Study on adrenergic function after development of tolerance to ethylene glycol dinitrate (EGDN) in rats

The effects of sustained exposure to ethylene glycol dinitrate (EGDN; 50 mg.kg-1.2, 10 days) on heart rate (HR) and mean arterial blood pressure (MAP), isolated strips from aorta and vena cava, catecholamine (CA) and DOPAC levels in brain, heart, adrenals and plasma, and synaptosomal uptake of noradrenaline (NA) have been investigated in rats. Aortic strips showed a decreased responsiveness to EGDN and were more sensitive to NA than were control strips 2, 24 and 96 hrs after cessation of EGDN. Acute cumulative doses of EGDN induced a decrease in MAP at all time intervals but 2 hrs after cessation of chronic EGDN-treatment, while NA induced a dose-dependent increase in MAP. MAP was lower 2 hrs after cessation of EGDN, than in the control rats, while HR was higher. After 24 hrs, MAP was slightly higher than in the controls and HR was still elevated. EGDN induced a decrease in the accumulation of L-DOPA and DOPAC in all brain structures measured, which was especially prominent 2 hrs after cessation of EGDN. The levels of CA's and DOPAC in peripheral tissues did generally not change significantly, although there was a tendency to a decrease. L-DOPA, NA and adrenaline (A) in plasma decreased significantly, while DOPAC and dopamine (DA) increased. No consistent effects on uptake of NA into synaptosomes could be distinguished. However, the amount of protein was generally lower at all times after cessation of EGDN. It is suggested that prolonged exposure to EGDN not only induces tolerance at the cellular level, but also interferes with arterial smooth muscle sensitivity to NA and with resetting of MAP and HR. The decrease in the synthesis and turnover of CA's and DOPAC in the brain indicated a decrease in nervous activity, which is reflected by a corresponding decrease of NA and A levels in plasma.