Endothelin in the Central Control of Cardiovascular and Respiratory Functions

Abstract

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, ETA and ETB 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 ETB-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 ETB-/s (n = 9) and ETB+/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 ETB-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.

Impaired Ventilatory Responses to Hypoxia in Mice Deficient in Endothelin-Converting-Enzyme-1

“…In contrast, heterozygous ECE-1ϩ/Ϫ newborns are apparently healthy and develop normally. In a recent study, the differences in respiratory function between adult heterozygous ECE-1ϩ/Ϫ and wild-type ECE-1ϩ/ϩ adult mice were found to be not significant (4). Newborn mice were not studied.…”

Endothelin 1 protects HN33 cells from serum deprivation-induced neuronal apoptosis through Ca2+-PKCα-ERK pathway

“…Indeed, it is well known that the ET-1 and its receptor are expressed in various regions of brain (Rubanyi and Polokoff, 1994;Kuwaki et al, 1999;van den Buuse and Webber, 2000). This suggested that ET-1 might be implicated in the pathogenesis of CNS disorders.…”

Neural control of breathing: insights from genetic mouse models

“…Studies looking at respiratory phenotypes in newborn mice with targeted gene deletions have started to establish links between the expression of specific genes and the development of carbon-dioxide sensitivity (see Table 2). Null mutant newborn mice lacking the Edn1 and Ednra genes had blunted ventilatory responses to hypercapnia (45,46). Ret ("rearranged during transfection") is a transmembrane tyrosine kinase signaling receptor for members of the glial cell line-derived neurotrophic factor (GDNF) family of ligands.…”