Inhibition of sympathetic neurotransmitter release by modulators of cyclic GMP in canine vascular smooth muscle.
The contractile response to neurally released norepinephrine (NE) from sympathetic nerve endings innervating vascular smooth muscle are inhibited by substances which raise either cyclic AMP and cyclic GMP concentrations in smooth muscle. However, cyclic AMP is believed to facilitate NE release from sympathetic nerves whereas the role of cyclic GMP in this process is undefined. We examined the effects of presumed modulation of the intraneuronal concentration of cyclic AMP and cyclic GMP on sympathetic neurotransmission to isolated canine mesenteric artery by measurement of the efflux of [2-14C]NE during transmural nerve stimulation (calcium dependent release of NE) and administration of tyramine (calcium independent release of NE) and measurement of the contractions to exogenous NE and tyramine. Stimulation of adenylate cyclase with forskolin, prostacyclin and iloprost, a stable prostacyclin analog, and inhibition of Type III cyclic AMP phosphodiesterase with neural specific rolipram, 'non-specific pelrinone and milrinone and isobutylmethylxanthine did not enhance the efflux of [2-14C]NE from sympathetic nerves innervating the blood vessels. Isoproterenol enhanced the efflux of [2-14C]NE. The effect was inhibited by propranolol but not affected by milrinone, amrinone or rolipram. Activators of guanylate cyclase (SIN-1a an active metabolic of molsidomine, nitroglycerin and sodium nitroprusside) and inhibitors of Type II cyclic GMP phosphodiesterase (M&B-22948 and verofyllin) inhibited the efflux of NE released by transmural nerve stimulation but not by tyramine. These data support the conclusion that cyclic GMP may be an inhibitory modulator of calcium and depolarization dependent NE release from sympathetic nerves, whereas neuronal cyclic AMP may not be a primary modulator of neurotransmission to vascular smooth muscle.
Greenberg
S S
SS
Department of Physiology, UMDNJ, New Jersey Medical School, Newark 07103.
Diecke
F P
FP
Cantor
E
E
Peevy
K
K
Tanaka
T P
TP
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D004285:Dogs; D004558:Electric Stimulation; D005260:Female; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000378:metabolism*
D000067956:Adenylyl Cyclase Inhibitors; D018377:Neurotransmitter Agents; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006152:Cyclic GMP; D009638:Norepinephrine