ABSTRACT
Cadmium (Cd) toxicity was produced in male rats to study the role of cholinoceptors in Cd-induced endothelial dysfunction. The changes in the tension of the aortic rings to constrictor and dilator agonists were compared with those of controls. A Cd-induced significant increase in phenylephrine response was associated with a decrease in basal dilator prostanoid release. In Cd-exposed rings, despite an obvious depression in the acetylcholine (ACh) response, the receptor-independent dilation to the calcium ionophore A23187, which elicits a receptor-independent endothelial relaxation, was slightly elevated (p<0.01), but the smooth muscle cell response to the NO donor, sodium nitroprusside (SNP) remained unaltered. Cadmium decreased both the maximal response to ACh (10(-5) M) and its pirenzepine (Prz) sensitive component. The M1 type cholinoceptor-mediated response to ACh decreased in Cd-exposed rings to 10.30 +/- 5.00% from 38.40 +/- 6.90% (p<0.001). Cadmium also reduced the share of indomethacin 1.64% to 13.92 +/- 2.89% (p<0.01), which correlated well with the changes in the M1-mediated response (r=0.991, p<0.0001). Most of the deleterious effect of Cd appears to be restricted to the M1-dependent ACh response. These findings suggest that Cd produces an endothelial dysfunction by impairing the M1 type cholinoceptor mediated response, which seems to be involved in prostanoid release.
Subject(s)
Cadmium/toxicity , Endothelium, Vascular/physiopathology , Peripheral Vascular Diseases/chemically induced , Receptor, Muscarinic M1/drug effects , Receptor, Muscarinic M1/physiology , Acetylcholine/administration & dosage , Acetylcholine/antagonists & inhibitors , Acetylcholine/pharmacokinetics , Administration, Oral , Animals , Aorta, Thoracic , Atropine/administration & dosage , Atropine/pharmacokinetics , Cadmium/administration & dosage , Cadmium/blood , Calcimycin/administration & dosage , Calcimycin/pharmacokinetics , Dose-Response Relationship, Drug , Drug Synergism , Endothelium, Vascular/drug effects , Gallamine Triethiodide/administration & dosage , Gallamine Triethiodide/pharmacokinetics , Glomerular Filtration Rate/drug effects , Hypertension/chemically induced , Hypertension/complications , Indomethacin/administration & dosage , Indomethacin/pharmacokinetics , Kidney Cortex/chemistry , Kidney Cortex/drug effects , Kidney Cortex/physiopathology , Kidney Diseases/chemically induced , Kidney Diseases/complications , Male , Muscle Contraction/drug effects , Muscle, Smooth, Vascular/drug effects , NG-Nitroarginine Methyl Ester/administration & dosage , NG-Nitroarginine Methyl Ester/pharmacokinetics , Nitroprusside/administration & dosage , Nitroprusside/pharmacokinetics , Peripheral Vascular Diseases/complications , Peripheral Vascular Diseases/physiopathology , Phenylephrine/administration & dosage , Phenylephrine/pharmacokinetics , Pirenzepine/administration & dosage , Pirenzepine/pharmacokinetics , Prostaglandins/metabolism , Rats , Rats, Wistar , Vasodilation/drug effectsABSTRACT
Because zinc attenuates endothelial cell dysfunction that proceeds atherosclerosis, depressed zinc status may be involved in the initiation of endothelial dysfunction. However, before recommending a zinc-enriched diet to reduce the risks for atherosclerosis, the effect of excess zinc on endothelial cell functions in normozincemic status should be known. Therefore, in this study, the effect of dietary zinc on normal endothelial cell functions in animals subjected to a diet containing 334 +/- 58 ppm zinc for 30 d was studied to see whether supplemented zinc has an effect on endothelial cells. Despite a slight increase in blood zinc, unaltered aortic and kidney zinc contents were associated with unchanged blood pressure in rats subjected to a zinc-enriched diet. Increased basal nitric oxide and prostacyclin were accompanied by a normal response to phenylephrine. Dietary zinc influenced neither endothelial-dependent nor endothelial-independent relaxations significantly. However, it elevated the share of M1-type cholinoceptor response as well as dilator prostaglandin release, which seems to be nitric oxide dependent. There was a strong correlation (r=0.826, p<0.05) between M1-type cholinoceptor response and prostacyclin release in zinc-treated rings. These results suggested that zinc ions increases M1-mediated prostacyclin release in normal endothelial cells without altering intracellular pathways.
