Vasorelaxation induced by the new nitric oxide donor cis-[Ru(Cl)(bpy)2(NO)](PF6) is due to activation of KCa by a cGMP-dependent pathway
Introduction
Nitric oxide (NO) plays an important role in the control of vascular tone, and it is a free radical gas, which is known as a multifunctional and ubiquitous biological messenger molecule. NO can bind to the heme site of soluble guanylyl cyclase (sGC) (Feelisch et al., 1988), activating the enzyme and catalyzing the conversion of GTP to cGMP (Noack and Feelisch, 1991) and inducing a downstream signaling cascade. This cascade includes activation of a kinase downstream from cGMP, protein kinase G and subsequent decrease of cytosolic calcium concentration, leading to vasodilation (McDonald and Murad, 1996, Murad, 1994).
Several NO donors have been used in clinical settings for decades (e.g., nitroglycerin and sodium nitroprusside). However, the growth of interest in the physiology of NO since the mid 1980s has led to the development of a variety of new NO donors that offer several advantages over conventional NO donors (Ignarro, 2002). The amount and duration of the NO released by respective NO donors determines their pharmacological properties.
Nitric oxide released from NO donors or cGMP have been shown to activate smooth-muscle K+ channels in cerebral arteries (Hempelmann et al., 2000, Hempelmann et al., 2001, Wang et al., 2000). Thus, a cGMP-mediated hyperpolarization due to the opening of K+ channels with subsequent deactivation of voltage-dependent Ca2+ channels and decreasing intracellular Ca2+ activity is one of the mechanism of NO-induced vasorelaxation (Lovren and Triggle, 1998, Sand et al., 2006, Wang et al., 2000).
When K+ channels open in the vascular smooth-muscle cell membrane, K+ efflux increases, causing membrane hyperpolarization, decreased Ca2+ entry (through voltage-operated Ca2+ channels) and vasodilatation (Bolotina et al., 1994). Several types of K+ channels have been identified in vascular smooth-muscle and endothelium. The most abundant includes the large conductance calcium dependent K+ channels and voltage-sensitive K+ channel (Kv). Also present are the intermediate and small-conductance calcium sensitive K+ channels (IKCa and SKCa), the ATP-sensitive K+ channel (KATP) and the inward-rectifying potassium channels (Kir) (Brayden, 1996, Vergara et al., 1998).
Recently, new metal complexes have been studied as NO donors, including nitrosyl ruthenium complexes (Bonaventura et al., 2004, Lunardi et al., 2006b, Wang et al., 2000).The ability of controlling the NO release to the biological medium could be done by the synthesis of an appropriated structure controlling chemical properties such as redox potential and photochemistry. The ruthenium complex used in this study release NO only under photoactivation. This study aimed to investigate the effect of NO released from the new NO donor cis-[Ru(Cl)(bpy)2(NO)](PF6) (RUNOCL) on the rat aorta relaxation and the mechanism involved in this relaxation and the effects of K+ channel blockers and guanylyl cyclase inhibitor (Scheme 1).
Section snippets
Animals
For vasodilation studies, male Wistar rats (200–250 g) were used. The rats were killed by decapitation and all the procedures are in compliance with the Ethical Animal Committee by the University of São Paulo, Brazil.
Measurements of cis-[Ru(Cl)(bpy)2(NO)](PF6) (RUNOCL)-induced vasodilation
The thoracic aorta was removed, cleaned of adherent connective tissues, and cut into rings 4 mm length. The endothelium was removed mechanically by gently rolling the lumen of the vessel on a thin wire. The aortic rings were placed between two stainless-steel stirrups and connected
Results
On denuded aortic rings pre-contracted with Phe (0.1 μM), RUNOCL (0.1–100 μM) caused a concentration-dependent developing relaxation with the ME:101.2 ± 3.7% and pD2: 6.62 ± 0.16, ⁎P<0.002 (n = 7) (Fig. 1), however the effect was evident only under photo-induction using a visible light system λ > 380 nm. The maximum aorta relaxation (Time-course) induced by RUNOCL was achieved in 1630 s. The synthesized NO donor also relaxed KCl (60 mM) pre-contracted tissue with the ME: 68.6 ± 10.0%, P < 0.01 and pD2: 3.92
Discussion
We reported for the first time that the new NO-donor RUNOCL induces vasorelaxation due to cGMP and Kca channel-activated pathway. Vascular relaxation to NO may occur due to guanylyl cyclase activation and also through a cGMP-independent activation of K+ channels directly on the vascular smooth-muscle cells (Bolotina et al., 1994). In agreement with these findings, we have shown that in response to NO donor the cytosolic calcium concentration decreased in the isolated vascular smooth-muscle
Acknowledgments
This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
References (27)
- et al.
A macrocyclic nitrosyl ruthenium complex is a NO donor that induces rat aorta relaxation
Nitric Oxide: Biology and Chemistry
(2004) - et al.
Role of potassium channels in the relaxation induced by the nitric oxide (NO) donor DEA/NO in the isolated rat basilar artery
Neurosci. Lett.
(2001) - et al.
The role of endothelium-derived nitric oxide in relaxations to levcromakalim in the rat aorta
Jpn. J. Pharmacol.
(1999) - et al.
Involvement of nitrosothiols, nitric oxide and voltage-gated K+ channels in photorelaxation of vascular smooth muscle
Eur. J. Pharmacol.
(1998) - et al.
Cytosolic calcium concentration is reduced by photolysis of a nitrosyl ruthenium complex in vascular smooth muscle cells
Nitric oxide
(2006) Regulation of cytosolic guanylyl cyclase by nitric oxide: the NO-cyclic GMP signal transduction system
Adv. Pharmacol.
(1994)- et al.
Nitric oxide donors mediate vasodilation in human placental arteries partly through a direct effect on potassium channels
Placenta
(2006) - et al.
Calcium-activated potassium channels
Curr. Opin. Neurobiol.
(1998) - et al.
Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle
Nature
(1994) Potassium channels in vascular smooth muscle
Clin. Exp. Pharmacol. Physiol.
(1996)
Mechanisms of calcium antagonist-induced vasodilation
Annu. Rev. Pharmacol. Toxicol.
Explanation of the discrepancy between the degree of organic nitrate decomposition, nitrite formation and guanylate cyclase stimulation
Eur. Heart J.
Effects of potassium channel inhibitors on the relaxation induced by the nitric oxide donor diethylamine nitric oxide in isolated human cerebral arteries
J. Neurosurg.
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