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Endothelin‐1 and the periaqueductal gray area of the rat: an autoradiographic and functional pharmacological study
Author(s) -
D'Amico Michele,
Dashwood Michael R.,
Warner Timothy D.
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15361.x
Subject(s) - endothelin receptor , endocrinology , periaqueductal gray , medicine , antagonist , receptor , receptor antagonist , endothelin 3 , blood pressure , microinjection , chemistry , biology , endothelins , central nervous system , midbrain
1 . Endothelin‐1 (ET‐1) injected centrally induces pressor effects and associated haemodynamic changes. Here we have evaluated the effects on systemic and regional cardiovascular parameters of injection of ET‐1 into the periaqueductal gray (PAG) area of anaesthetized rats. In addition, we have used the ET A receptor‐selective antagonist, FR 139317, the ETB receptor‐selective antagonist, BQ‐788, and the ET A / ET B receptor non‐selective antagonist, SB 209670, to identify the receptor(s) mediating these effects. We have also used in vitro autoradiography to identify binding sites for ET‐1 in the PAG. 2 . In vitro autoradiography showed dense binding of [ 125 I]‐PD 151242 (for ET A receptors) in the PAG area, with the binding sites being homogeneously distributed within the dorsal, lateral and ventral subregions. Tissues incubated with [ 125 I]‐BQ 3020 (for ET B receptors) had little binding. 3 . Injection of ET‐1 (0.1, 1 and 10 pmol per rat) in the dorsolateral PAG area significantly increased, in a dose‐dependent manner the mean arterial blood pressure (MAP). The highest dose of ET‐1 (10 pmol) also decreased the heart rate by 18±1%, n =6 (P>0.05). Increases in blood pressure induced by ET‐1 (1 pmol; 31±6.6 mmHg, n =6) were greatly reduced by pre‐administration to the PAG area of FR 139317 (5 nmol per rat) or SB 209670 (3 nmol per rat) (97 and 94%, respectively), but were unaffected by BQ‐788 (5 nmol per rat). Similarly, FR 139317 and SB 209670 prevented the decrease in heart rate induced by ET‐1 while BQ‐788 did not affect it. 4 . Injection of ET‐1 to the PAG area caused falls in renal blood flow (RBF) as measured by an ultrasonic flow probe, and increased renal vascular resistance (RVR). Pre‐treatment of the PAG with FR 139317 or SB 209670, but not with BQ‐788, prevented this ET‐1‐induced effect. 5 . Injection of ET‐1 (10 pmol) also increased total peripheral resistance (TPR; control, 2.39±0.2 mmHg ml −1 min 100 g body weight) by 100±9% ( n =5) and reduced the cardiac output (CO; control, 94.7±3.1 ml min −1 ) by 30±3% ( n =5), as determined by radioactive microspheres. Vascular resistances were increased in other organs, such as skeletal muscle (88±5%, n =4), the colon (55±7%, n =4) and the stomach (47±3%, n =4). Pretreatment of the PAG area with FR 139317 or SB 209670 reduced the increases in TPR and vascular resistance, and the reduction in CO caused by ET‐1. BQ‐788 did not affect the responses to ET‐1. 6 . Thus, there are predominantly ET A binding sites within the PAG area and injection of ET‐1 into the PAG area causes complex haemodynamic changes which are sensitive to ET A receptor antagonism. ET A receptors are, therefore, the predominant mediators of the actions of ET‐1 in the PAG of the rat.