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Pulmonary hypertension secondary to left ventricular dysfunction: the role of nitric oxide and endothelin‐1 in the control of pulmonary vascular tone
Author(s) -
Deuchar Graeme A,
Docherty Andrew,
MacLean Margaret R,
Hicks Martin N
Publication year - 2002
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704529
Subject(s) - pulmonary hypertension , medicine , right ventricular hypertrophy , pulmonary artery , nitric oxide , endothelin receptor , basal (medicine) , endothelin 1 , endocrinology , nitric oxide synthase , ventricular pressure , cardiology , blood pressure , receptor , insulin
Using an in vivo model of pulmonary hypertension (PHT) secondary to left ventricular dysfunction (LVD), the pulmonary arterial response to the nitric oxide synthase (NOS) blocker L ‐NAME (30 μmol.min −1 i.v.) and the subsequent responses to cumulatively administered endothelin‐1 (ET‐1) (0.001 – 4 nmol.kg −1 i.v.) or big ET‐1 (0.1 – 2.0 nmol.kg −1 i.v.) were studied. Additionally, the effect of the non‐selective ET‐1 receptor antagonist, SB209670, was investigated. Eight weeks after coronary artery ligation or sham operation, rabbits demonstrated increased mean pulmonary arterial pressure (PAP) accompanied by right ventricular hypertrophy. Blockade of NOS caused a greater increase in basal PAP (increased by 7.7±1.1 mmHg c.f . 3.8±1.0 mmHg in controls, P <0.05) and uncovered a greater pulmonary pressor response to exogenous ET‐1 in rabbits with PHT (increased by 10.2±2.3 mmHg c.f . 4.9±1.0 mmHg in controls, P <0.05). Big ET‐1 evoked a pulmonary pressor effect, in both groups of rabbits, that was increased following blockade of NOS and was more potent in rabbits with PHT. The non‐selective ET‐1 receptor antagonist, SB209670, reduced basal PAP (from 16.9 mmHg to 15.9 mmHg, P <0.05) in rabbits with PHT and blocked the response to ET‐1 in the presence of L ‐NAME. In conclusion, the results demonstrate that basal NO activity masks a pulmonary pressor response to exogenously administered ET‐1. An increased responsiveness to ET‐1 was shown in the pulmonary arterial bed of rabbits with PHT secondary to LVD, implicating a pathophysiological role for ET‐1 in this model.British Journal of Pharmacology (2002) 135 , 1060–1068; doi: 10.1038/sj.bjp.0704529