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Effect of Redox Agents on the Response of Rat Aorta to Nitric Oxide and Sodium Nitroprusside K

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Effect of Redox Agents on the Response of Rat Aorta to Nitric Oxide and Sodium Nitroprusside K Research Paper Effect of redox agents on the response of rat aorta to nitric oxide and sodium nitroprusside K. K. Sardar, S. N. Sarkar, D. U. Bawankule, S. K. Mishra, V. Raviprakash ABSTRACT Objective: To study the redox regulation of vascular responses to endogenous nitric oxide (NO) and NO derived from nitrovasodilator sodium nitroprusside (SNP) in isolated rat aorta. Materials and Methods: To determine the influence of reducing [ascorbic acid (1 mM) and reduced glutathione (GSH) (1 mM)] and oxidizing agents [oxidized glutathione (GSSG) (1 mM) and CuSO (1 and 5 μM)] on the vasodilation caused by acetylcholine (ACh; 10-11-10-5 M) and Division of Pharmacology and 4 -9 -4 Toxicology, Indian Veterinary SNP (10 -10 M). Isometric tensions were measured in isolated aorta by a force transducer and Research Institute, recorded in a computer, using Chart V4.1.2 software. Izatnagar - 243 122, UP, India Results: ACh and SNP produced relaxation of rat aortic rings that was dependent on concentra­ tion. The rings were preconstricted with L-phenylephrine (1 μM). It was observed that oxidizing Received: 18.10.2005 and reducing agents caused opposite effects on vasodilation induced by NO in rat aorta. Ascor- Revised: 29.12.2005 bic acid and GSH potentiated the responses to NO, causing a leftward shift in the concentra- Accepted: 3.1.2006 tion-response curve of ACh with significant increase in the pD2 and the Emax. GSSG and CuSO4 inhibited relaxation caused by ACh and shifted the concentration-response curve to the right. Correspondence to: In concentration-responses induced by SNP, ascorbic acid significantly increased the pD and S.N. Sarkar 2 E-mail: [email protected] Emax values from 5.85 ± 0.08 to 6.24 ± 0.05 and 80.83 ± 1.37% to 89.26 ± 1.49%, respectively. However, CuSO4 significantly decreased these values from 5.85 ± 0.02 to 4.56 ± 0.10 and 77.18 ± 0.82% to 53.52 ± 1.60%, respectively. Potentiation of NO response by reducing agents may be related to either increased availability of nitroxyl anion (NO-) or reduction in superoxide ·- anion radical (O2 ). The opposite could be true for the oxidizing agents. Conclusion: The findings of this study suggest that reducing agents like ascorbic acid can im­ prove the vascular responses to NO under oxidative stress. KEY WORDS: Reducing agents, vasodilators, vitamin C. Introduction that inflict direct cellular damage. Vascular disease due to Nitric oxide (NO) is a potent vasodilator. It is synthesised impaired NO bioactivity is primarily attributed to superoxide anion radical (O ·-), which is capable of rapidly inactivating endogenously by the vascular endothelium that plays an 2 [2] important role in the regulation of vascular functions. endothelium-derived NO. Therefore, the aim of the Endothelial dysfunction is associated with various vascular therapeutic interventions is to increase the NO bioavailability either by increasing NO production or decreasing O ·­ disorders like atherosclerosis, systemic and pulmonary 2 hypertension, arterial thrombotic disorders, angina pectoris, generation in the endothelium. Oxidative stress has been and stroke.[1] NO is also generated from a number of clinically identified as an important factor in the development of [3] important compounds called nitrovasodilators. These nitric tolerance to organic nitrates. oxide donor drugs are used in the treatment of disease Release of NO from the nitrovasodilators involves redox conditions related to NO deficiency, such as, angina pectoris regulation via endogenous reductants and oxidants. Sodium and pulmonary hypertension. Cellular redox state is believed nitroprusside (SNP), a multivalent anion and NO donor, to be an important factor in determining response in vascular requires 1 electron reduction to initiate NO release. However, smooth muscle that is related to NO. In addition, it determines the nitrovasodilator 3-morpholino-sydnonimine (SIN-1) can cellular responses and diseases that are induced by stress. spontaneously release NO by undergoing 1 electron oxidation.[4] Inherent in these responses are reactive oxygen species (ROS) In the living system, NO can exist in a variety of redox forms, Indian J Pharmacol | April 2006 | Vol 38 | Issue 2 | 125-30 125 Sardar et al. such as, nitrosonium cation (NO+), NO free radical (NO·), and Mumbai, respectively. All other chemicals used were of nitroxyl anion (NO–) depending on the source of the NO. It is analytical grade. not known which among these forms is responsible for vascular Animals relaxation. Evidences suggest that NO– is more physiologically Healthy, adult, male Wistar rats (150-200 g) were procured relevant.[5] However, according to Dierks and Burstyn,[6],[7] NO· from the Laboratory Animal Resources Section of the Institute. is the only redox state that can activate soluble guanylyl cyclase They were kept in polypropylene cages with standard food and (sGC). If it is so, the relaxant activity of NO– should be due to water ad libitum. The rats were killed by cervical dislocation; its oxidation to NO·. This was contradicted by the finding that the thoracic aorta was dissected out and kept in the modified NO– from Angeli’s salt (Sodium trioxodinitrate, Na N O ) could 2 2 3 Kreb-Henseleit solution (MKHS). The MKHS contained (in mM, mediate vascular relaxation without conversion of NO– to NO·, pH 7.4) NaCl, 118; KCl, 4.7; CaCl .2H O, 2.5; MgSO .7H O, 1.2; and this relaxation was mediated through GC activation.[8],[9] 2 2 4 2 NaHCO , 11.9; KH PO , 1.2 and D-glucose, 11.1 in triple­ NO is believed to cause relaxation of vascular smooth 3 2 4 distilled water. After removal of adherent tissues, aorta was muscle by activation of sGC and consequent rise in intracellular cut into rings of 3-4 mm length. The experiment on the rats cyclic GMP. Activation of sGC can be accomplished with NO was done as per the guidelines of the Institute Ethics donors.[10] Redox active agents can alter the activity of sGC.[7],[11] Committee. Thiol reductants like dithiothreitol and reduced glutathione (GSH) cause inhibitory as well as stimulatory effects on sGC, Recording of tension in aortic rings while thiol oxidant, such as, oxidized glutathione (GSSG) The rat aortic rings were held between two L-shaped hooks inhibits the activity of sGC. Available literature reveals the made of 30-gauge stainless steel wire. They were mounted in importance of cellular redox state or processes in the a thermostatically controlled (37±0.5oC) organ bath of 20 ml regulation of the activity of sGC and the response in vascular capacity, containing MKHS and equilibrated for 1 hour under smooth muscle that is related to NO. As both endogenous NO a resting tension of 1.5 g. The perfusing solution was and NO donors primarily act through stimulation of sGC, it is continuously aerated with carbogen. During equilibration, the important to examine the effects of redox reagents on the bathing fluid was changed every 15 min. The change in tension vasodilator responses elicited by NO. was measured with an isometric force transducer (Model: MLT Several underlying signaling processes in vascular 0202/D, Powerlab, Australia) and recorded in a computer, using dysfunction are influenced by alterations in the status of Chart V4.1.2 software (Powerlab, Australia). In some aortic intracellular redox. A better understanding of the regulation rings, the endothelium was removed mechanically by inserting of function of vascular smooth muscle cell will provide further a wet cotton wick. insight into the pathophysiological mechanisms that contribute Assessment of redox regulation in rat aorta to vascular changes and end-organ damage associated with The aortic rings were primed with L-phenylephrine (1 μM) hypertension. It could permit identification of potential novel and when the contraction attained plateau, ACh (1 μM) was therapeutic targets in the prevention and management of added to determine the endothelial integrity. A contractile or vascular disorders. Oxidative stress plays an important role relaxant response to ACh confirmed the absence or the in the dysfunction of endothelium and development of presence of functional endothelium. The tissues were washed atherosclerosis. Modification of vascular risk factors and with MKHS to restore the baseline tension. They were then employment of antioxidants have been shown to improve contracted submaximally with L-phenylephrine (1 μM). When endothelial function. In rat coronary artery, redox compounds the contraction was stable ACh (10-11-10-5 M) or SNP (10-9­ have been shown to influence nitrovasodilator induced 10-4 M) was added cumulatively at an increment of 1 log, until relaxation in vitro.[12] In patients with coronary artery disease, maximal reversal of the contraction induced by L­ where vasodilator responses to acetylcholine (ACh) and SNP phenylephrine was obtained. After several washes with MKHS, were reduced, ascorbic acid produced a beneficial effect.[13] the tissues were exposed to the individual reducing or oxidizing Anderson et al.[14] also demonstrated the efficacy of agents for 30 min before the second concentration-response antioxidants in the therapy of coronary artery disease. Ulker curve was elicited with ACh (10-11-10-5 M) or SNP (10-9-10-4 M). et al.[15, 16] showed that antioxidants, such as, ascorbic acid The reducing agents used were ascorbic acid (1 mM) and GSH and tocopherol protected hypertension associated with (1 mM) while the oxidizing agents were GSSG (1 mM) and enhanced oxidative stress. As information on the cellular redox CuSO (1 and 5 μM in separate preparations). The effects of state in influencing vasodilation of rat aorta by NO is scanty, 4 individual reducing or oxidizing agents on basal tension, we evaluated the effects of different reducing and oxidizing contraction induced by L-phenylephrine, vasodilatory potency, agents on the relaxation induced with ACh and SNP in rat aorta.
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