliac beds. In contrast to the vasoconstriction with i.v. aminophylline, when the drug was infused directly into the iliac artery, it elicited marked iliac vasodilation. Thus, in the intact conscious dog, i.v. aminophylline, in a dose that had little effect on heart rate, increased LV contractility and reduced preload. The increase in contractility was dependent in part on intact f-adrenergic nervous activity and endogenous catecholamine stores. The increases in systemic, coronary, iliac and mesenteric resistances involved a-adrenergic mechanisms. These actions appear to involve autonomic mechanisms, because the only direct effect of aminophylline on the iliac artery was marked vasodilation.THEOPHYLLINE ethylenediamine (aminophylline) is widely used in the treatment of cardiovascular and respiratory disease. In part, the therapeutic rationale is based on the concept that aminophylline is a potent peripheral vasodilator. It has been shown to decrease total systemic," 2 renal3'5 and, in particular, coronary', 6-11 vascular resistances in anesthetized animal preparations. Ritchie12 noted that experimentally, it can be demonstrated that the xanthines dilate coronary arteries and increase coronary blood flow, and this finding has led to their use in treating coronary artery disease. The most widely used methylated xanthine derivative is aminophylline, which is a combination of theophylline and ethylenediamine. The latter substance, believed to be therapeutically inert, increases the solubility of theophylline. 12 Because aminophylline is widely used clinically and because of the observation that the effects of many interventions differ substantially in anesthetized and conscious animals,'3 we studied this drug in intact, conscious dogs.A primary goal of this study was to determine the effects of aminophylline on regional blood flow distribution using techniques designed to yield continuous direct measurements in healthy, conscious animals in which the effects of anesthesia and surgical trauma on circulatory and reflex control were absent.To understand the act...

Bamiphylline improves exercise-induced myocardial ischemia through a novel mechanism of action.

“…The hypothesis that the vasoconstrictor effect of methylxanthines involves catecholamines is supported by the observation that the increase of vascular resistance caused by aminophylline in the conscious dog is attenuated by a-adrenergic blockade. 39 Of note, in our study, bamiphylline did not affect heart rate or arterial blood pressure under resting conditions, suggesting that prejunctional A1 adenosine receptors are not active at rest. Another potential mechanism by which bamiphylline can limit subepicardial perfusion might be inhibition of ATP-sensitive potassium channels.…”

Effect of intravenous aminophylline on plasma levels of catecholamines and related cardiovascular and metabolic responses in man.

“…At these concentrations in vitro, theophylline is a very weak inhibitor of phosphodiesterase activity3638 and is not associated with an elevation in tissue levels of cyclic AMP.39'40 Although 10 ,uM theophylline relaxed carbachol contracted bovine tracheal muscles by 85-95%,39 similar concentrations had little or no effect in isolated heart muscle preparations.40'4' Perfusion of the canine sinus node artery with low concentrations of aminophylline (1-10 ,ug/ml) did not cause a change in heart rate, but a much higher concentration (100 ,ug/ml) resulted in an immediate tachycardia. "I Rutherford et al 13 observed positive inotropic, chronotropic and pressor responses after i.v. aminophylline, 10 mg/kg, in the conscious dog.…”

“…In contrast to systemic administration, direct infusion of aminophylline into the iliac artery resulted in vasodilatation. These investigators and others'1 13,42 have proposed that the cardiac and hemodynamic effects of theophylline may be explained, at least in part, by the release of endogenous catecholamines. Our findings that plasma catecholamines increase during theophylline administration in man also supports this hypothesis.…”

“…A single concentration was used, based on preliminary experiments showing no effect of concentration on binding. At equilibrium (12)(13)(14)(15)(16) hours as determined by preliminary studies), 1-ml aliquots of buffer and plasma were frozen for theophylline assay.…”

The Effect of Aminophylline on Right Heart Function in Young Pigs after Ligation of the Right Coronary Artery

“…Improvement in both global myocardial performance (Parker et al 1966b;Falicov et al 1973;Rutherford et al 1981;Matthay 1985;Matthay & Mahler 1986) and right heart performance have been demonstrated with intravenous aminophylline (Bisgard & Will 1977;Matthay et al 1978). It is difficult, however, to decide how much an improvement in left ventricle function (e.g.…”