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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

Synthetic route for obtaining the cyclohexane nitrate (HEX).
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Figure 1: Synthetic route for obtaining the cyclohexane nitrate (HEX).

Mentions: Therapies targeting to increase NO levels have great applicability in cardiovascular diseases. NO donors (e.g., nitroglycerin and sodium nitroprusside) have been used in clinical practice for decades against angina pectoris, pulmonary hypertension, and cardiac ischemia (Münzel et al., 2011). However, tolerance developed after the long-term use of these agents impairs the chronic treatment of hypertension (Napoli and Ignarro, 2003; Csont and Ferdinandy, 2005). Considering the clinical potential for NO donors, we synthesized the cyclohexane nitrate (HEX) from cliclohexanol as illustrated in the synthetic route presented in Figure 1. Therefore, our aims were: (a) characterize this novel organic nitrate as a NO donor; and (b) evaluate its effects on cardiovascular system of normotensive and hypertensive rats. Our data show that HEX increases NO levels in endothelium-denudated mesenteric arteries, promoting vasorelaxation by the activation of NO/cGMP/PKG pathway and ATP-sensitive K+ channel (KATP). Furthermore, we experimentally demonstrated that HEX is able to reduce blood pressure in hypertensive rats.


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)

Synthetic route for obtaining the cyclohexane nitrate (HEX).
© Copyright Policy
Related In: Results  -  Collection

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

Figure 1: Synthetic route for obtaining the cyclohexane nitrate (HEX).
Mentions: Therapies targeting to increase NO levels have great applicability in cardiovascular diseases. NO donors (e.g., nitroglycerin and sodium nitroprusside) have been used in clinical practice for decades against angina pectoris, pulmonary hypertension, and cardiac ischemia (Münzel et al., 2011). However, tolerance developed after the long-term use of these agents impairs the chronic treatment of hypertension (Napoli and Ignarro, 2003; Csont and Ferdinandy, 2005). Considering the clinical potential for NO donors, we synthesized the cyclohexane nitrate (HEX) from cliclohexanol as illustrated in the synthetic route presented in Figure 1. Therefore, our aims were: (a) characterize this novel organic nitrate as a NO donor; and (b) evaluate its effects on cardiovascular system of normotensive and hypertensive rats. Our data show that HEX increases NO levels in endothelium-denudated mesenteric arteries, promoting vasorelaxation by the activation of NO/cGMP/PKG pathway and ATP-sensitive K+ channel (KATP). Furthermore, we experimentally demonstrated that HEX is able to reduce blood pressure in hypertensive rats.

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