Age dependence of myocardial Na+-K+-ATPase activity and digitalis intoxication in the dog and guinea pig.

Abstract

SUMMARY Infants and young animals tolerate higher doses of digitalis glycosides, relative to body weight, than adults. One possible explanation for this could be an age-dependent difference in the myocardial digitalis receptor, the Na + -K + -ATPase. Two functions of this enzyme were studied in adult, 1-and 6-week-old dogs and guinea pigs: in vitro myocardial uptake of rubidium ( 86 Rb) and binding of ouabain. In guinea pigs, rubidium uptake (pmol Rb/mg LV per 15 min) was: 1 week old: 100.9 ± 7.1 (mean + SE); 6 week: 79.8 ± 6.7; adult: 55.2 ± 7.9; (1 week: 6 week: P< 0.025; 1 week: adult, P< 0.001; 6 week: adult, P < 0.025). Similarly in dogs, rubidium uptake was significantly greater at 1 week than at 6 weeks (208 ± 13 vs. 144 ± 9; P < 0.001) and the latter greater than in adults (111 ± 4) (P < 0.005). Other groups of anesthetized adult and 6-week-old dogs were given digoxin, 0.3 mg/kg, iv. The young dogs took significantly longer to become cardiotoxic (17.3 ± 3.4 min vs. 9.3 ± 1.4 min; P< 0.025), while their myocardial digoxin uptake was at least as great. Rubidium uptake showed an average decrease of 56% after digoxin but residual uptakes were not different in the two groups. Data for ouabain binding showed similar differences between the various groups of dogs studied. Increased myocardial Na + -K + -ATPase activity, reflected in greater active cation transport and specific enzyme binding, has been demonstrated in young animals and may be partly responsible for their greater tolerance to digitalis glycosides. Circ Res 48: 329-333, 1981

Enzyme cytochemical study of rat cardiac muscle II. Ca++-ATPase and ouabain-sensitive, K+-dependent p-nitrophenylphosphatase.

“…Besch et al (8), and Marsh et al (30) showed that isolated vesicles of sarcolemma exhibit the activation by Na+ and K+ of Na+-K+.ATPase and its associated K+-NPPase activity. However, biochemical demonstration of Na+-K+-ATPase in T-tubule has not been reported before, since it seemed to be impossible to obtain a homogenous subcellular fraction of T-tubule from cardiac muscle as a rigid intracellular organization.…”

Role of Thyroid State in Age-Dependent Cardiac Effects of Ouabain in Guinea Pigs

“…In the present study we have confirmed that the positive inotropic and toxic effects of oua bain are age-related, namely the responsive ness increases with age [2,3,9], As pre viously reported, we also found that hypo thyroidism amplifies the myocardial re sponse to ouabain [6,7,17], A possible explanation for the inverse re lationship between the thyroid state and the (age-related) responsiveness to ouabain, is the modulation of Na+-K+,ATPase by thy roid hormones, which is brought about by increasing the number of enzyme molecules as well as their activity [10,11,13]. The involvement of Na+-K+,ATPase is further supported by studies demonstrating devel opmental changes in myocardial Na+-K+,ATPase activity, such that enzyme activ ity is larger in newborns than in adults [15,23]. Interestingly, in contrast to the guinea pig (and in support of our hypothesis), the newborn rat has very low levels of thyroid hormones: total T4 = 0.3-0.4 pg/dl, and un detectable levels of total T3.…”

Comparative Effects of Verapamil, Nifedipine, and Diltiazem on Contractile Function in the Isolated Immature and Adult Rabbit Heart

“…This greater dependency of the immature heart may reflect the greater external cell surface area of the immature myocardial cells (13), developmental differences in sarcolemmal Ca regulation (2,6,14,15), and/or the relative immaturity of the SR in the developing heart (4,13,16,22,25). This hypothesis is entirely consistent with the age-related difference in the contractile response to the inorganic calcium channel blocker manganese (7) and further supported by the rightward shift ofthe contractile response versus extracellular [Ca] relationship in newborn compared with adult hearts (23,26).…”