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

Abstract

In acidosis, catecholamines are attenuated, and higher doses are often required to improve cardiovascular function. Colforsin activates adenylate cyclase in cardiomyocytes without beta-adrenoceptor. Here, six beagles were administered 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 CO 2 inhalation. Anesthesia was induced with propofol and maintained with isoflurane. Cardiovascular function was measured by thermodilution and a Swan-Ganz catheter at baseline and 60 min after 0.3 μg/kg/min (low), 0.6 μg/kg/min (middle), and 1.2 μg/kg/min (high) colforsin administration. The median pH was 7.38 [range 7.33–7.42] and 7.01 [range 6.96–7.08] 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: 3.9 ± 0.2 L/kg/m 2 [mean ± standard error], low: 5.2 ± 0.4 L/kg/min 2 , middle: 7.0 ± 0.4 L/kg/m 2 , high: 9.4 ± 0.2 L/kg/m 2 ; P < 0.001) and Acidosis condition (baseline: 6.1 ± 0.3 L/kg/m 2 , low: 6.2 ± 0.2 L/kg/m 2 , middle: 7.2 ± 0.2 L/kg/m 2 , high: 8.3 ± 0.2 L/kg/m 2 ; P < 0.001). Colforsin significantly increased heart rate and decreased systemic vascular resistance compared to values at baseline. Both drugs increased pulmonary artery pressure, but colforsin (high: 13.3 ± 0.6 mmHg in Normal and 20.1 ± 0.2 mmHg in Acidosis) may have lower clinical impact on the pulmonary artery than dobutamine (high: 19.7 ± 0.6 in Normal and 26.7 ± 0.5 in Acidosis). Interaction between both drugs and experimental conditions was observed in terms of cardiovascular function, which were similarly attenuated with colforsin and dobutamine under acute respiratory acidosis.

Cardiorespiratory effects of intramuscular alfaxalone combined with low-dose medetomidine and butorphanol in dogs anesthetized with sevoflurane

“…Hypoventilation occurred for 10–20 minutes duration after MBA administration. A rapid increase in PaCO 2 likely stimulates catecholamine secretion and enhances cardiovascular function ( Walley et al , 1990 ; Itami et al , 2019 , 2022 ). Although the catecholamine concentration was not measured in this study, the improvement in CO early after MBA administration is potentially due to hypercapnia.…”

“…Although the catecholamine concentration was not measured in this study, the improvement in CO early after MBA administration is potentially due to hypercapnia. Furthermore, hypercapnia has vasodilatory effects ( Walley et al , 1990 , Itami et al , 2019 , 2022 ). Decreased systemic vascular resistance is conceivably associated with increased stroke volume, which, in turn, is associated with increased CO.…”

Use of a gum elastic bougie in a cat with severe upper airway stenosis

“…Hypercapnia is defined as a partial pressure of carbon dioxide in arterial blood (PaCO 2 ) or PetCO 2 >55 mmHg ( Gaynor et al , 1999 ). Hypercapnia is caused by many factors, including airway obstruction ( Haskins, 2015 ), and persistent hypercapnia causes respiratory acidosis and increased intracranial pressure ( Itami et al , 2019 ). In addition, hypercapnia and hypoxemia cause reductions in cardiac output and blood pressure, delayed recovery, and inadequate tissue perfusion ( McDonell and Kerr, 2015 ).…”

Adenylyl cyclase isoforms 5 and 6 in the cardiovascular system: complex regulation and divergent roles

“…The strong coronary vasodilator function of colforsin may therefore be applicable for the treatment of heart disease where coronary blood flow is limited and βAR-dependent signaling is also downregulated (Yoneyama et al, 2002). In a model of canine respiratory acidosis causing cardiac dysfunction, colforsin increased cardiac rate and decreased systemic vascular resistance to the same degree as did dobutamine, without attenuation by acidosis (Itami et al, 2019). Colforsin has also demonstrated pulmonary artery vasodilation (Yokochi et al, 2010), which is mediated largely through AC6 rather than AC5 (Sikarwar et al, 2018), indicating that colforsin may not be AC5-selective (Jaggupilli FIGURE 10 Possible modification sites on the parent compound forskolin molecule, for the design of selective AC5 or AC6 activators.…”