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Pulmonary arterial dysfunction in insulin resistant obese Zucker rats.

Moral-Sanz J, Menendez C, Moreno L, Moreno E, Cogolludo A, Perez-Vizcaino F - Respir. Res. (2011)

Bottom Line: Insulin resistance and obesity are strongly associated with systemic cardiovascular diseases.The hyporesponsiveness to vasoconstrictors was reversed by L-NAME and prevented by the iNOS inhibitor 1400W.In contrast to rat models of type 1 diabetes or other mice models of insulin resistance, the obese Zucker rats did not show any of the characteristic features of pulmonary hypertension but rather a reduced vasoconstrictor response which could be prevented by inhibition of iNOS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain.

ABSTRACT

Background: Insulin resistance and obesity are strongly associated with systemic cardiovascular diseases. Recent reports have also suggested a link between insulin resistance with pulmonary arterial hypertension. The aim of this study was to analyze pulmonary vascular function in the insulin resistant obese Zucker rat.

Methods: Large and small pulmonary arteries from obese Zucker rat and their lean counterparts were mounted for isometric tension recording. mRNA and protein expression was measured by RT-PCR or Western blot, respectively. KV currents were recorded in isolated pulmonary artery smooth muscle cells using the patch clamp technique.

Results: Right ventricular wall thickness was similar in obese and lean Zucker rats. Lung BMPR2, KV1.5 and 5-HT2A receptor mRNA and protein expression and KV current density were also similar in the two rat strains. In conductance and resistance pulmonary arteries, the similar relaxant responses to acetylcholine and nitroprusside and unchanged lung eNOS expression revealed a preserved endothelial function. However, in resistance (but not in conductance) pulmonary arteries from obese rats a reduced response to several vasoconstrictor agents (hypoxia, phenylephrine and 5-HT) was observed. The hyporesponsiveness to vasoconstrictors was reversed by L-NAME and prevented by the iNOS inhibitor 1400W.

Conclusions: In contrast to rat models of type 1 diabetes or other mice models of insulin resistance, the obese Zucker rats did not show any of the characteristic features of pulmonary hypertension but rather a reduced vasoconstrictor response which could be prevented by inhibition of iNOS.

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Endothelial function and eNOS protein expression. (A) Concentration-response curve to acetylcholine in endothelium intact conductance PA rings precontracted with phenylephrine 10-7M (left) and resistance PA rings precontracted with phenyleprine to reach a 75% of KCl contraction with or without L-NAME 10-4 M (right) from lean and obese Zucker rats (n = 4-6). (B) Concentration-response curve to sodium nitroprusside in conductance PA rings contracted by 5-HT (10-4M) in the presence of L-NAME (10-4M, n = 5). (C) eNOS mRNA levels in resistance PA analyzed by RT-PCR and normalized by β-actin expression (n = 5) and (D) eNOS protein expression from whole lung homogenated analyzed by Western blot and normalized by β-actin expression (n = 8). Results indicate mean ± s.e.m.
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Figure 3: Endothelial function and eNOS protein expression. (A) Concentration-response curve to acetylcholine in endothelium intact conductance PA rings precontracted with phenylephrine 10-7M (left) and resistance PA rings precontracted with phenyleprine to reach a 75% of KCl contraction with or without L-NAME 10-4 M (right) from lean and obese Zucker rats (n = 4-6). (B) Concentration-response curve to sodium nitroprusside in conductance PA rings contracted by 5-HT (10-4M) in the presence of L-NAME (10-4M, n = 5). (C) eNOS mRNA levels in resistance PA analyzed by RT-PCR and normalized by β-actin expression (n = 5) and (D) eNOS protein expression from whole lung homogenated analyzed by Western blot and normalized by β-actin expression (n = 8). Results indicate mean ± s.e.m.

Mentions: The endothelial function was tested in endothelium intact PA preconstricted with phenylephrine (10-7M in conductance arteries or a concentration titrated to induce a contraction 75% of the response to KCl in resistance PA). Increasing concentrations of ACh induced a similar relaxant response in obese and lean rats in conductance arteries (Figure 3A). Resistance arteries from obese rats required higher concentrations of phenylephrine to achieve a tone similar to the lean ones (5 ± 2 · 10-6M vs 7 ± 2 · 10-7M, respectively). The analysis of the concentration-response curves to ACh shows that there were not significant changes in the Emax values between groups in conductance (Emax 53 ± 7 vs 67 ± 9%, respectively) or resistance vessels (Emax 59 ± 8 vs 66 ± 4%, respectively). Similarly, the concentration of ACh required for half-maximal relaxation in conductance (pD2 values 6.4 ± 0.1 vs 6.2 ± 0.2, respectively) or in resistance vessels (pD2 values 6.1 ± 0.2 vs 5.8 ± 0.2, respectively) was similar in both groups. In the presence of the NOS inhibitor L-NAME, similar concentrations of phenylephrine were required to induce ~75% of KCl contraction in arteries from the obese and lean rats (3 ± 2·10-8M and 2 ± 0.6·10-8M, respectively) but these concentrations were significantly lower than those required in the absence of L-NAME. Moreover, in the presence of this inhibitor, the relaxation to acetylcholine was completely abolished in both strains (Figure 3D). In addition, no changes were found in the response to the endothelium-independent vasodilator sodium nitroprusside in conductance PA (Figure 3B). Expression of eNOS mRNA in resistance PA (Figure 3C) or eNOS protein in whole lung (Figure 3D) was also similar in both strains.


Pulmonary arterial dysfunction in insulin resistant obese Zucker rats.

Moral-Sanz J, Menendez C, Moreno L, Moreno E, Cogolludo A, Perez-Vizcaino F - Respir. Res. (2011)

Endothelial function and eNOS protein expression. (A) Concentration-response curve to acetylcholine in endothelium intact conductance PA rings precontracted with phenylephrine 10-7M (left) and resistance PA rings precontracted with phenyleprine to reach a 75% of KCl contraction with or without L-NAME 10-4 M (right) from lean and obese Zucker rats (n = 4-6). (B) Concentration-response curve to sodium nitroprusside in conductance PA rings contracted by 5-HT (10-4M) in the presence of L-NAME (10-4M, n = 5). (C) eNOS mRNA levels in resistance PA analyzed by RT-PCR and normalized by β-actin expression (n = 5) and (D) eNOS protein expression from whole lung homogenated analyzed by Western blot and normalized by β-actin expression (n = 8). Results indicate mean ± s.e.m.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3111360&req=5

Figure 3: Endothelial function and eNOS protein expression. (A) Concentration-response curve to acetylcholine in endothelium intact conductance PA rings precontracted with phenylephrine 10-7M (left) and resistance PA rings precontracted with phenyleprine to reach a 75% of KCl contraction with or without L-NAME 10-4 M (right) from lean and obese Zucker rats (n = 4-6). (B) Concentration-response curve to sodium nitroprusside in conductance PA rings contracted by 5-HT (10-4M) in the presence of L-NAME (10-4M, n = 5). (C) eNOS mRNA levels in resistance PA analyzed by RT-PCR and normalized by β-actin expression (n = 5) and (D) eNOS protein expression from whole lung homogenated analyzed by Western blot and normalized by β-actin expression (n = 8). Results indicate mean ± s.e.m.
Mentions: The endothelial function was tested in endothelium intact PA preconstricted with phenylephrine (10-7M in conductance arteries or a concentration titrated to induce a contraction 75% of the response to KCl in resistance PA). Increasing concentrations of ACh induced a similar relaxant response in obese and lean rats in conductance arteries (Figure 3A). Resistance arteries from obese rats required higher concentrations of phenylephrine to achieve a tone similar to the lean ones (5 ± 2 · 10-6M vs 7 ± 2 · 10-7M, respectively). The analysis of the concentration-response curves to ACh shows that there were not significant changes in the Emax values between groups in conductance (Emax 53 ± 7 vs 67 ± 9%, respectively) or resistance vessels (Emax 59 ± 8 vs 66 ± 4%, respectively). Similarly, the concentration of ACh required for half-maximal relaxation in conductance (pD2 values 6.4 ± 0.1 vs 6.2 ± 0.2, respectively) or in resistance vessels (pD2 values 6.1 ± 0.2 vs 5.8 ± 0.2, respectively) was similar in both groups. In the presence of the NOS inhibitor L-NAME, similar concentrations of phenylephrine were required to induce ~75% of KCl contraction in arteries from the obese and lean rats (3 ± 2·10-8M and 2 ± 0.6·10-8M, respectively) but these concentrations were significantly lower than those required in the absence of L-NAME. Moreover, in the presence of this inhibitor, the relaxation to acetylcholine was completely abolished in both strains (Figure 3D). In addition, no changes were found in the response to the endothelium-independent vasodilator sodium nitroprusside in conductance PA (Figure 3B). Expression of eNOS mRNA in resistance PA (Figure 3C) or eNOS protein in whole lung (Figure 3D) was also similar in both strains.

Bottom Line: Insulin resistance and obesity are strongly associated with systemic cardiovascular diseases.The hyporesponsiveness to vasoconstrictors was reversed by L-NAME and prevented by the iNOS inhibitor 1400W.In contrast to rat models of type 1 diabetes or other mice models of insulin resistance, the obese Zucker rats did not show any of the characteristic features of pulmonary hypertension but rather a reduced vasoconstrictor response which could be prevented by inhibition of iNOS.

View Article: PubMed Central - HTML - PubMed

Affiliation: Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain.

ABSTRACT

Background: Insulin resistance and obesity are strongly associated with systemic cardiovascular diseases. Recent reports have also suggested a link between insulin resistance with pulmonary arterial hypertension. The aim of this study was to analyze pulmonary vascular function in the insulin resistant obese Zucker rat.

Methods: Large and small pulmonary arteries from obese Zucker rat and their lean counterparts were mounted for isometric tension recording. mRNA and protein expression was measured by RT-PCR or Western blot, respectively. KV currents were recorded in isolated pulmonary artery smooth muscle cells using the patch clamp technique.

Results: Right ventricular wall thickness was similar in obese and lean Zucker rats. Lung BMPR2, KV1.5 and 5-HT2A receptor mRNA and protein expression and KV current density were also similar in the two rat strains. In conductance and resistance pulmonary arteries, the similar relaxant responses to acetylcholine and nitroprusside and unchanged lung eNOS expression revealed a preserved endothelial function. However, in resistance (but not in conductance) pulmonary arteries from obese rats a reduced response to several vasoconstrictor agents (hypoxia, phenylephrine and 5-HT) was observed. The hyporesponsiveness to vasoconstrictors was reversed by L-NAME and prevented by the iNOS inhibitor 1400W.

Conclusions: In contrast to rat models of type 1 diabetes or other mice models of insulin resistance, the obese Zucker rats did not show any of the characteristic features of pulmonary hypertension but rather a reduced vasoconstrictor response which could be prevented by inhibition of iNOS.

Show MeSH
Related in: MedlinePlus