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

Date Published: July 10, 2019

Publisher: Public Library of Science

Author(s): Takaharu Itami, Kiwamu Hanazono, Norihiko Oyama, Tadashi Sano, Kohei Makita, Kazuto Yamashita, Ferenc Gallyas.

http://doi.org/10.1371/journal.pone.0213414

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 CO2 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/m2 [mean ± standard error], low: 5.2 ± 0.4 L/kg/min2, middle: 7.0 ± 0.4 L/kg/m2, high: 9.4 ± 0.2 L/kg/m2; P < 0.001) and Acidosis condition (baseline: 6.1 ± 0.3 L/kg/m2, low: 6.2 ± 0.2 L/kg/m2, middle: 7.2 ± 0.2 L/kg/m2, high: 8.3 ± 0.2 L/kg/m2; 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.

Partial Text

Colforsin daropate is a forskolin derivative that directly activates adenylate cyclase in cardiomyocytes and vascular smooth muscle without mediating the catecholamine beta-adrenoceptor. As with dobutamine, a catecholamine beta agonist, colforsin increases cardiac contractility and reduces peripheral vascular resistance [1,2]. When forskolin was first discovered, it was poorly soluble in water, and its clinical application as an injection was limited. Colforsin was prepared as a water-soluble forskolin derivative and became available in 1999 [3].

To the best of our knowledge, this study is the first to evaluate the dose-dependent cardiovascular function of colforsin in dogs. Colforsin had a cardiovascular action similar to that of dobutamine. It increased CI and HR and decreased SVRI in a dose-dependent manner. Both drugs also increased pulmonary artery pressure, but colforsin may have a lower clinical impact on pulmonary artery than dobutamine. However, under acute respiratory acidosis, CI, HR, and SVRI were attenuated with both colforsin and dobutamine. 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.

The cardiovascular effects of colforsin and dobutamine are similar in healthy beagles under isoflurane anesthesia. In acute respiratory acidosis induced by carbon dioxide inhalation, the cardiovascular function was enhanced by endogenous catecholamine secretion. In addition, the rates of change in CI, HR, and SVRI caused by colforsin and dobutamine administration were attenuated. Therefore, it may be necessary to increase the colforsin and dobutamine doses under respiratory acidosis relative to those administered under the normal condition. Since colforsin had little effect on the mPAP, it may be more suitable as an inodilator than dobutamine in the treatment of diseases which increase the mPAP. Our next steps are to induce a pulmonary hypertension canine model, confirm the effects of colforsin on it, adapt colforsin administration for patients with pulmonary hypertension in our institution, and compare its efficacy with that of existing catecholamines.

 

Source:

http://doi.org/10.1371/journal.pone.0213414

 

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