bq-123 and Acidosis

Perfusate pH may influence the tone of vascular smooth muscle by affecting the release of endothelium-derived vasoactive factors or by directly modulating function of the smooth muscle. This study was designed to investigate the role of endothelium-derived factors on acidosis-induced responses of isolated canine tibial nutrient artery suspended in an organ chamber for the measurement of isometric contractile force. To investigate the specific role of the endothelium in half the rings, the endothelium was removed mechanically. Concentration-response curves to KCl were obtained in the absence or presence of inhibition of two important endothelium-derived relaxing factors, nitric oxide and prostacyclin, and an inhibitor of receptors for the endothelium-derived contracting factor, endothelin-1. Acidification of the perfusate from pH 7.45 to 7.0 significantly attenuated the contractions to KCl in arterial rings with endothelium (the mean of the effective concentration causing 50% of the maximal response for KCl at pH 7.45 and 7.0 was 12.31 +/- 0.40 nM and 14.60 +/- 0.55 nM, respectively). This difference was abolished by mechanical removal of the endothelium. In rings with endothelium, inhibition of nitric oxide or prostacyclin did not abolish the attenuation of KCl-induced contractions occurring with acidosis (the mean of the effective concentration causing 50% of the maximal response for KCl at pH 7.45 and 7.0 was 11.18 +/- 0.60 nM and 13.60 +/- 0.60 nM, respectively). Inhibition of endothelin-A receptors did not alter contractions to KCl at pH 7.45. However, the acidosis-induced attenuation of contractions with KCl was abolished by the endothelin-A-receptor antagonist BQ-123 (the mean of the effective concentration causing 50% of the maximal response at pH 7.45 and 7.0 was 13.8 +/- 1.34 nM and 13.2 +/- 1.34 nM, respectively). These results suggest that acidosis-induced relaxation of canine tibial nutrient artery is endothelium dependent and that activation of endothelin-A receptors during acidosis is coupled to a release of an endothelium-derived relaxing factor.

Topics: Acidosis; Animals; Anti-Inflammatory Agents, Non-Steroidal; Dogs; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Enzyme Inhibitors; Indomethacin; Muscle, Smooth, Vascular; omega-N-Methylarginine; Peptides, Cyclic; Potassium Chloride; Receptor, Endothelin A; Receptors, Endothelin; Tibia; Tibial Arteries

1. The possible contribution of endogenous endothelin (ET) to the pathogenesis of seizure-associated pulmonary oedema was examined in mechanically ventilated rats after intravenous bolus injection of the gamma-aminobutyric acid (GABA) antagonist, bicuculline (1.2 mg kg-1). 2. Recurrent seizure activity elicited by bicuculline injection led to rapidly developing pulmonary oedema. Within 4 min after bicuculline application (1.2 mg kg-1), arterial O2 partial pressure (PaO2) significantly dropped from 17.49 +/- 1.20 kPa to 7.51 +/- 2.21 kPa (P < 0.01) and arterial CO2 partial pressure (PaCO2) significantly increased from 4.64 +/- 0.56 kPa to 8.15 +/- 0.99 kPa (P < 0.01). Gradually a progressive acidosis developed. Moreover, mean arterial blood pressure (MABP) and end-inspiratory airway pressure (Paw) rapidly increased. 3. Concomitantly there was a time-dependent increase of big ET-1 and ET-1 levels in bronchoalveolar lavage (BAL) as determined by combined reverse phase high performance liquid chromatography (h.p.l.c.) and radioimmunoassay. BAL levels of both peptides increased up to 8 min after bicuculline injection and slowly decreased subsequently. In contrast, BAL from animals injected with vehicle did not contain detectable amounts of ET. 4. Pretreatment with the endothelin-converting enzyme inhibitor, phosphoramidon (5.4 mg kg-1, i.v.) for 5 min significantly (P < 0.001) reduced peak ET-1 levels in BAL fluid by 65.4 +/- 9.9% at 8 min after bicuculline injection. Simultaneously it afforded protection from hypoxia. PaCO2 did not increase and PaO2 decreased only slightly from 14.63 +/- 1.00 kPa to 12.97 +/- 0.61 kPa (P > 0.05) after phosphoramidon pretreatment. In contrast, vehicle-treated animals that received bicuculline showed both significant hypercapnia as well as profound hypoxia. Phosphoramidon significantly diminished the maximum increase in Paw by 76.7 +/- 12.4% (P <0.005), but only slightly affected the MABP. Phosphoramidon pretreatment had no effect on the acidosis.5. Pretreatment with the ETA receptor antagonist, BQ-123 (1 mg kg-1, i.v.), for 5 min did not affect the levels of ET-1 in the BAL fluid at 8 min after bicuculline injection but did ameliorate the development of hypoxia. No hypercapnia developed and Pa02 decreased only moderately from 16.65 +/-0.25 kPa to 14.19 +/-2.15 kPa (P>0.05) in BQ-123-treated animals. In contrast, vehicle-treated animals that received bicuculline exhibited significant hypercapnia as well as profound hypoxia. BQ-

Topics: Acidosis; Animals; Aspartic Acid Endopeptidases; Bicuculline; Blood Gas Analysis; Blood Pressure; Bronchoalveolar Lavage Fluid; Convulsants; Electroencephalography; Endothelin-Converting Enzymes; Endothelins; Glycopeptides; In Vitro Techniques; Male; Metalloendopeptidases; Peptides, Cyclic; Protease Inhibitors; Pulmonary Edema; Rats; Rats, Wistar; Seizures