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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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KV currents and KV1.5 expression. (A) KV current traces recorded in enzymatically isolated PASMC from lean and obese Zucker rats with depolarizing pulses from -60 mV to +60 mV in 10 mV increments. The current-voltage relationship measured at the end of depolarizing pulse is shown at the bottom (n = 9) and the membrane capacitance in the inset. (B) Effects of hypoxia on Kv currents in both strains (n = 7). (C) KV1.5 mRNA expression in resistance PA from lean and obese Zucker rats analyzed by RT-PCR and normalized by β-actin expression (n = 5). (D) KV1.5 protein expression in whole lung homogenates analyzed by Western blot and normalized by β-actin expression (n = 6). Results indicate mean ± s.e.m.
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Figure 2: KV currents and KV1.5 expression. (A) KV current traces recorded in enzymatically isolated PASMC from lean and obese Zucker rats with depolarizing pulses from -60 mV to +60 mV in 10 mV increments. The current-voltage relationship measured at the end of depolarizing pulse is shown at the bottom (n = 9) and the membrane capacitance in the inset. (B) Effects of hypoxia on Kv currents in both strains (n = 7). (C) KV1.5 mRNA expression in resistance PA from lean and obese Zucker rats analyzed by RT-PCR and normalized by β-actin expression (n = 5). (D) KV1.5 protein expression in whole lung homogenates analyzed by Western blot and normalized by β-actin expression (n = 6). Results indicate mean ± s.e.m.

Mentions: Similar cell capacitance (17.8 ± 1.1 and 18.4 ± 0.7 pF in obese and lean rats, respectively), as a measure of the cell size, and similar KV current density (Figure 2A) were found in lean and obese PASMC. Moreover, hypoxia induced a similar inhibition of KV currents in both strains (Figure 2B). In accordance with patch-clamp data, no changes in KV1.5 mRNA transcription in resistance PA (Figure 2C) or whole lung protein expression (Figure 2D) were found in obese as compared to lean rats.


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)

KV currents and KV1.5 expression. (A) KV current traces recorded in enzymatically isolated PASMC from lean and obese Zucker rats with depolarizing pulses from -60 mV to +60 mV in 10 mV increments. The current-voltage relationship measured at the end of depolarizing pulse is shown at the bottom (n = 9) and the membrane capacitance in the inset. (B) Effects of hypoxia on Kv currents in both strains (n = 7). (C) KV1.5 mRNA expression in resistance PA from lean and obese Zucker rats analyzed by RT-PCR and normalized by β-actin expression (n = 5). (D) KV1.5 protein expression in whole lung homogenates analyzed by Western blot and normalized by β-actin expression (n = 6). 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 2: KV currents and KV1.5 expression. (A) KV current traces recorded in enzymatically isolated PASMC from lean and obese Zucker rats with depolarizing pulses from -60 mV to +60 mV in 10 mV increments. The current-voltage relationship measured at the end of depolarizing pulse is shown at the bottom (n = 9) and the membrane capacitance in the inset. (B) Effects of hypoxia on Kv currents in both strains (n = 7). (C) KV1.5 mRNA expression in resistance PA from lean and obese Zucker rats analyzed by RT-PCR and normalized by β-actin expression (n = 5). (D) KV1.5 protein expression in whole lung homogenates analyzed by Western blot and normalized by β-actin expression (n = 6). Results indicate mean ± s.e.m.
Mentions: Similar cell capacitance (17.8 ± 1.1 and 18.4 ± 0.7 pF in obese and lean rats, respectively), as a measure of the cell size, and similar KV current density (Figure 2A) were found in lean and obese PASMC. Moreover, hypoxia induced a similar inhibition of KV currents in both strains (Figure 2B). In accordance with patch-clamp data, no changes in KV1.5 mRNA transcription in resistance PA (Figure 2C) or whole lung protein expression (Figure 2D) were found in obese as compared to lean rats.

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