Figure 1.
Models of pulmonary hypertension.
Hemodynamic recordings of hypoxia and thromboxane pulmonary hypertension models. While the hypoxia resulted in a decrease in arterial pressure and the intravenous infusion of thromboxane resulted in an increase, both methods were able to increase pulmonary pressure with minor effects on pulmonary blood flow.
Table 1.
Effects of Hypoxia and Subsequent CK-2019165 or Nitroprusside.
Table 2.
Effects of Thromboxane and Subsequent CK-2019165 or Nitroprusside in Anesthetized Pigs.
Figure 2.
Effects of intravenous CK-165 on hypoxia induced pulmonary hypertension.
The efficacy of intravenous CK-165 (4 mg/kg) and nitroprusside (2 µg/kg) were examined and compared in the porcine hypoxia model of pulmonary hypertension. All changes were plotted as percent change from baseline. The relatively longer half life, the more gradual and greater effects on mean pulmonary vascular resistance and blood flow were noted. (* p<0.05, ** p<0.01 CK-165 vs. nitroprusside).
Figure 3.
Effects of nebulized CK-165 on hypoxia induced pulmonary hypertension.
The efficacy of nebulized CK-165 (4 mg/kg) and nitroprusside (2 µg/kg) were examined and compared in the porcine hypoxia model of pulmonary hypertension. All changes were plotted as percent change from baseline. When delivered continuously, similar effect profiles are observed between CK-165 and nitroprusside.
Figure 4.
Effects of intravenous CK-165 on thromboxane induced pulmonary hypertension.
The efficacy of intravenous CK-165 (4 mg/kg) and nitroprusside (2 µg/kg) were examined and compared in the porcine thromboxane model of pulmonary hypertension. All changes were plotted as percent change from baseline. The relatively longer half life, the more gradual and greater effects on mean arterial pressure, mean pulmonary vascular resistance and blood flow were noted. (* p<0.05, ** p<0.01 CK-165 vs. nitroprusside).
Figure 5.
Dose response and pharmacodynamics of CK-165 in rats with U46619 induced pulmonary hypertension.
CK-165 decreased RVSP rapidly after nebulization at both 5 mg/kg and 30 mg/kg by 20.4±8.6 and 58.2±6.9% at 6 minutes, respectively (p<0.01 compared with baseline). The maximum decrease in RVSP, Emax, observed with CK-165 (75±7.53%) is similar to that seen with the prostacyclin analog, treprostinil (58±8.09%) and the phosphodiesterase 5 inhibitor, sildenafil (61±7.65%).
Figure 6.
The effect of CK-165 and sildenafil in rats with monocrotaline-induced pulmonary hypertension.
CK-165 decreased RSVP following intratracheal nebulization of 30 mg/kg in rats with monocrotaline induced pulmonary artery hypertension by 18.0±3.8% (p<0.05) when compared with vehicle treated group. The decrease is similar to that in monocrotaline rats treated with 100 mg/kg/day sildenafil (20.3±4.5%) for 7 days and treatment with CK-165 does not appear to have additive effects when co-administered with sildenafil.
Figure 7.
Determination of EC50 for CK-2018571 in pulmonary artery tissue rings.
CK-2018571 inhibits phenylephrine-induced pulmonary artery contraction in isolated tissue rings from naïve and monocrotaline-treated rats. Pulmonary artery rings were pre-contracted with 1 µM phenylephrine and isometric tension was recorded in the presence of increasing concentrations of CK-2018571. CK-2018571 elicited relaxation in tissues from naïve rats with pEC50 = 6.08±0.03, and in tissues from monocrotaline-treated rats with pEC50 = 6.08±0.10.