Effect of BAY 41-2272 in the pulmonary hypertension induced by heparin-protamine complex in anaesthetized dogs

1. BAY 41-2272 is a potent activator of the nitric oxide-independent site of soluble guanylate cyclase and has been recently introduced as a new therapeutic agent to treat chronic pulmonary hypertension (PH) in neonatal sheep. Because the in vivo heparin-protamine interaction may lead to severe PH, the aim of the present study was to evaluate the effects of BAY 41-2272 in the PH induced by heparin-protamine interaction in anaesthetized dogs. 2. Sixteen male dogs (10 mongrel dogs and six Beagles) were anaesthetized and instrumented for acquisition of mean arterial blood pressure (MABP), mean pulmonary arterial pressure (MPAP), heart rate (HR), pulmonary capillary wedge pressure (PCWP), cardiac index (CI) and indices of systemic and pulmonary vascular resistance (ISVR and IPVR, respectively). Plasma cGMP levels and S(p)o(2) were evaluated. 3. Intravenous administration of heparin (500 IU/kg) followed 3 min later by protamine (10 mg/kg) caused marked PH, as evaluated by the increase in MPAP, PCWP and IPVR. This was accompanied by a significant fall in MABP and a transient increase in HR. Infusion of BAY 41-2272 (10 microg/kg per h, starting 10 min before heparin administration) augmented plasma cGMP levels and slightly and significantly increased HR and CI, without affecting the other cardiovascular parameters. The elevation in IPVR, MPAP and PCWP triggered by the heparin-protamine interaction was significantly reduced in animals exposed to BAY 41-2272. 4. In vehicle-treated dogs, the S(p)o(2) values decreased significantly at the peak of the PH and this was significantly attenuated by treatment with BAY 41-2272. In addition, BAY 41-2272 (10 micromol/L) had no effect on the activated partial thromboplastin time of citrated plasma after the addition of heparin-protamine. 5. In conclusion, BAY 41-2272 was effective in reducing canine PH induced in vivo by the heparin-protamine interaction, thus indicating its potential in the treatment of this type of disorder.