Effect of endogenous mediators in secondary pulmonary hypertension : an in vitro study of pulmonary resistance arteries
The vasodilator response to acetylcholine (ACh) was investigated in the hypobaric chronic hypoxic rat model of secondary PHT. The maximum vasodilator response to ACh was significantly increased in the PRAs of chronic hypoxic rats when compared to normoxic control rats. The presence of hypoxia-induced PHT influenced the mediator profile responsible for the ACh-induced vasodilatation. In control rat PRAs, the ACh-induced vasodilator response appears to be mediated by endothelium-derived hyperpolarising factor (EDHF) via small and large Ca2+-activated K+ channels (SKCa and BKCa, respectively). In chronic hypoxic rat PRAs, the ACh-induced vasodilatation was mediated by nitric oxide (NO), prostacyclin (PGI2), and EDHF. However, the involvement of EDHF in the ACh-induced vasodilator response requires confirmation through the use of electrophysiology. The novel vasoconstrictor peptide human urotensin-II (hU-II) was shown to only elicit vasoconstriction in 30% of humans PRAs in the presence of the NO synthase (NOS) inhibitor, L-NAME. However, hU-II was revealed as a vasodilator of human pulmonary and systematic resistance arteries (SRAs) which was equipotent with another potent endogenous vasodilator peptide, adrenomedullin. The hU-II-induced vasodilatation was shown to be mediated by PGI2 and EDHF via BKCa and SKCa channels. Again, the involvement of EDHF in the hU-II-induced vasodilator response awaits confirmation through electrophysiological studies. The in vivo and in vitro response to endothelin-1 (ET-1) was investigated in the PRAs of patients with different severities of left ventricular dysfunction (LVD), using PRAs from patients undergoing lung resection for bronchial carcinoma as controls. The LVD patients groups were classified according to their ejection fraction, as assessed by echocardiographic assessment. The patients were divided into the following groups: an ejection fraction (EF) of >40% = good LVD; an EF of 30-40% = moderate LVD; and an EF of <30% = poor LVD. The in vivo experiments (which were not conducted by myself) showed a significant increase in the baseline measurement of pulmonary vascular resistance (PVR) between the good and poor groups, demonstrating the development of PHT as a consequence of severe LVD. The in vitro experiments revealed no significant increase in the potency of, or maximum contractile response to, ET-1 as the severity of LVD progressed.