Sialic acid removal modulates the myocardial and vascular activity of calcium channel ligands.
Selective removal of sialic acid from isolated guinea pig left atrial strips and rabbit thoracic aortic ring segments was performed by neuraminidase prepared from Clostridium perfringens and was controlled electron microscopically. Preincubation of these organs (2 units/mL; 2 hr) resulted in enzyme mediated hydrolysis of total tissue sialic acid; 55.2% for atria and 60.9% for aorta. Contractile force of atria and arterial diameter of thoracic aorta were measured isometrically and isotonically by means of a force displacement transducer. Pretreatment of both organs with neuraminidase (2 units/mL; 2 hr) in a carbogen saturated organ bath caused a moderate left-hand shift of the cumulative concentration response curves for the dihydropyridine type calcium antagonist nisoldipine, the phenylalkylamine derivative gallopamil and the benzothiazepine diltiazem. EC50 values were significantly lower (P less than 0.05), particularly in the atrial muscle, when compared to untreated preparations. There was no effect of neuraminidase on the negative inotropic and vasodilator potency of the calcium channel modulator fendiline. Conversely, neuraminidase induced a right-hand shift in the concentration response curves shown by the pure calcium agonist (-)-S-Bay K 8644 leading to significantly higher EC50 values in both organs. Similarly, the contractile potency of calcium chloride (atria) and potassium chloride (aorta) was attenuated upon neuraminidase treatment. From the results obtained it is concluded that sialic acid removal may modulate the action of calcium channel ligands through an inhibitory effect on transmembrane calcium fluxes and/or by decreasing the external calcium availability. Whether the present results suggest a functional role for sialic acid in the regulation of calcium channels warrants further investigation.
Werner
G
G
Institute of Pharmacology, University of Cologne, Federal Republic of Germany.
Addicks
K
K
Fricke
U
U
Klaus
W
W
Sarram
M
M
Gielen
W
W
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D006224:Cricetinae; D004110:Diltiazem / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005275:Fendiline / Q000494:pharmacology; D005711:Gallopamil / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D019158:N-Acetylneuraminic Acid; D009439:Neuraminidase; D015737:Nisoldipine / Q000494:pharmacology; D011817:Rabbits; D012794:Sialic Acids / Q000302:isolation & purification / Q000378:metabolism*
D015220:Calcium Channels; D012794:Sialic Acids; D005711:Gallopamil; D015737:Nisoldipine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009439:Neuraminidase; D004110:Diltiazem; D019158:N-Acetylneuraminic Acid; D005275:Fendiline; D002118:Calcium