Differential effects of acidosis, high potassium concentrations, and metabolic inhibition on noradrenaline release and its presynaptic muscarinic regulation.
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 plus minus 0.05). After 10 min of global myocardial ischaemia overflow of endogenous noradrenaline was significantly reduced (S2/S1: 0.18 plus minus 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 plus minus 0.05, 0.43 plus minus 0.14, and 0.37 plus minus 0.09, respectively; P< 0.05). The muscarinic agonist carbachol (10 microM) inhibited stimulated noradrenaline release under normoxic conditions (S2/S1: 0.41 plus minus 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.
Haunstetter
Armin
A
Department of Cardiology, University of Heidelberg, Heidelberg, Germany. armin-haunstetter@med.uni-heidelberg.de
Schulze Icking
Babette
B
Backs
Johannes
J
Krüger
Carsten
C
Haass
Markus
M
D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D004558:Electric Stimulation; D005947:Glucose / Q000172:deficiency*; D006168:Guinea Pigs; D006947:Hyperkalemia / Q000378:metabolism*; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology; D017202:Myocardial Ischemia / Q000378:metabolism / Q000503:physiopathology; D009638:Norepinephrine / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000502:physiology; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism / Q000502:physiology
D018721:Muscarinic Agonists; D011976:Receptors, Muscarinic; D002217:Carbachol; D005947:Glucose; D009638:Norepinephrine