Differential effects of acidosis, high potassium concentrations, and metabolic inhibition on noradrenaline release and its presynaptic muscarinic regulation

作者：Haunstetter A^*; Icking BS; Backs J; Kruger C; Haass M

来源：Pharmacological Research, 2002, 45(3): 221-228.

DOI：10.1006/phrs.2001.0943

• cardiac ischaemia
• muscarinic presynaptic regulation
• sympathetic innervation

It was the aim of the present study to characterize the effect of single components of ischaemia, such as inhibition of aerobic and anaerobic energy production by combined anoxic and glucose-free perfusion (metabolic inhibition), high extracellular potassium concentrations (hyperkalaemia), and acidosis, on (1) the stimulated release of noradrenaline from the in situ perfused guinea-pig heart and (2) its presynaptic modulation by the muscarinic agonist carbachol. The release of endogenous noradrenaline from efferent cardiac sympathetic nerve endings was induced by electrical stimulation of the left stellate ganglion (1 min, 5 V, 12 Hz) and quantified in the coronary venous effluent by high-performance liquid chromatography. Under control conditions, two consecutive electrical stimulations (S1, S2) elicited a similar noradrenaline overflow (S2/S1: 0.98 +/- 0.05). After 10 min of global myocardial ischaemia overflow of endogenous noradrenaline was significantly reduced (S2/S1: 0.18 +/- 0.03; P < 0.05). When studied separately, metabolic inhibition, hyperkalaemia (16 mM), and acidosis (pH 6.0) each markedly attenuated stimulated noradrenaline overflow (S2/S1: 0.65 +/- 0.05, 0.43 +/- 0.14, and 0.37 +/- 0.09, respectively; P < 0.05). The muscarinic agonist carbachol (10 muM) inhibited stimulated noradrenaline release under non-noxic conditions (S2/S1: 0.41 +/- 0.07; P < 0.05). However, after 10 min of global myocardial ischaemia the inhibitory effect of carbachol on noradrenaline overflow was completely lost. Single components of ischaemia had a differential effect on presynaptic muscarinic modulation. Whereas hyperkalaemia (8-16 mM) did not affect muscarinic inhibition of noradrenaline release, carbachol lost its inhibitory effect during acidosis and metabolic inhibition. In conclusion, hyperkalaemia, metabolic inhibition, and severe acidosis each contribute to reduced overflow of noradrenaline after 10 min of myocardial ischaemia. However, presynaptic muscarinic inhibition of noradrenaline release was not affected by hyperkalaemia, but was sensitive to metabolic inhibition and low degrees of acidosis.

• 出版日期2002-3