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Intermittent hypoxia regulates the renin-angiotensin system in the rat carotid body
S104
ABSTRACTS / Journal of Molecular and Cellular Cardiology 42 (2007) S102–S124
In Langendorff perfused rat heart, pressure development decrease to the infra-basal level by the washout of isoproterenol (iso). Since it has been reported that iso decreases intracellular magnesium (Mg) concentration, we hypothesized that iso washout-induced decrease in cardiac contractility is induced by the decrease of intracellular Mg concentration. We examined the relationship between cardiac contractility and Mg content in the hearts by using Langendorff perfused rat heart model and atomic absorption spectrophotometry. Application of iso (10 nM, 15 min; iso group) caused positive chronotropic and inotropic effects. After washout of iso (30 min), heart rate (HR) recovered to the basal level, but left ventricular developed pressure (LVDP) decreased to significantly lower level than that of time matched control (70.7 ± 3.9 vs. 88.9 ± 7.1%, respectively; p < 0.05), without myocardial damage. When iso was applied with high Mg (12 mM; iso + high Mg group), iso washout-induced deterioration of LVDP was significantly inhibited (86.9 ± 4.0%, p < 0.05 vs. iso group). In iso + high Mg group, Mg content was kept at high level (762.3 ± 36.2 μg/g dry). When extracellular Ca concentration was decreased, in order to mimic the Ca blocking effect of Mg, iso washout-induced decrease in contractility was not inhibited. Intracellular Mg content decreased from 739.2 ± 15.2 (control group) to 721.6 ± 25.5 μg/g dry (iso group). These results suggest that intracellular Mg may play an important role to maintain the cardiac contractility. Keywords: Magnesium; Isoproterenol; Langendorff perfused model doi:10.1016/j.yjmcc.2007.03.230
The restorative effect of ANP or chronic NEP inhibition on blunted cardiac vagal reflexes in aged rats Colleen J. Thomas, Robyn L. Woods. Howard Florey Institute, University of Melbourne and DEPM, Monash University, Victoria, Australia The cardiac hormone atrial natriuretic peptide (ANP) augments cardiopulmonary vagal afferent reflexes in young rats. Since impaired vagal tone is a potentially damaging feature of ageing, we investigated whether acute or chronic elevation of ANP levels may restore depressed vagal reflex function in aged rats. We found that cardiac high pressure mechanoreceptor and cardiac chemoreceptor (Be zold-Jarisch) vagal afferent-activated reflexes were impaired by 32–39% (p < 0.05) in conscious, chronically-instrumented 24-month-old vs. 6-month-old rats. Bradycardia to high pressure baroreceptor activation or the Bezold-Jarisch reflex was restored during acute ANP infusion in old rats (by 91 ± 15% and 60 ± 18%, respectively, p < 0.05) to levels compatible with those in younger rats. Neutral endopeptidase (NEP) degrades ANP. Following 1 week of NEP inhibitor treatment (Candoxatrilat, 5 mg/kg/day, iv), cardiopulmonary vagal reflexes in old rats were restored to levels similar to those
in NEP inhibitor-treated young rats. In conclusion, these studies show that impaired cardiopulmonary vagal reflex control of heart rate is a feature of normal ageing. The findings that acute ANP infusion or chronic NEP inhibition improves the depressed cardiopulmonary reflexes of old rats may support a new potential therapeutic role for agents that manipulate the natriuretic peptide system to restore cardioprotective reflex function in the elderly. Keywords: Cardiopulmonary vagal reflexes; NEP inhibition; Ageing doi:10.1016/j.yjmcc.2007.03.231
Intermittent hypoxia regulates the renin-angiotensin system in the rat carotid body Sylvia S.Y. Lam, G.L. Tipoe1, Y.W. Tjong, E.C. Liong1, M.L. Fung. Department of Physiology, University of Hong Kong, Pokfulam, Hong Kong, China. 1Department of Anatomy, University of Hong Kong, Pokfulam, Hong Kong, China The CB plays an important role in cardiorespiratory changes in intermittent hypoxia (IH, inspired oxygen level cyclic between 21 and 5% per minute for 8 h diurnally) but the expression and role of RAS in IH resembling sleep apneic conditions are not known. The aim of this study was to examine the hypothesis that IH upregulates the RAS in the rat CB. Immunohistochemical studies revealed that the immunoreactivity of AT1 receptor was localized to the glomic clusters of type-I cells containing tyrosine hydroxylase. The AT1 receptor expression was markedly elevated in the 3-day IH group and it reached a plateau at day 7. In parallel, RTPCR studies showed that levels of mRNA expression of angiotensinogen (AGT), AT1a and AT2 receptors, and angiotensin converting enzyme (ACE) were significantly increased in the 7-day IH group, comparing with the normoxic control. These data suggest that IH upregulates the expression of RAS in the rat CB. Moreover, intracellular calcium response to angiotensin II was enhanced in the fura2 loaded dissociated glomus cells from 3-day IH rats when compared with the normoxic control. Thus, the upregulation of AGT, angiotensin receptors and ACE expression could play a role in the enhancement of CB excitability during IH, which is relevant to the early pathogenesis in sleepdisordered breathing. Acknowledgments Supported by research grants from Research Grants Council, HKSAR and the University of Hong Kong. Keywords: Intermittent hypoxia; Carotid body; Renin–angiotensin system doi:10.1016/j.yjmcc.2007.03.232
ABSTRACTS / Journal of Molecular and Cellular Cardiology 42 (2007) S102–S124
In Langendorff perfused rat heart, pressure development decrease to the infra-basal level by the washout of isoproterenol (iso). Since it has been reported that iso decreases intracellular magnesium (Mg) concentration, we hypothesized that iso washout-induced decrease in cardiac contractility is induced by the decrease of intracellular Mg concentration. We examined the relationship between cardiac contractility and Mg content in the hearts by using Langendorff perfused rat heart model and atomic absorption spectrophotometry. Application of iso (10 nM, 15 min; iso group) caused positive chronotropic and inotropic effects. After washout of iso (30 min), heart rate (HR) recovered to the basal level, but left ventricular developed pressure (LVDP) decreased to significantly lower level than that of time matched control (70.7 ± 3.9 vs. 88.9 ± 7.1%, respectively; p < 0.05), without myocardial damage. When iso was applied with high Mg (12 mM; iso + high Mg group), iso washout-induced deterioration of LVDP was significantly inhibited (86.9 ± 4.0%, p < 0.05 vs. iso group). In iso + high Mg group, Mg content was kept at high level (762.3 ± 36.2 μg/g dry). When extracellular Ca concentration was decreased, in order to mimic the Ca blocking effect of Mg, iso washout-induced decrease in contractility was not inhibited. Intracellular Mg content decreased from 739.2 ± 15.2 (control group) to 721.6 ± 25.5 μg/g dry (iso group). These results suggest that intracellular Mg may play an important role to maintain the cardiac contractility. Keywords: Magnesium; Isoproterenol; Langendorff perfused model doi:10.1016/j.yjmcc.2007.03.230
The restorative effect of ANP or chronic NEP inhibition on blunted cardiac vagal reflexes in aged rats Colleen J. Thomas, Robyn L. Woods. Howard Florey Institute, University of Melbourne and DEPM, Monash University, Victoria, Australia The cardiac hormone atrial natriuretic peptide (ANP) augments cardiopulmonary vagal afferent reflexes in young rats. Since impaired vagal tone is a potentially damaging feature of ageing, we investigated whether acute or chronic elevation of ANP levels may restore depressed vagal reflex function in aged rats. We found that cardiac high pressure mechanoreceptor and cardiac chemoreceptor (Be zold-Jarisch) vagal afferent-activated reflexes were impaired by 32–39% (p < 0.05) in conscious, chronically-instrumented 24-month-old vs. 6-month-old rats. Bradycardia to high pressure baroreceptor activation or the Bezold-Jarisch reflex was restored during acute ANP infusion in old rats (by 91 ± 15% and 60 ± 18%, respectively, p < 0.05) to levels compatible with those in younger rats. Neutral endopeptidase (NEP) degrades ANP. Following 1 week of NEP inhibitor treatment (Candoxatrilat, 5 mg/kg/day, iv), cardiopulmonary vagal reflexes in old rats were restored to levels similar to those
in NEP inhibitor-treated young rats. In conclusion, these studies show that impaired cardiopulmonary vagal reflex control of heart rate is a feature of normal ageing. The findings that acute ANP infusion or chronic NEP inhibition improves the depressed cardiopulmonary reflexes of old rats may support a new potential therapeutic role for agents that manipulate the natriuretic peptide system to restore cardioprotective reflex function in the elderly. Keywords: Cardiopulmonary vagal reflexes; NEP inhibition; Ageing doi:10.1016/j.yjmcc.2007.03.231
Intermittent hypoxia regulates the renin-angiotensin system in the rat carotid body Sylvia S.Y. Lam, G.L. Tipoe1, Y.W. Tjong, E.C. Liong1, M.L. Fung. Department of Physiology, University of Hong Kong, Pokfulam, Hong Kong, China. 1Department of Anatomy, University of Hong Kong, Pokfulam, Hong Kong, China The CB plays an important role in cardiorespiratory changes in intermittent hypoxia (IH, inspired oxygen level cyclic between 21 and 5% per minute for 8 h diurnally) but the expression and role of RAS in IH resembling sleep apneic conditions are not known. The aim of this study was to examine the hypothesis that IH upregulates the RAS in the rat CB. Immunohistochemical studies revealed that the immunoreactivity of AT1 receptor was localized to the glomic clusters of type-I cells containing tyrosine hydroxylase. The AT1 receptor expression was markedly elevated in the 3-day IH group and it reached a plateau at day 7. In parallel, RTPCR studies showed that levels of mRNA expression of angiotensinogen (AGT), AT1a and AT2 receptors, and angiotensin converting enzyme (ACE) were significantly increased in the 7-day IH group, comparing with the normoxic control. These data suggest that IH upregulates the expression of RAS in the rat CB. Moreover, intracellular calcium response to angiotensin II was enhanced in the fura2 loaded dissociated glomus cells from 3-day IH rats when compared with the normoxic control. Thus, the upregulation of AGT, angiotensin receptors and ACE expression could play a role in the enhancement of CB excitability during IH, which is relevant to the early pathogenesis in sleepdisordered breathing. Acknowledgments Supported by research grants from Research Grants Council, HKSAR and the University of Hong Kong. Keywords: Intermittent hypoxia; Carotid body; Renin–angiotensin system doi:10.1016/j.yjmcc.2007.03.232