Alpha1L-adrenoceptors in canine pulmonary artery.

The aim of this study was to characterize the alpha-adrenoceptors of the canine pulmonary artery. Arterial rings from lower lung lobes were suspended for isometric-tension recording in the presence of cocaine (5 x 10(-6) M), hydrocortisone (3 x 10(-5) M), propranolol (5 x 10(-6) M), and rauwolscine (10(-7) M) to inhibit neuronal uptake, extraneuronal uptake, and beta- and alpha2-adrenoceptors, respectively. Prazosin was more potent against contractions evoked by phenylephrine (pA2 of 9.7) compared with methoxamine (pA2 of 8.4). SZL49 (10(-8) and 3 x 10(-8) M), an irreversible alpha1-adrenergic antagonist, inhibited responses to phenylephrine but not methoxamine. With norepinephrine, low concentrations of prazosin (3 x 10(-10) M and 10(-9) M) caused inhibition of the concentration-response curve; a higher concentration (3 x 10(-9) M) failed to produced further inhibition, whereas increasing the concentration of the antagonist (to 10(-8) and 3 x 10(-8) M) caused further rightward shifts in the concentration-response curve. The Arunlakshana and Schild plot revealed two components corresponding to pA2 values of 9.8 and 8.4. After SZL49 (3 x 10(-8) M), the Arunlakshana and Schild plot for the interaction between norepinephrine and prazosin was linear and generated a pA2 of 8.3. Contractions evoked by phenylephrine were inhibited by the alpha1B/alpha1D-adrenoceptor antagonist, chloroethylclonidine (10(-5) M), or by the alpha1B-antagonist, risperidone (pA2 value of 8.5), but were relatively resistant to inhibition by the selective alpha1D-antagonist, BMY7378 (-log K(B) of 6.1). The results suggest that two alpha1-adrenoceptor subtypes mediate contraction of the canine pulmonary artery. One subtype has high affinity for prazosin (alpha1H, likely to be alpha1B), is activated by phenylephrine, and is inhibited by SZL49. The other subtype has lower affinity for prazosin (alpha1L), is stimulated by methoxamine, and is relatively resistant to SZL49. The physiologic agonist, norepinephrine, causes contraction by activating both subtypes.

Hypoxic pulmonary endothelial cells release a diffusible contractile factor distinct from endothelin.

Hypoxia (0% O2) evokes a late-phase, endothelium-dependent contractile response in porcine isolated pulmonary arteries that may be caused by a cyclooxygenase-independent, endothelium-derived contractile factor. The aim of this study was to further analyze the mechanism underlying this hypoxic response. Proximal porcine pulmonary arterial rings were suspended for isometric tension recording in organ chambers. Hypoxia (0% O2) caused a late-phase, endothelium-dependent contractile response that was not inhibited by the endothelin (ET)A-receptor antagonist BQ-123 (10(-6) M), by the ETB-receptor antagonist BQ-788 (10(-7) M), or by their combination. In contrast, ET-1 caused a concentration-dependent contraction of arterial rings that was inhibited by BQ-123 (10(-6) M) and a relaxation that was abolished by BQ-788 (10(-7) M) or by endothelial cell removal. Therefore, the endothelium-dependent contraction to hypoxia is not mediated by ET. Hypoxia caused only relaxation in endothelium-denuded rings. However, when a pulmonary valve leaflet, a rich source of pulmonary endothelial cells, was placed into the lumen of endothelium-denuded rings, hypoxia caused a late-phase contractile response that was similar to that observed in arterial rings with native endothelium. This hypoxic contraction persisted in the presence of indomethacin (10(-5) M) and N-nitro-L-arginine methyl ester (3 x 10(-5) M) to block cyclooxygenase and nitric oxide synthase, respectively. These results suggest that hypoxic contraction of pulmonary arteries is mediated by a diffusible, contractile factor released from hypoxic endothelial cells. This contractile mediator is distinct from ET.