Enhancement of Acute Myocardial Lesions by Asthma Drugs in Rats

Abstract

ABSTRAC~Asthma morbidity and mortality have risen significantly in the last 10 years. The reasons for the increase are multifactorial. One proposed explanation is possible myocardial toxicity arising from the use of8-agonists alone or in combination with methylxanthines. Previous studies have shown that 8-agonists given alone and 8-agonist/methylxanthine combinations given at higher than recommended clinical doses induced doserelated cardiotoxicity and sudden death in rats. The objective of the present study was to determine whether or not 8-agonists given alone and in combination with methylxanthines at recommended clinical doses also induce cardiotoxicity and sudden death in rats. The 8-agonists, isoproterenol hydrochloride (1 5 pg/kg), fenoterol hydrobromide (40 pg/kg), and terbutaline hemisulfate (0.4 mg/kg) were given in single sc doses separately and concurrently with the methylxanthines aminophylline hydrate (20 mg/kg) and caffeine (40 mg/kg), which were given ip to a susceptible animal model, the heavy Sprague-Dawley rat. 8-agonist-induced myocardial toxicity (necrosis) was observed. The toxicity was enhanced by aminophylline resulting in the sudden death (most likely due to ventricular fibrillation) of some animals. A decrease in serum iron levels was observed in rats of all 8-agonist and/or methylxanthine-treated groups.

Ischemic Cardiomyopathy Following Seizure Induction by Domoic Acid

“…32 This finding is supported by earlier studies showing that injection of kainic acid or NMDA into the paraventricular nucleus resulted in lesions of the parvocellular elements and evoked an excitotoxin-induced myocardial necrosis resembling the acute myocardial necrosis reported with systemic ␤-agonist administration. [33][34][35] These studies support the hypothesis that the reported cardiotoxicity is a consequence of a catecholamine surge mediated by excitotoxin stimulation of glutamate receptors in the CNS. Other neuronal pathologies, such as stroke and epilepsy, have also been shown to result in long-term abnormal electrocardiographic activity and arrhythmias.…”

Does terbutaline damage the developing heart?

“…At the same time, we did obtain quantitative alterations in the number of nuclei, in keeping with previous findings of treatment effects on DNA synthesis and concentration (Garofolo et al, 2003), reinforcing the pharmacologic effectiveness of our treatment paradigms. Given that similar or even lower doses of terbutaline evoke necrosis in the mature rat myocardium (Magnusson and Hansson, 1973;Whitehurst et al, 1994), it is evident that the developing heart is less sensitive to this adverse effect than is that of the adult, rather than more sensitive, as would have been predicted from the lack of bAR desensitization in the neonate (Auman et al, 2001b(Auman et al, , 2002a. The subsequent emergence of the necrotic response is thus not relevant to the use of terbutaline for tocolysis in preterm labor.…”

“…With regard to the chick model, it is unlikely that the disparity represents differential sensitivities of the two species. In the adult, avian and rodent species show similar sensitivities to terbutaline-induced cardiac damage (Marmo et al, 1974;Magnusson and Hansson, 1973;Whitehurst et al, 1994), although some species of squirrels are indeed resistant (Levinsky et al, 1978). One important difference, however, is that drugs introduced into the chick egg are not subject to placental clearance or maternal drug metabolism and hence act throughout the pre-hatch period.…”

“…For each animal, one slide, containing two tissue sections, was examined (Olympus BX 50 microscope) by a toxicologic pathologist who was blinded to the identity of the sections. A standard set of qualitative parameters was evaluated as described earlier (Whitehurst et al, 1994;Kodavanti et al, 2003), and included: the presence and nature of myocardial inflammation; necrosis; degeneration (vacuolation); interstitial edema; fibrosis, mineralization, and pericarditis. A scale of 0-5 was based on the number of affected muscle fibers and the degree of inflammation: 0¼normal (no recognizable necrosis); 1¼minimal edema around muscle fibers; 2¼slight/mild edema, very few inflammatory cells; 3¼moderate numbers of inflammatory cells, edema, and separation of muscle fibers; 4¼moderately severe increases in inflammatory cells, edema, and separation of muscle fibers with moderately severe degeneration; and 5¼severe increases in inflammatory cells, edema, and degeneration of muscle fibers.…”

“…Mature cells are somewhat protected from excessive bAR stimulation because they are capable of desensitization, which uncouples the receptors from response elements (Joseph et al, 1983;Stiles, 1989;Palczewski and Benovic, 1991). Nevertheless, previous studies in adult pigeon and rat hearts have shown that terbutaline can elicit histological damage (Magnusson and Hansson, 1973;Marmo et al, 1974;Whitehurst et al, 1994). Moreover, in the fetus or neonate, bARs are resistant to desensitization (Stein et al, 1992;Zeiders et al, 1997), which would potentially worsen any adverse effects.…”