Endothelin in the central, control of cardiovascular and respiratory functions

1. Exogenously administered endothelin (ET) modulates the activity of cardi ovascular and respiratory neurons in the central nervous system (CNS) and, thus, affects arterial blood pressure (ABP) and ventilation. However, a phy siological role(s) for endogenous ET in the CNS has not been elucidated, To address this question, we examined ABP and ventilation in mutant mice defi cient in ET-1, ETA and ETB receptors and endothelin-converting enzyme-1, wh ich were made by gene targeting, 2. Respiratory frequency and volume was measured in mice by whole body plet hysmography when animals breathed normal room air and hypoxic and hypercapn ic gas mixtures, A few days after respiratory measurements, a catheter was implanted into the femoral artery under halothane anaesthesia, On the follo wing day, the ABP of awake mice was measured through the indwelling cathete r and heart rate was calculated from the ABP signal. After 2 h ABP measurem ent, arterial blood was collected through the catheter and pH and the parti al pressures of O-2 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 f or 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 si gnificantly lower than corresponding values in ET-1(+/+) mice. Under restin g conditions, there was no significant difference in respiratory parameters between mutants and their corresponding controls. However, reflex increase s of ventilation to hypoxia and hypercapnia were significantly attenuated i n ET-1(+/-), ET-1(-/-) and ETA-/- mice. 4. In another series of experiments in ET-1(+/-) mice, we found that sympat hetic nerve activity (SNA) was augmented and reflex excitation of phrenic n erve activity (PNA) in response to hypoxia and hypercapnia was blunted. Att enuation 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 peripher al 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 mediat e this mechanism.