thiourea and 9-(tetrahydro-2-furyl)-adenine

The Na+/Ca2+ exchanger (NCX) may be an important modulator of Ca2+ entry and exit. The present study investigated whether NCX was affected by prostacyclin and nitric oxide (NO) released from the vascular endothelium, as NCX contains phosphorylation sites for PKA and PKG.. Rat aortic rings were set up in organ baths. Tension was measured across the ring with a force transducer.. Lowering extracellular [Na+] ([Na+]o) to 1.18 mM induced vasoconstriction in rat endothelium-denuded aortic rings. This effect was blocked by the NCX inhibitor KB-R7943 (2-2-[4-(4-nitrobenzyloxy)phenyl] ethyl isothiourea methanesulphonate; 1 microM). In endothelium-intact aortic rings, decreasing [Na+]o did not constrict the aortic rings significantly, but after treatment with the guanylate cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; 1 microM) or the NOS inhibitor L-NAME (N(omega)-nitro-L-arginine methyl ester; 50 microM), a vasoconstriction that was similar in size to that in endothelium-denuded preparations was evident. The vasorelaxation induced by the NO donor sodium nitroprusside sodium nitroprusside dihydrate (30 nM) was the same in the endothelium-denuded aortic rings preconstricted with either low Na+ (1.18 mM), the thromboxane A2 agonist U46619 (9,11-dideoxy-9alpha, 11alpha-methanoepoxy prostaglandin F(2alpha); 0.1 microM) or high K+ (80 mM).. The results suggest that the endothelium inhibits NCX operation via guanylate cyclase/NO. This is stronger than for other constrictors such as phenylephrine and may relate to concomitant NCX-stimulated NO release from the endothelium. This finding may be important where NCX operates in reverse mode, such as during ischaemia, and highlights a new mechanism whereby the endothelium modulates Ca2+ homoeostasis in vascular smooth muscle.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenine; Adenylyl Cyclase Inhibitors; Adenylyl Cyclases; Animals; Aorta, Thoracic; Dinoprost; Endothelium, Vascular; Enzyme Inhibitors; Guanylate Cyclase; In Vitro Techniques; Indomethacin; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitroprusside; Oxadiazoles; Potassium; Prostaglandin-Endoperoxide Synthases; Quinoxalines; Rats; Rats, Sprague-Dawley; Sodium; Sodium-Calcium Exchanger; Thiourea; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

1. In the present work we have characterized the relaxant response induced by light stimulation (LS) in the lower urinary tract from sheep, pig and rat, establishing its relationship with nitrergic neurotransmission. 2. Urethral, but not detrusor, preparations showed pronounced photo-relaxation (PR) which declined progressively following repetitive LS. Sheep urethral PR was again restored either spontaneously or (to a greater extent) by exogenous nitric oxide (NO) addition and by electrical field stimulation (EFS) of intrinsic nitrergic nerves. 3. Greater NO generation was detected from sheep urethral than from detrusor homogenates following illumination. 4. Sheep urethral PR was inhibited by oxyhaemoglobin, but not by methaemoglobin, carboxy-PTIO, extracellular superoxide anion generators or superoxide dismutase. Guanylyl cyclase but not adenylyl cyclase activation mediates urethral relaxation to LS. 5. Urethral PR was more resistant to inhibition by L-thiocitrulline than EFS-induced responses, although this agent prevented PR restoration by high-frequency EFS. 6. Urethral PR was TTX insensitive and partially modified in high-K+ solutions. Cold storage for 24 h greatly impaired urethral PR, although it was restored by high-frequency EFS. 7. Repetitive exposure to LS, EFS or exogenous NO induced changes in the shape of the EFS-induced nitrergic relaxation, possibly by pre-synaptic mechanisms. 8. In conclusion, we suggest the presence of an endogenous, photo-labile, nitro-compound store in the urethra, which seems to be replenished by neural nitric oxide synthase activity, indicating a close functional relationship with the nitrergic neurotransmitter.

Topics: Adenine; Animals; Citrulline; Cold Temperature; Culture Techniques; Electric Stimulation; Enzyme Inhibitors; Female; Light; Muscle Relaxation; Muscle, Smooth; Nitric Oxide; Oxadiazoles; Oxyhemoglobins; Phosphodiesterase Inhibitors; Photic Stimulation; Potassium; Purinones; Quinoxalines; Rats; Rats, Wistar; Sheep; Superoxides; Swine; Synaptic Transmission; Tetrodotoxin; Thiourea; Time Factors; Urethra