Cardiovascular effects of intravenous colforsin in normal and acute respiratory acidosis canine models: a dose-response study

In acidosis, catecholamines are attenuated and higher doses are often required to improve cardiovascular function. Colforsin activates adenylate cyclase in cardiomyocytes without mediating the beta adrenoceptor. In this study, six beagles were administered either colforsin or dobutamine four times during eucapnia (partial pressure of arterial carbon dioxide 35-40 mm Hg; normal) and hypercapnia (ibid 90-110 mm Hg; acidosis) conditions. The latter was induced by carbon dioxide inhalation. Anesthesia was induced with propofol and maintained with isoflurane. Cardiovascular function was measured by thermodilution and a Swan-Ganz catheter. Cardiac output, heart rate, and systemic vascular resistance were determined at baseline and 60 min after 0.3 g/kg/min (low), 0.6 g/kg/min (middle), and 1.2 g/kg/min (high) colforsin administration. The median pH was 7.38 [range 7.34-7.42] and 7.04 [range 7.01-7.08] at baseline in the Normal and Acidosis conditions, respectively. Endogenous adrenaline and noradrenaline levels at baseline were significantly (P < 0.05) higher in the Acidosis than in the Normal condition. Colforsin induced cardiovascular effects similar to those caused by dobutamine. Colforsin increased cardiac output in the Normal condition (baseline: 198.8 mL/kg/min [range 119.6-240.9], low: 210.8 mL/kg/min [range 171.9-362.6], middle: 313.8 mL/kg/min [range 231.2-473.2], high: 441.4 mL/kg/min [range 373.9-509.3]; P < 0.001) and the Acidosis condition (baseline: 285.0 mL/kg/min [range 195.9-355.0], low: 297.4 mL/kg/min [213.3-340.6], middle: 336.3 mL/kg/min [291.3-414.5], high: 366.7 mL/kg/min [339.7-455.7] ml/kg/min; P < 0.001). Colforsin significantly increased heart rate (P < 0.05 in both conditions) and decreased systemic vascular resistance (P < 0.05 in both conditions) compared to values at baseline. Systemic vascular resistance was lower in the Acidosis than in the Normal condition (P < 0.001). Dobutamine increased pulmonary artery pressure, whereas colforsin did not. Colforsin offsets the effects of endogenous catecholamines and may not increase cardiac output during hypercapnia.