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

Abstract

The effects of neomycin (7.0 mM) on 45Ca movements and distribution were investigated in canine aortae and in canine carotid and terminal mesenteric arteries. Uptake of ⁴⁵Ca was measured in calcium-free solution; the ⁴⁵Ca tissue spaces in the carotid and terminal mesenteric arteries were 2–4 times greater than those observed in the aorta. Exposure of the aortae and the terminal mesenteric arteries to 1.5 mM Ca⁺⁺ during the washout elicited large increases in ⁴⁵Ca efflux in both preparations (increase in terminal mesenteric > aorta). Moreover, in all three arterial preparations, neomycin reduced ⁴⁵Ca uptake and induced a sustained increase in ⁴⁵Ca efflux (effects on terminal mesenteric > carotid > aorta). The terminal mesenteric and carotid arteries may accumulate and bind ⁴⁵Ca at superficial membrane sites (readily exchangeable ⁴⁵Ca) to a greater degree than does the aorta. If Ca⁺⁺ located at these membrane sites contributes directly to the maintenance of mechanical responsiveness, then agents which alter membrane binding of Ca⁺⁺ (e.g. neomycin) may exert a stronger action on these highly reactive vessels. Thus, contractile responsiveness in peripheral arteries may depend upon depots of superficially bound Ca⁺⁺ to a greater degree than in the more centrally located aorta.

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

“…If present findings with an isolated heart muscle model relate to other excitable tissues, then an interference by aminoglycoside antibiotics with Ca++ influx across cell membranes may well explain the depressant properties of these drugs previously observed in a variety of functionally related and unrelated tissues in both man and lower animals (1)(2)(3)(4)(5)(6)(7)(8)(9). Importantly, present observations also provide a mechanistic explanation for cardiac irregularities occasionally detected in patients treated with aminoglycoside antibiotics (4,(21)(22)(23).…”

“…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.…”

“…These agents, in addition to their useful antibacterial activity, also (a) inhibit synaptic transmission at various neuroeffector junctions (1,2), (b) depress cerebral neuron responses to catecholamines (3), (c) depress cardiovascular function (4)(5)(6)(7)(8), and Received for publication 11 November 1977 and in revised form 2 February 1978. (d) relax different types of smooth muscles (5,9). Although the precise mechanisms responsible for these varied events have not been completely resolved, a Ca++ antagonistic property of the aminoglycosides has been proposed for many years (1).…”

Distribution of ¹⁴C-Gentamicin in Vascular Smooth Muscle

“…In previous studies the uptake of 4sCa in vascular smooth muscle was markedly inhibited by gentamicin (3) and by other aminoglycoside antibiotics (14,17). Under these conditions, it was postulated that aminoglycoside antibiotics interfere with the uptake and/or binding of a specific fraction of Ca2+ and, in this manner, may alter the ability of vascular smooth muscle to respond to stimulatory agents (3,17).…”

“…In selected iso lated arterial smooth muscle preparations from dogs, rabbits and different nonhuman primate species, it was found that the aminoglycoside antibiotics interfere with excitation-contraction coupling in vascular smooth muscle by preventing reuptake or rebinding of Ca2+ at specific superficial cellular sites (3,13,14,17). Furthermore, in vascular preparations in which contractile responsiveness was highly dependent upon superficially bound Ca2+, neomycin had a stronger inhibitory effect (2,14). This type of an effect would be expected if an agent acted primarily at relatively superficial calcium sites or stores.…”