Alteration of Contractile Function and Calcium Ion Movements in Vascular Smooth Muscle by Gentamicin and Other Aminoglycoside Antibiotics

Abstract

Experiments were conducted to examine the effects of certain aminoglycoside antibiotics on contractile responses.and related calcium ion (Ca2+) movements in isolated vascular smooth muscle. Gentamicin, kanamycin, and streptomycin decreased contractile responses produced by norepinephrine, histamine, and high K+ in rabbit aortic strips. The inhibitory action of these antibiotics on mechanical function was more pronounced when the Ca2+ concentration of the bathing solution was decreased from 1.5 mM (normal Ca2+ solution) to 0.05 mM (low Ca2+ solution). The uptake of radiocalcium ("'Ca) into the isolated media-intimal layer of rabbit aortae was decreased in a maintained manner by each antibiotic. With gentamicin, the inhibitory effect on 4"Ca uptake was shown to be dependent upon the concentration of gentamicin employed and to be more evident in a 0.1 mM Ca2+ solution than in a normal Ca2+ solution. In addition, the rate of 4"Ca efflux from the rabbit aortic media-intimal layer was increased in a sustained manner by gentamicin, streptomycin, and kanamycin. Furthermore, contractile responses induced by high K+ and norepinephrine in canine carotid arterial strips were inhibited by gentamicin. Present findings indicate that aminoglycoside antibiotics interfere with Ca2+-linked events leading to activation of the contractile mechanism of vascular smooth muscle. These in vitro findings may partially explain the occurrence of in vivo cardiovascular depression that has occasionally been observed after the administration of chemically related antimicrobial agents.Severe hypotensive episodes have been observed occasionally in man (3,9,24,25) and repeatedly in experimental animals (3,4,18,20,21) after the administration of aminoglycoside antibiotics (neomycin-streptomycin group). Although the mechanism(s) involved in this adverse side effect has not been completely resolved, recent studies suggest that these agents may alter peripheral vascular smooth muscle contractility. In the constant flow-rate perfused hind-limb preparation of thf dog, Cohen et al.(3) observed that the intraarterial administration of streptomycin and kanamycin decreased hind-limb vascular resistance. Evidence of streptomycin-induced dilatation of the renal vasculature was obtained in the in situ perfused canine kidney by Wolf and Wigton (30). The pharmacologic action involved in this peripheral vasomotor effect has not been determined, but several reports have associated this group of antibiotics with alteration of calcium ion (Ca2+) function in certain mammalian organ systems.

Cardiovascular Depressant Effects of Neomycin and Gentamicin in Rhesus Monkeys

“…In rabbit aortic smooth muscle, gentamicin, kanamycin, streptomycin, and neomycin inhibit the uptake of radiolabelled Ca2+ at superficial binding sites (Adams, Goodman, Lupean & Weiss, 1973;Adams et al, 1974;. By affecting a Ca2+ fraction located at superficial sites, aminoglycoside antibiotics inhibit the ability of arterial muscle to respond to vasoconstrictor agents that normally use this and other interrelated Ca2 + pools to generate tension changes in the vessel wall Adams & Goodman, 1975 …”

Effects of Neomycin on ⁴⁵Ca Binding and Distribution in Canine Arteries

“…Muscles were incubated with 45Ca in either normal solution or O-Ca solution and then washed out with a O-Ca solution. Figure 1 Previous washout experiments with 45Ca indicated that neomycin [2,12) and other aminoglycoside antibiotics [3] induced a sustained increase in 45Ca efflux from rabbit aortic strips. To examine the effects of neomycin on 45Ca efflux in canine arteries, muscles were first incubated in O-Ca solution with added 45Ca for 1 h and then washouts were performed.…”

Gentamicin blockade of slow Ca++ channels in atrial myocardium of guinea pigs.

“…On the other hand, La... displaces and replaces Ca++ at various superficial membrane sites, thereby reducing net availability of Ca++ for translocation (17,19). We have previously reported that aminoglycosides decrease the uptake and increase the efflux of 45Ca in vascular smooth muscle by affecting superficial membrane sites and, through this Ca++-dependent action, inhibit contractile responses of arteries to a variety ofvasoconstrictor agents (5,6,20). Based on present mechanical findings, it seems that gentamicin also disrupts the excitationcontraction coupling process in heart muscle, perhaps by inhibiting the binding of Ca++ at superficial membrane sites responsible for availability of Ca++ for transsarcolemmal systolic influx.…”