Impairment by lovastatin of neural relaxation of the rabbit sphincter of Oddi.
We sought whether inhibition of cholesterol biosynthesis by lovastatin influenced the nitrergic relaxation response of the sphincter of Oddi. Rabbit sphincters of Oddi rings were tested for changes in isometric tension in response to field stimulation in the presence of 4 microM guanethidine and 1 microM atropine. Tissue samples were then analyzed for cAMP and cGMP content by radioimmunoassay for nitric oxide concentration by electron spin resonance and for vasoactive intestinal peptide and calcitonin gene-related peptide (CGRP) release by radioimmunoassay. Membrane G(salpha) protein was determined by Western blot analysis. Field stimulation relaxed the preparations with an increase in nitric oxide, cAMP and cGMP concentrations at increased calcitonin gene-related peptide and vasoactive intestinal polypeptide (VIP) release. Preparations from rabbits pre-treated with lovastatin (5 mg/kg/day intragastrically, over 5 days) contracted under the same conditions with an attenuated cGMP-increase at preserved increase in NO content and neuropeptide release. The relaxation was recaptured combining lovastatin with farnesol (1 mg/kg intravenously, twice a day for 5 days). The field stimulation-induced increase in cyclic nucleotides was also restored. Lovastatin decreased membrane G(salpha) protein content, which was re-normalized by farnesol. Farnesol treatment reinstates neurogenic relaxation of the sphincter of Oddi deteriorated by lovastatin possibly by normalizing G-protein coupling.
Sari
R
R
First Department of Medicine, University of Szeged, Koranyi fasor 8, H-6720, Szeged, Hungary.
Nemeth
J
J
Porszasz
R
R
Horvath
P
P
Blasig
I E
IE
Ferdinandy
P
P
Nagy
I
I
Lonovics
J
J
Szilvassy
Z
Z
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004558:Electric Stimulation; D005204:Farnesol / Q000494:pharmacology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009126:Muscle Relaxation / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D011817:Rabbits; D009803:Sphincter of Oddi / Q000187:drug effects* / Q000294:innervation / Q000502:physiology; D014660:Vasoactive Intestinal Peptide / Q000378:metabolism
D000924:Anticholesteremic Agents; D018377:Neurotransmitter Agents; D009569:Nitric Oxide; D014660:Vasoactive Intestinal Peptide; D005204:Farnesol; D002784:Cholesterol; D008148:Lovastatin; D000242:Cyclic AMP; D019205:GTP-Binding Protein alpha Subunits, Gs; D006152:Cyclic GMP; D015740:Calcitonin Gene-Related Peptide