Extracellular Ca(2+)-dependent potentiation by cocaine of serotonin- and norepinephrine-induced contractions in rat vascular smooth muscle.
Using front-surface fluorometry, we determined the effects of cocaine on force and cytosolic Ca2+ concentration ([Ca2+]i) in the rat aorta. We also examined the effects of cocaine on 45Ca2+ influx. Cocaine (10(-7) to 10(-4) M) alone did not alter the resting level of [Ca2+]i and force. Cocaine (< 10(-4) M), in a concentration-dependent manner, potentiated the 10(-6) M serotonin (5-HT)-induced or 10(-8) M norepinephrine (NE)-induced sustained increase in [Ca2+]i and force in the presence of extracellular Ca2+, whereas it had no potentiating effects in Ca(2+)-free solution. Similar potentiating effects of cocaine were observed in pharmacologically denervated strips. Cocaine (10(-5) M) produced a leftward shift of concentration-response curves for both 5-HT- and NE-induced increases in [Ca2+]i and force with no effect on the maximal response or the relations between [Ca2+]i and force. Cocaine (10(-5) M also accelerated the 45Ca2+ influx during activation by 10(-6) M 5-HT or by 10(-8) M NE. Cocaine (> 10(-3) M) inhibited 5-HT-, NE-, and high-K+ depolarization-induced contractions accompanied by decreases in [Ca2+]i in normal physiological salt solution and 5-HT- or NE-induced transient increase in [Ca2+]i and force in Ca(2+)-free physiological salt solution. Thus, low concentrations of cocaine potentiate NE- or 5-HT-induced contraction by augmenting the increase in [Ca2+]i. These potentiating effects may derive from either an increase in the affinity of the receptors to agonists or an increase in the Ca2+ influx. On the other hand, high concentrations of cocaine (> 10(-3) M) have a relaxant effect on vascular smooth muscle, as a result of a decrease in [Ca2+]i.
Watanabe
C
C
Division of Molecular Cardiology, Research Institute of Angiocardiology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
Yamamoto
H
H
Kobayashi
S
S
Kanaide
H
H
D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D003042:Cocaine / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D004357:Drug Synergism; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
D012701:Serotonin; D003042:Cocaine; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine