ABSTRACT
A close link between arsenic exposure and hypertension has been well-established through many epidemiological reports, yet the mechanism underlying it remains unclear. Here we report that nanomolar concentrations of monomethylarsonous acid (MMA(III)), a toxic trivalent methylated arsenic metabolite, can potentiate agonist-induced vasoconstriction and pressor responses. In freshly isolated rat aortic ring, exposure to nanomolar MMA(III) (100-500 nM) potentiated phenylephrine (PE)-induced vasoconstriction while at higher concentrations (≥2.5 µM), suppression of vasoconstriction and apoptosis of vascular smooth muscle were observed. Potentiation of agonist-induced vasoconstriction was also observed with other contractile agonists and it was retained in endothelium-denuded aortic rings, suggesting that these events are agonist-independent and smooth muscle cell dependent. Interestingly, exposure to MMA(III) resulted in increased myosin light chain phosphorylation while PE-induced Ca2+ influx was not affected, reflecting that Ca2+ sensitization is involved. In line with this, MMA(III) enhanced agonist-induced activation of small GTPase RhoA, a key contributor to Ca2+ sensitization. Of note, treatment of MMA(III) to rats induced significantly higher pressor responses in vivo, demonstrating that this event can occur in vivo indeed. We believe that RhoA-mediated Ca2+ sensitization and the resultant potentiation of vasoconstriction by MMA(III) may shed light on arsenic-associated hypertension.
Subject(s)
Hypertension/chemically induced , Organometallic Compounds/toxicity , Pressoreceptors/drug effects , Vasoconstriction/drug effects , Animals , Aorta, Thoracic/drug effects , Aorta, Thoracic/metabolism , Aorta, Thoracic/pathology , Aorta, Thoracic/physiopathology , Apoptosis/drug effects , Arsenic Poisoning/physiopathology , Arsenicals/metabolism , Calcium Signaling/drug effects , Cells, Cultured , Enzyme Activation/drug effects , Hypertension/etiology , In Vitro Techniques , Male , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Myosin Light Chains/metabolism , Osmolar Concentration , Phosphorylation/drug effects , Rats , Rats, Sprague-Dawley , Vasoconstrictor Agents/antagonists & inhibitors , Vasoconstrictor Agents/chemistry , Vasoconstrictor Agents/pharmacology , rhoA GTP-Binding Protein/agonistsABSTRACT
Ginseng, one of most well-known herbal medicines, is widely and indiscreetly used among the patients with cardiovascular disorders, raising concern over abuse of this medicine and unwanted effects. In this study, we investigated the effects of ginsenoside Rg3 (Rg3), an active ingredient of ginseng, on vascular contractility and structural integrity to explore its potential vascular toxicity. In isolated rat aorta, Rg3 suppressed the normal agonist-induced contractile response. This suppression persisted even after a rigorous washout. In the endothelium-denuded aortic ring, impairment of vascular contractility by Rg3 was retained, suggesting that vascular smooth muscle was affected. In primary vascular smooth muscle cells, Rg3 abolished agonist-induced Ca(2+) increase, indicating that Ca(2+) regulation was disrupted. Rg3 suppressed the contraction induced by Bay K8644, an L-type Ca(2+) channel activator, whereas store-operated Ca(2+) channel or intracellular Ca(2+) store-mediated contraction was not affected, suggesting that the L-type Ca(2+) channel was selectively impaired by Rg3. These in vitro results were further confirmed in vivo where Rg3 treatment significantly attenuated the agonist-induced pressor response. More importantly, 4-week repeated treatment with Rg3 in normal animals induced eutrophic outward remodeling in the thoracic aorta, that is, it brought about an increased luminal area without changes in the wall area. These results suggest that Rg3 can induce the vascular smooth muscle dysfunction by disturbing Ca(2+) influx from the L-type Ca(2+) channel, ultimately leading to impaired vascular contractility and structural remodeling.
Subject(s)
Aorta, Thoracic/drug effects , Ginsenosides/toxicity , Muscle, Smooth, Vascular/drug effects , Panax/metabolism , Vasoconstriction/drug effects , Animals , Aorta, Thoracic/pathology , Apoptosis/drug effects , Blood Pressure/drug effects , Blood Pressure/physiology , Calcium/analysis , Calcium/metabolism , Calcium Channels, L-Type/drug effects , Calcium Signaling/drug effects , Cytosol/chemistry , Cytosol/drug effects , Cytosol/metabolism , Male , Muscle, Smooth, Vascular/physiopathology , Organ Culture Techniques , Panax/chemistry , Plant Extracts/toxicity , Rats , Rats, Sprague-Dawley , Vasoconstriction/physiologyABSTRACT
PURPOSE: The study is designed to develop an educational CD-Program for prevention and control of obesity among primary school students. METHOD: The study is conducted from June 15, 2000 to April 15, 2002. Based on the course of program development suggested by Dick and Cray (1990), the study followed the planning, development, education and evaluation of a program. RESULT: The developed CD-Program consists 2 parts each for lower and higher grades of primary school students. The introduction part of the first trial for lower grade students uses quiz to encourage their motivations, the body proceeds with motion pictures and animations to trigger their interests. The introduction part of the second trial for the lower grades consists of remembering the exhibition lecture. The first trial for higher grades of primary school students builds on the contents of the low grades. Its body part, how to determine obesity and calculate ones own obesity, puts ones own weight and height in by the mouse. For the second trial of the higher grades, the body consists of life-style, diet, and regiments. CONCLUSION: The merits of this CD-Program are that to be possible an interaction between teachers and students.
