Diminished inotropic responses but unaltered toxicity to acetylstrophanthidin in the senescent beagle.

Abstract

SUMMARY The toxic and inotropic effects of a rapid-acting cardiac glycoside, acetylstrophanthidin (ACS), administered as a rapid i.v. bolus was compared in six healthy adult (age 2-3 years) and seven senescent (age 12-14 years) beagles. In the conscious state no age difference was observed in the dosage of ACS at which toxicity, defined as ventricular tachycardia (VT), occurred. Serum levels of ACS at toxicity were 70 ± 15 ng/ml in the senescent and 65 ± 12 ng/ml in the adult (NS). On a separate occasion, the inotropic effect, dP/dt/P50, and the toxic end point were measured in the anesthetized state. As in the awake state, no age difference was seen in the dosage to VT. The control dP/dt/P,, measured with a left ventricular Millar catheter during brief periods of right ventricular pacing at 250 beats/min was not age related. However, the increase in contractility in response to ACS was two times greater in the adult than the senescent (p < 0.001). This difference persisted when A-blockade was effected with practolol. Thus, in senescence, while glycoside toxicity is unaltered, the inotropic efficacy of ACS is significantly diminished. This age difference in inotropy cannot be attributed to an age difference in serum levels of the drug or in sympathetic tone. Additional studies indicated that glycoside inhibition of Na+-K+ ATPase isolated from these dogs was not age related, suggesting that the mechanism for the diminished inotropic response is distal to the inhibition of this receptor enzyme.AGE is an important determinant in the response to cardiac glycosides. Most mammalian species exhibit altered sensitivity to the inotropic and toxic effects of digitalis preparations in the neonatal period compared with the young adult. 1-4 These differences have been attributed to both maturational changes in the volume distribution of glycosides5 6 and to different effects of these agents at the cellular level.7 8With advanced age, many physiologic changes occur in the cardiovascular system in both man and animals.9 10 Although the performance of cardiac muscle isolated from the heart of senescent animals in many ways is indistinguishable from that of its adult counterpart, the response to some interventions that impose a stress on the excitation-contraction system is altered in senescent myocardium.11 In particular, the inotropic response to ouabain is diminished in senescent myocardium when compared with the adult, while the response to an increase in [Ca++] in the bathing fluid or to paired pacing is not age related.'2The purpose of the present study is to extend these observations on the effect of advanced age on the response to cardiac glycosides in isolated cardiac muscle to the intact organism. Specifically, we compare the toxic and inotropic responsiveness to a rapidacting cardiac glycoside in intact, senescent dogs. While the glycoside is used primarily to elucidate agerelated alterations that occur in the cardiovascular system as a result of advanced age, the study may also have practical implications. The marke...

RNA from heart of young and old rats leads to the expression of protein(s) in Xenopus oocytes that alter the transport activity of rat Na+,K+-ATPases differently

“…Correspondingly, one may expect that the old heart should be less sensitive to ouabain than the young heart because of the loss of inhibition by RP-Y. In agreement with these predictions, in aged rat and canine myocardium the inotropic responsiveness to ouabain was found to be diminished [11,12].…”

Evaluation of Left Ventricular Tei Index (Index of Myocardial Performance) in Healthy Dogs and Dogs with Mitral Regurgitation

“…However, there has been no report describing an association between the LV Tei index and age in older human patients. However, an age-related LV relaxation abnormality was reported in senescent beagles [13]. Therefore, the mild elevation of the LV Tei index in addition to the decrease of E/A in old dogs without cardiac disease may indicate a potential depression of LV diastolic function with age.…”

Myocyte repolarization modulates myocardial function in aging dogs

“…Additionally, in old muscles, the basal cytoplasmic Na ϩ level may prevent further increases in Na ϩ load, a key regulator of the positive FFR and other mechanisms of contractile reserve (49). This possibility is supported by the diminished inotropic responsiveness of the intact senescent dog heart to the cardiac glycoside acetylstrophantidin (11), whose positive contractile action is due to enhanced Ca 2ϩ load secondary to inhibition of the Na ϩ /K ϩ pump, and intracellular accumulation of Na ϩ (49). In a comparable manner, the pharmacological potentiation of the I NaL with ATX-II results in an increase in developed force of the adult myocardium at basal cycle length, but it suppresses the positive contractile FFR.…”