Involvement of cyclic nucleotides in renal artery smooth muscle relaxation.
The elevation of vascular smooth muscle tone in the renal arteries during kidney transplantation and nephron-sparing surgery plays a major role in postsurgical organ dysfunction. Therefore, a better understanding of the intracellular mechanisms of contraction and relaxation is of fundamental interest to improve urological treatment. The present study was designed to investigate the complex intracellular system of cyclic nucleotides involved in the regulation of smooth muscle relaxation by using swine renal artery rings in the Schuler organ bath. Phenylephrine (PE) induced dose-dependent and fully reversible isometric contractions with a threshold concentration of 10 nM and an EC(50) of 804 nM. The receptor was identified as alpha(1A)-subtype by the selective antagonist WB4101. Increasing the intracellular concentration of cyclic 3':5'-adenosine monophosphate (cAMP) by dibutyryl-cAMP (5 mM) and forskolin (5 micro M) resulted in a decreased contractiltity of 48.0% and 76.3%, respectively. Elevation of the cytosolic content of cyclic 3':5'-guanosine monophosphate (cGMP) using dibutyryl-cGMP (1 mM), sodium nitroprusside (100 micro M) and SIN-1 (100 micro M) decreased the average PE-induced contraction by 16.4%, 41.9% and 62.4%, respectively. The unselective phosphodiesterase inhibitors theophylline (1 mM), papaverine (100 micro M) and IBMX (5 mM) reduced the PE-induced contraction by 37.3%, 93.1% and 95.5%, respectively. Furthermore, selective inhibition of phosphodiesterases by milrinone (PDE(3)-selective) resulted in a decreased contractility by 1.3% (50 micro M), 29.5% (100 micro M) and 93.5% (5 mM), and using rolipram (PDE(4) selective), the PE-induced contraction was inhibited by 57.9% (50 micro M) and 81.9% (100 micro M). The results suggest the involvement of cAMP and cGMP in the relaxation of renal artery smooth muscle cells. Moreover, phosphodiesterases, especially PDE(3) and PDE(4), seem to play a critical role in the regulation of renal artery smooth muscle tone.
Karsten
A J
AJ
Molecular and Clinical Drug Research, An der Heeresstr. 49, 66822 Lebach, Germany.
Derouet
H
H
Ziegler
M
M
Eckert
R E
RE
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism*; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D012077:Renal Artery / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000502:physiology*
D010726:Phosphodiesterase Inhibitors; D018340:Receptors, Adrenergic, alpha-1; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP