TY - JOUR
T1 - Endothelin in the central control of cardiovascular and respiratory functions
AU - Kuwaki, Tomoyuki
AU - Ling, G. Y.
AU - Onodera, M.
AU - Ishii, T.
AU - Nakamura, A.
AU - Ju, K. H.
AU - Cao, W. H.
AU - Kumada, M.
AU - Kurihara, H.
AU - Kurihara, Y.
AU - Yazaki, Y.
AU - Ohuchi, T.
AU - Yanagisawa, Masashi
AU - Fukuda, Y.
N1 - Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 1999
Y1 - 1999
N2 - 1. Exogenously administered endothelin (ET) modulates the activity of cardiovascular and respiratory neurons in the central nervous system (CNS) and, thus, affects arterial blood pressure (ABP) and ventilation. However, a physiological role(s) for endogenous ET in the CNS has not been elucidated. To address this question, we examined ABP and ventilation in mutant mice deficient in ET-1, ET(A) and ET(B) receptors and endothelin-converting enzyme-1, which were made by gene targeting. 2. Respiratory frequency and volume was measured in mice by whole body plethysmography when animals breathed normal room air and hypoxic and hypercapnic gas mixtures. A few days after respiratory measurements, a catheter was implanted into the femoral artery under halothane anaesthesia. On the following day, the ABP of awake mice was measured through the indwelling catheter and heart rate was calculated from the ABP signal. After 2 h ABP measurement, arterial blood was collected through the catheter and pH and the partial pressures of O2 and CO2 were measured by a blood gas analyser. 3. Compared with corresponding controls, the mean (±SEM) ABP in ET-1(+/-) and ET(B)-deficient mice was significantly higher (118±2 vs 106±3 mmHg for ET-1(+/-) (n = 22) and ET- 1(+/+) (n = 17) mice, respectively; 127±3 vs 109±4 mmHg for ET(B)(-/s) (n = 9) and ET(B)(+/s) (n = 9) mice, respectively; P < 0.05 for both). In ET-1(+/- ) mice, PCO2 tended to be higher and PO2 was significantly lower than corresponding values in ET-1(+/+) mice. Under resting conditions, there was no significant difference in respiratory parameters between mutants and their corresponding controls. However, reflex increases of ventilation to hypoxia and hypercapnia were significantly attenuated in ET-1(+/-), ET-1(-/-) and ETA(-/-) mice. 4. In another series of experiments in ET-1(+/-) mice, we found that sympathetic nerve activity (SNA) was augmented and reflex excitation of phrenic nerve activity (PNA) in response to hypoxia and hypercapnia was blunted. Attenuation of the reflex PNA response to hypercapnia was also observed in the medulla-spinal cord preparation from ET- 1(-/-) mice. 5. Elevation of ABP in ET(B)-deficient mice was most likely due to a peripheral mechanism, because SNA and respiratory reflexes were not different from those in control animals. 6. We conclude that endogenous ET-1 plays an important role in the central neural control of circulation and respiration and that ETA receptors mediate this mechanism.
AB - 1. Exogenously administered endothelin (ET) modulates the activity of cardiovascular and respiratory neurons in the central nervous system (CNS) and, thus, affects arterial blood pressure (ABP) and ventilation. However, a physiological role(s) for endogenous ET in the CNS has not been elucidated. To address this question, we examined ABP and ventilation in mutant mice deficient in ET-1, ET(A) and ET(B) receptors and endothelin-converting enzyme-1, which were made by gene targeting. 2. Respiratory frequency and volume was measured in mice by whole body plethysmography when animals breathed normal room air and hypoxic and hypercapnic gas mixtures. A few days after respiratory measurements, a catheter was implanted into the femoral artery under halothane anaesthesia. On the following day, the ABP of awake mice was measured through the indwelling catheter and heart rate was calculated from the ABP signal. After 2 h ABP measurement, arterial blood was collected through the catheter and pH and the partial pressures of O2 and CO2 were measured by a blood gas analyser. 3. Compared with corresponding controls, the mean (±SEM) ABP in ET-1(+/-) and ET(B)-deficient mice was significantly higher (118±2 vs 106±3 mmHg for ET-1(+/-) (n = 22) and ET- 1(+/+) (n = 17) mice, respectively; 127±3 vs 109±4 mmHg for ET(B)(-/s) (n = 9) and ET(B)(+/s) (n = 9) mice, respectively; P < 0.05 for both). In ET-1(+/- ) mice, PCO2 tended to be higher and PO2 was significantly lower than corresponding values in ET-1(+/+) mice. Under resting conditions, there was no significant difference in respiratory parameters between mutants and their corresponding controls. However, reflex increases of ventilation to hypoxia and hypercapnia were significantly attenuated in ET-1(+/-), ET-1(-/-) and ETA(-/-) mice. 4. In another series of experiments in ET-1(+/-) mice, we found that sympathetic nerve activity (SNA) was augmented and reflex excitation of phrenic nerve activity (PNA) in response to hypoxia and hypercapnia was blunted. Attenuation of the reflex PNA response to hypercapnia was also observed in the medulla-spinal cord preparation from ET- 1(-/-) mice. 5. Elevation of ABP in ET(B)-deficient mice was most likely due to a peripheral mechanism, because SNA and respiratory reflexes were not different from those in control animals. 6. We conclude that endogenous ET-1 plays an important role in the central neural control of circulation and respiration and that ETA receptors mediate this mechanism.
KW - Blood pressure
KW - Central nervous system
KW - Endothelin
KW - Gene targeting
KW - Mice
KW - Respiratory regulation
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U2 - 10.1046/j.1440-1681.1999.03177.x
DO - 10.1046/j.1440-1681.1999.03177.x
M3 - Article
C2 - 10626068
AN - SCOPUS:0033405788
SN - 0305-1870
VL - 26
SP - 989
EP - 994
JO - Clinical and Experimental Pharmacology and Physiology
JF - Clinical and Experimental Pharmacology and Physiology
IS - 12
ER -