Endothelin-1-induced contraction of mesenteric small arteries is mediated by ryanodine receptor Ca2+ channels and cyclic ADP-ribose.
Contraction of vascular smooth muscle by endothelin-1 is dependent on extracellular and intracellular Ca2+. However, the role of ryanodine-sensitive Ca2+ stores in endothelin-1-induced contraction is unknown. Vascular contraction was measured in mesenteric small arteries (200-300 microm intraluminal diameter) isolated from Sprague-Dawley rats and maintained at a constant intraluminal pressure of 40 mm Hg. The presence of functional ryanodine receptor Ca2+ release channels (RyRC) was demonstrated by the finding that ryanodine (10 microM), which locks the RyRC in a subconductance state, produced significant contraction of small arteries in the presence of 15 mM KCl. This effect was inhibited by dantrolene (10 microM), a RyRC inhibitor. Dantrolene significantly reduced the ET(A) receptor-mediated contraction to endothelin-1 (10(-11)-10(-9) M). The ability of dantrolene to reverse contraction induced by endothelin-1 was also determined. Dantrolene (1-10 microM) produced concentration-dependent relaxation of vessels precontracted to 38+/-3% of resting diameter with endothelin-1 but had no effect in vessels precontracted to a similar degree with phenylephrine or KCl. Because activation of RyRC may be dependent on production of cyclic ADP-ribose, the effect of nicotinamide (2 mM), an inhibitor of ADP-ribosyl cyclase, on contraction to endothelin-1 was determined. Nicotinamide had an inhibitory effect similar to that produced by dantrolene. A combination of nicotinamide and dantrolene had no greater effect than either agent alone, suggesting a common pathway for cyclic ADP-ribose and RyRC. In summary, endothelin-1 induces contraction of small mesenteric arteries through ET(A) receptor-mediated production of cyclic ADP-ribose and activation of RyRC.
Giulumian
A D
AD
Vascular Biology Center, Medical College of Georgia, Augusta 30912, USA.
Meszaros
L G
LG
Fuchs
L C
LC
D000246:Adenosine Diphosphate Ribose / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D036563:Cyclic ADP-Ribose; D003620:Dantrolene / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology*; D008638:Mesenteric Arteries / Q000187:drug effects*; D009125:Muscle Relaxants, Central / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052250:Nitric Oxide Synthase Type III; D019335:Nitroarginine / Q000494:pharmacology; D026902:Potassium Channel Blockers; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects*
D015220:Calcium Channels; D019332:Endothelin-1; D009125:Muscle Relaxants, Central; D026902:Potassium Channel Blockers; D019837:Ryanodine Receptor Calcium Release Channel; D036563:Cyclic ADP-Ribose; D000246:Adenosine Diphosphate Ribose; D019335:Nitroarginine; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D003620:Dantrolene