The interaction of cadmium with atrial natriuretic factor: A study in in vivo and in vitro models
Abstract
The involvement of atrial natriuretic factor (ANF) and its receptor in cadmium-induced cardiovascular alterations and neurotoxicity is not known. The objective of this study was to examine the mechanisms underlying cadmium-induced changes in the ANF peptide and its receptor in cardiovascular toxicity. In rats on short term cadmium (Cd) exposure (0.01, 0.1, 0.5 and 1.0 mg/kg, i.p., twice a day for 7 days and a maintenance period of 30 days), atrial ANF levels were decreased significantly in the Cd 1 mg/kg group and plasma ANF levels were not altered. Hypothalamic ANF content decreased significantly in 0.1-1.0 mg/kg Cd groups. Plasma renin activity and concentration were not altered by Cd treatment. However, plasma aldosterone was significantly decreased in Cd 1.0 mg/kg group. Binding of $\sp{125}$I-ANF to its receptors in kidneys, adrenals and aorta was not significantly altered. Cd treatment decreased urine volume indicating nephrotoxicity. In PC12 cells, the ratio of $\sp{125}$I-ANF(1-28) ligand internalized to surface bound at 4 min of incubation was significantly decreased in Cd treated cells, along with significant decreases in ligand internalization in Cd coincubated cells. Also decreased number of binding sites were observed in Cd treated cells along with decreased receptor-ligand crosslinking on Cd treatment. Neuromodulation by ANF involved significant decrease in K$\sp+$-stimulated ($\sp3$H) NE release in rat hypothalamic slices. This action is proposed to be mediated by ANF-B receptors. 8 Br-cGMP mimicked this action. In Cd treated animals (0.5 mg/kg twice a day for 7 days and maintained for 30 days), ANF neuromodulation in the hypothalamus was blocked, even though Cd content was undetectable. Cd preincubated (0.5 mM) slices showed a 49.1% block in neurotransmitter release indicating that Cd may block calcium channels leading to decreased K$\sp+$-stimulated release of ($\sp3$H) NE. Hence, Cd-induced cardiovascular toxicity and neurotoxicity may be partly mediated by alteration in the release and possibly the synthesis of ANF peptide, disruption of ANF function through alterations in receptor dynamics and possibly alteration in cellular calcium homeostasis and membrane integrity. Central ANF function is sensitive to cadmium and this effect may be partly responsible for the cardiovascular and neurotoxic responses to cadmium.
Degree
Ph.D.
Advisors
Isom, Purdue University.
Subject Area
Toxicology|Pharmacology
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