Studies in the isolated artery helped define whether small and/or large arteries were responsible for HPV and whether vascular smooth muscle and/or endothelial cells were the effectors. However, as will become evident below, distinctions between sensor, mediator, effector, and even modulator, tend to become somewhat blurred in the isolated artery.
For a number of years, progress in the study of isolated pulmonary arteries was hampered due to a lack of consistency of the hypoxic response in the particular vessels studied. While prior studies in intact animals and in isolated lungs had established that HPV was most probably located in the small diameter arteries, the technology was not available to study in vitro arteries less than ~ 1 mm in diameter. With the development of such technology, Madden et al.(30) showed that cat pulmonary arterial rings less than 300 Jim in diameter had a consistent, reproducible hypoxic constrictor response whereas rings greater than 500 |xm diameter never developed more than a small amount of force. In this and in an earlier study by Lloyd (25) in rabbit isolated artery strips, the contractile response to hypoxia was graded; with the rabbit arteries beginning to contract at a Po2 of 200 Torr, the cat between 350 and 300 Torr, and both peaking at Po2's between 50 and 30 Torr. The similarity of the hypoxic response in the isolated cat pulmonary arteries to that in isolated lungs from other species (41) suggested that the isolated, small diameter pulmonary artery was a useful model in which to investigate mechanisms of HPV. As in the isolated lung, there have been reports of HPV in isolated veins (58) although it is generally believed that their contribution to the overall response is minor compared to the arteries.
The possibility that the vascular endothelium was responsible for HPV through release of a contracting factor was proposed by Holden and McCall (20) who showed that removing the endothelium effectively eliminated HPV in pig main pulmonary artery. Later studies in isolated arteries showed that while the endothelium was not required for HPV, its full expression did seem to require a basal release of ET-1 (24) and/or another endothelium-derived contracting factor. Thus, the endothelium rather than being the effector, was more likely a source of modulators. An interesting sidelight of the investigation into the role of the endothelium in HPV has come from studies in isolated rat pulmonary arteries. These arteries exhibit a biphasic response to hypoxia (8). The initial contraction to hypoxia (phase 1) is followed by a relaxation and, if hypoxia is maintained, the artery contracts again (phase 2). Whether phase 1 or phase 2 is endothelium-dependent has been the subject of some debate but current consensus favors phase 2 (also see Chapter 12).
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