DIMINISHED INOTROPIC RESPONSE BUT UNALTERED TOXICITY TO ACETYLSTROPHANTHIDIN IN THE SENESCENT BEAGLE

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/P50 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 β-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.