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The new nitric oxide donor cyclohexane nitrate induces vasorelaxation, hypotension, and antihypertensive effects via NO/cGMP/PKG pathway.

Mendes-Júnior Ld, Guimarães DD, Gadelha DD, Diniz TF, Brandão MC, Athayde-Filho PF, Lemos VS, França-Silva Mdo S, Braga VA - Front Physiol (2015)

Bottom Line: In addition, pD2 was decreased after non-selective blockade of K(+) channels (pD2 = 3.6 ± 0.1 vs. 5.1 ± 0.1) or by inhibiting KATP channels (pD2 = 4.3 ± 0.1 vs. 5.1 ± 0.1).Furthermore, starting at 6 weeks after the induction of 2K1C hypertension, oral treatment with the HEX (10 mg/Kg/day) for 7 days reduced blood pressure in hypertensive animals (134 ± 6 vs. 170 ± 4 mmHg, respectively).Furthermore, HEX acutely reduces blood pressure and heart rate as well as produces antihypertensive effect in renovascular hypertensive rats.

View Article: PubMed Central - PubMed

Affiliation: Biotechnology Center, Federal University of Paraíba João Pessoa, Brazil.

ABSTRACT
We investigated the cardiovascular effects induced by the nitric oxide donor Cyclohexane Nitrate (HEX). Vasodilatation, NO release and the effects of acute or sub-chronic treatment with HEX on cardiovascular parameters were evaluated. HEX induced endothelium-independent vasodilatation (Maximum effect [efficacy, ME] = 100.4 ± 4.1%; potency [pD2] = 5.1 ± 0.1). Relaxation was attenuated by scavenging nitric oxide (ME = 44.9 ± 9.4% vs. 100.4 ± 4.1%) or by inhibiting the soluble guanylyl cyclase (ME = 38.5 ± 9.7% vs. 100.4 ± 4.1%). In addition, pD2 was decreased after non-selective blockade of K(+) channels (pD2 = 3.6 ± 0.1 vs. 5.1 ± 0.1) or by inhibiting KATP channels (pD2 = 4.3 ± 0.1 vs. 5.1 ± 0.1). HEX increased NO levels in mesenteric arteries (33.2 ± 2.3 vs. 10.7 ± 0.2 au, p < 0.0001). Intravenous acute administration of HEX (1-20 mg/kg) induced hypotension and bradycardia in normotensive and hypertensive rats. Furthermore, starting at 6 weeks after the induction of 2K1C hypertension, oral treatment with the HEX (10 mg/Kg/day) for 7 days reduced blood pressure in hypertensive animals (134 ± 6 vs. 170 ± 4 mmHg, respectively). Our data demonstrate that HEX is a NO donor able to produce vasodilatation via NO/cGMP/PKG pathway and activation of the ATP-sensitive K(+) channels. Furthermore, HEX acutely reduces blood pressure and heart rate as well as produces antihypertensive effect in renovascular hypertensive rats.

No MeSH data available.


Related in: MedlinePlus

Relaxation induced by cumulative addition of HEX (10−10–10−3 M) in cranial mesenteric artery rings pre-contracted with PHE (10 μM). (A) Denuded Endothelium vs. Denuded Endothelium + TEA (3 mM). (B) Denuded Endothelium vs. Denuded Endothelium + TEA (1 mM). (C) Denuded Endothelium vs. Denuded Endothelium + 4-AP. (D) Denuded Endothelium vs. Denuded Endothelium + GLIB. Results are mean ± s.e.m. *p < 0.05 vs. Denuded Endothelium.
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Figure 4: Relaxation induced by cumulative addition of HEX (10−10–10−3 M) in cranial mesenteric artery rings pre-contracted with PHE (10 μM). (A) Denuded Endothelium vs. Denuded Endothelium + TEA (3 mM). (B) Denuded Endothelium vs. Denuded Endothelium + TEA (1 mM). (C) Denuded Endothelium vs. Denuded Endothelium + 4-AP. (D) Denuded Endothelium vs. Denuded Endothelium + GLIB. Results are mean ± s.e.m. *p < 0.05 vs. Denuded Endothelium.

Mentions: In cranial mesenteric artery rings without functional endothelium, pretreatment with TEA (3 mM), which in that concentration acts as a non-selective K+ channels blocker, shifted the concentration-response curve to the right decreasing the HEX potency (Figure 4A), as observed by the pD2 value when compared with the control (pD2 = 3.65 ± 0.17 vs. 5.11 ± 0.12, respectively, n = 5, p < 0.05). In order to assess the subtypes of K+ channels, more specific K+ channels blockers were used. The vasorelaxant responses induced by increasing concentrations of HEX were not significantly modified by tissue pre-exposure to TEA (BKCa blocker) or 4-AP (KV blocker). On the other hand, when GLIB (KATP channel blocker) was used, the HEX-induced vasodilatation was attenuated (pD2 = 4.38 ± 0.09 vs. 5.11 ± 0.12, n = 6, p < 0.05) without changing in maximum effect as illustrated in Figures 4B–D.


The new nitric oxide donor cyclohexane nitrate induces vasorelaxation, hypotension, and antihypertensive effects via NO/cGMP/PKG pathway.

Mendes-Júnior Ld, Guimarães DD, Gadelha DD, Diniz TF, Brandão MC, Athayde-Filho PF, Lemos VS, França-Silva Mdo S, Braga VA - Front Physiol (2015)

Relaxation induced by cumulative addition of HEX (10−10–10−3 M) in cranial mesenteric artery rings pre-contracted with PHE (10 μM). (A) Denuded Endothelium vs. Denuded Endothelium + TEA (3 mM). (B) Denuded Endothelium vs. Denuded Endothelium + TEA (1 mM). (C) Denuded Endothelium vs. Denuded Endothelium + 4-AP. (D) Denuded Endothelium vs. Denuded Endothelium + GLIB. Results are mean ± s.e.m. *p < 0.05 vs. Denuded Endothelium.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4553900&req=5

Figure 4: Relaxation induced by cumulative addition of HEX (10−10–10−3 M) in cranial mesenteric artery rings pre-contracted with PHE (10 μM). (A) Denuded Endothelium vs. Denuded Endothelium + TEA (3 mM). (B) Denuded Endothelium vs. Denuded Endothelium + TEA (1 mM). (C) Denuded Endothelium vs. Denuded Endothelium + 4-AP. (D) Denuded Endothelium vs. Denuded Endothelium + GLIB. Results are mean ± s.e.m. *p < 0.05 vs. Denuded Endothelium.
Mentions: In cranial mesenteric artery rings without functional endothelium, pretreatment with TEA (3 mM), which in that concentration acts as a non-selective K+ channels blocker, shifted the concentration-response curve to the right decreasing the HEX potency (Figure 4A), as observed by the pD2 value when compared with the control (pD2 = 3.65 ± 0.17 vs. 5.11 ± 0.12, respectively, n = 5, p < 0.05). In order to assess the subtypes of K+ channels, more specific K+ channels blockers were used. The vasorelaxant responses induced by increasing concentrations of HEX were not significantly modified by tissue pre-exposure to TEA (BKCa blocker) or 4-AP (KV blocker). On the other hand, when GLIB (KATP channel blocker) was used, the HEX-induced vasodilatation was attenuated (pD2 = 4.38 ± 0.09 vs. 5.11 ± 0.12, n = 6, p < 0.05) without changing in maximum effect as illustrated in Figures 4B–D.

Bottom Line: In addition, pD2 was decreased after non-selective blockade of K(+) channels (pD2 = 3.6 ± 0.1 vs. 5.1 ± 0.1) or by inhibiting KATP channels (pD2 = 4.3 ± 0.1 vs. 5.1 ± 0.1).Furthermore, starting at 6 weeks after the induction of 2K1C hypertension, oral treatment with the HEX (10 mg/Kg/day) for 7 days reduced blood pressure in hypertensive animals (134 ± 6 vs. 170 ± 4 mmHg, respectively).Furthermore, HEX acutely reduces blood pressure and heart rate as well as produces antihypertensive effect in renovascular hypertensive rats.

View Article: PubMed Central - PubMed

Affiliation: Biotechnology Center, Federal University of Paraíba João Pessoa, Brazil.

ABSTRACT
We investigated the cardiovascular effects induced by the nitric oxide donor Cyclohexane Nitrate (HEX). Vasodilatation, NO release and the effects of acute or sub-chronic treatment with HEX on cardiovascular parameters were evaluated. HEX induced endothelium-independent vasodilatation (Maximum effect [efficacy, ME] = 100.4 ± 4.1%; potency [pD2] = 5.1 ± 0.1). Relaxation was attenuated by scavenging nitric oxide (ME = 44.9 ± 9.4% vs. 100.4 ± 4.1%) or by inhibiting the soluble guanylyl cyclase (ME = 38.5 ± 9.7% vs. 100.4 ± 4.1%). In addition, pD2 was decreased after non-selective blockade of K(+) channels (pD2 = 3.6 ± 0.1 vs. 5.1 ± 0.1) or by inhibiting KATP channels (pD2 = 4.3 ± 0.1 vs. 5.1 ± 0.1). HEX increased NO levels in mesenteric arteries (33.2 ± 2.3 vs. 10.7 ± 0.2 au, p < 0.0001). Intravenous acute administration of HEX (1-20 mg/kg) induced hypotension and bradycardia in normotensive and hypertensive rats. Furthermore, starting at 6 weeks after the induction of 2K1C hypertension, oral treatment with the HEX (10 mg/Kg/day) for 7 days reduced blood pressure in hypertensive animals (134 ± 6 vs. 170 ± 4 mmHg, respectively). Our data demonstrate that HEX is a NO donor able to produce vasodilatation via NO/cGMP/PKG pathway and activation of the ATP-sensitive K(+) channels. Furthermore, HEX acutely reduces blood pressure and heart rate as well as produces antihypertensive effect in renovascular hypertensive rats.

No MeSH data available.


Related in: MedlinePlus