Functional effects of 4-aminopyridine (4-AP) on pulmonary and systemic vessels from normoxic control and hypoxic pulmonary hypertensive rats

Abstract

The effects of the outward rectifying potassium channel blocker, 4-aminopyridine, on contractile tone and on contractile responses to the spasmogens, 5-hydroxytryptamine and endothelin-1, were examined in pulmonary arteries (main and intralobar) and systemic vessels (aorta and mesenteric artery) from rats with and without hypoxic pulmonary hypertension. Hypoxic pulmonary hypertension was induced by exposure of rats to 10% oxygen for 1 week. The development of pulmonary hypertension was associated with (i) depolarization of the cell membrane in intralobar pulmonary artery, but not aorta, and (ii) an increase in sensitivity to 5-hydroxytryptamine in pulmonary, but not systemic, vessels; sensitivity to endothelin-1 was unchanged. 4-Aminopyridine contracted all of the vessels studied. In pulmonary hypertension the sensitivity to 4-aminopyridine was increased ten-fold in pulmonary vessels but was unchanged in systemic vessels. Threshold concentrations of 4-aminopyridine (< or =3x10(-3) M) augmented contractions to 5-hydroxytryptamine in main pulmonary artery and aorta from control rats but failed to augment contractions to 5-hydroxytryptamine in main pulmonary artery from pulmonary hypertensive rats. Responses to endothelin-1 were not augmented by 4-aminopyridine. The membrane depolarization and the increases in sensitivity to 4-aminopyridine and 5-hydroxytryptamine seen in pulmonary hypertension are compatible with the concept that potassium channel function is altered in pulmonary, but not systemic, vessels from pulmonary hypertensive rats. Our data suggest that in main pulmonary artery a common mechanism is responsible for (i) the augmentation of 5-hydroxytryptamine responses by 4-aminopyridine in control rats, and (ii) the sensitization to 5-hydroxytryptamine seen in pulmonary hypertensive, compared with control, rats in the absence of 4-aminopyridine. Hence, we conclude that the sensitization to 5-hydroxytryptamine may be due to downregulation of 4-aminopyridine-sensitive potassium channels.

Characterization of agonist-induced vasoconstriction in mouse pulmonary artery

“…That said, the crux of our study rests on the vasoreactivity of mouse PA rings to different stimuli. Our findings suggest that the mouse PA bears similar electropharmacological mechanical properties to PA rings from rats (7,13,22,42,44,46,54,60,61,68) and humans (24,55). For example, membrane depolarization by high K ϩ caused a slow and sustained contraction in mouse PA rings; the kinetics are very similar to that observed in rat PA (1,54,66,68) and human (55) PA rings.…”

Voltage-gated K+ channels at an early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets

“…It was reported over 20 years ago that PASMC isolated from main pulmonary arteries of adult rats exposed to variable lengths of in vivo hypoxia were depolarized within the first 7 days of hypoxic exposure and remained depolarized for up to 60 days of hypoxic exposure (37). More recent studies have found that after 1-4 wk of in vivo chronic hypoxia PASMC in 200-to 1,200-um-diameter pulmonary arteries and cells isolated from these arteries of adult rats were depolarized (10,27,30,34). Even more recently, it was shown that PASMC isolated from resistance pulmonary arteries exposed to moderate levels of hypoxia for only 24 h were depolarized (15).…”

“…Although we are not aware of any other studies using newborn animals, others have examined the effect of chronic hypoxia on K ϩ channels in the pulmonary circulation of adult animals. Exposure of adult rats to 1-4 wk of in vivo chronic hypoxia augmented the sensitivity to and the magnitude of 4-AP-induced constriction in both first-branch intrapulmonary arteries (10,22) and 300-mdiameter pulmonary arteries (27). Isolated, perfused lungs of control rats and rats exposed to hypoxia for 2 days or 3 wk (30) showed similar constrictor responses to 4-AP.…”

Contribution of glibenclamide-sensitive, ATP-dependent K+ channel activation to acetophenone analogues-mediated in vitro pulmonary artery relaxation of rat

“…The Animal Experimentation Ethics Committee of The Chinese University of Hong Kong (HKSAR, PR of China) approved experiments performed in this study (approval no: 00/017/MIS). Experimental procedures involved in isometric tension measurement of isolated pulmonary artery (1 mm in length, 1st intra-lobar branch, O.D.¨800 Am) (Lau et al, 2003) (gassed with 16% O 2 /6% CO 2 balanced with N 2 , pO 2 100 mmHg) (MacLean et al, 1996) (resting tension: 2.0 T 0.1 mN, corresponded to a transmural pressure of¨15 mmHg) have been described previously (Doggrell et al, 1999;Thomas and Wanstall, 2003). Fat and connective tissues were carefully removed under the dissecting microscope.…”