Pulmonary hypertension secondary to left ventricular dysfunction: the role of nitric oxide and endothelin-1 in the control of pulmonary vascular tone

1 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 mumol.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. 2 Eight weeks after coronary artery ligation or sham operation, rabbits demonstrated increased mean pulmonary arterial pressure (PAP) accompanied by right ventricular hypertrophy. 3 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). 4 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. 5 The non-selective ET-I 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. 6 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.