Effect of Bay 41‐2272 in the Pulmonary Hypertension Induced by Heparin–protamine Complex in Anaesthetized Dogs

Abstract

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.

Stimulators and Activators of Soluble Guanylate Cyclase: Review and Potential Therapeutic Indications

“…These observations are comparable to the findings in the anesthetized dog following administration of another sGC activator, BAY 41-2272 [123]. These findings suggest that sGC activators can increase sGC enzyme activity in vascular beds from different species [123, 157]. …”

“…In the intact chest rat, intravenous administration of the sGC activator, BAY 60-2770, produced dose-related decreases in systemic arterial pressure, increases in cardiac output, and decreases in systemic vascular resistance, and the cardiovascular responses were slow in onset and long in duration [157]. These observations are comparable to the findings in the anesthetized dog following administration of another sGC activator, BAY 41-2272 [123]. These findings suggest that sGC activators can increase sGC enzyme activity in vascular beds from different species [123, 157].…”

Increased adhesive properties of neutrophils in sickle cell disease may be reversed by pharmacological nitric oxide donation

“…Guanylate cyclase inhibitors, such as BAY 41-2272, have been successfully used to treat animal models of cardiovascular disease, pulmonary hypertension and inflammation. [23][24][25] Alternatively, drugs that have a more cell-specific effect, such as inhibitors of phosphodiesterases (PDE) may prove more effective in specifically reversing altered SCD neutrophil function. For example, sildenafil, a PDE5-specific inhibitor, is being tested clinically in SCD patients with pulmonary hypertension 26 and should it be found that this or any other PDE is expressed in leukocytes, such PDE inhibitors may also have the potential for abrogating altered SCD neutrophil adhesion.…”

Pulmonary and systemic vasodilator responses to the soluble guanylyl cyclase stimulator, BAY 41-8543, are modulated by nitric oxide

“…The pyrazolopyridine compound BAY 41-8543 is a NO-independent stimulator of sGC that has been shown to reduce systemic and pulmonary arterial pressure and relax isolated vessels from a variety of organ systems (33,37,38). BAY 41-2272 is closely related to BAY 41-8543, and this sGC stimulator has been shown to have significant pulmonary vasodilator activity in a variety of species (9,10,13,15,34,37). BAY 41-2272 has been shown to reduce right ventricular hypertrophy and pulmonary vascular remodeling in a chronic hypoxia-induced model of pulmonary hypertension (8).…”