Nucleotide precursors modify the effects of isoproterenol. Studies on heart function and cardiac adenine nucleotide content in intact rats

Abstract

In closed-chest rats, isoproterenol (ISO, 25 mg/kg), 5 hours after subcutaneous administration, increased heart rate by 53%, left ventricular (LV) dP/dt(max) by 80%, and cardiac output by 37%. LV systolic pressure (LVSP, -10%), mean arterial pressure (MAP, -12%), and total peripheral resistance (TPR, -36%) were diminished. In separate experiments, continuous intravenous infusion of adenine (50 mg/kg/hr) for 5 hours reduced heart rate (-11%), LVSP (-16%), MAP (-20%), TPR (-33%), and LV dP/dt(max) (-20%). Cardiac output was increased (+20%). Inosine has been shown to have similar effects, except for a decline in cardiac output. Adenine (50 mg/kg/hr) attenuated the ISO-induced increase in heart rate and LV dP/dt(max) and aggravated the decline in LVSP, MAP, and TPR. The increase in cardiac output was not changed. Inosine (200 mg/kg/hr) modified the ISO effects to a similar extent. Ribose (200 mg/kg/hr) added to the adenine infusion did not have functional effects. However, it aggravated the modifying influence of inosine on LVSP, LV dP/dt(max), and MAP. ISO reduced the cardiac ATP content (μmol/g) from a control value of 5.02±0.06 (n=12) to 3.51±0.13 (n=10). Adenine (3.56±0.21, n=7) and ribose (3.64±0.11, n=9) alone did not affect it, but inosine attenuated it (4.33±0.08, n=8). Adenine and inosine in combination with ribose abolished the ISO-induced ATP decline (5.18±0.23, n=7, and 4.76±0.10, n=8, respectively). These results demonstrate that the cardiac ATP content can be restored very quickly by exploiting the salvage pathways, provided that the available pool of 5-phosphoribosyl-1-pyrophosphate is elevated by ribose.