Abstract
Ischaemic heart disease is a leading cause of mortality globally, placing a huge strain on health care systems. Treatment can involve percutaneous coronary interventions or in severe cases, revascularisation using surgical procedures, such as coronary artery bypass grafting. Coronary bypass surgical procedures can often require the heart to be placed under ischaemic arrest conditions for the duration of the surgical revascularisation. Prolonged ischaemia, particularly in cases involving multi-vessel bypass, can lead to serious post-surgical complications, such as a decrease in contractile function, due to ischaemic injury to the myocardium. To minimise the ischaemic duration, the myocardium can be reperfused periodically throughout the surgery to allow the return of blood flow. However, this reperfusion can also exacerbate the oxidative stress damage, causing ischaemic reperfusion injury, which results in ventricular dysfunction and low cardiac output syndrome. In order to improve cardiac output, positive inotropic agents are used to increase the force of contraction and support ventricular function. Currently used therapeutic agents, such as catecholamines, however, cause an increased risk of tachycardia and arrhythmias as well as increase the myocardial demand for oxygen, which places further strain on the injured myocardium exacerbating the injury. Pharmacological studies have shown carbon monoxide to have beneficial effects, including positive inotropic properties, and is currently being investigated as a potential therapeutic agent.
This study investigates the direct inotropic effect of the organic carbon monoxide donor, oCOm-21, in non-vascularised papillary and atrial cardiac preparations. The results showed that oCOm-21 (0.3 – 10 µM) produced a concentration dependent positive inotropic effect in the absence of the increased vascular perfusion. Incubation with the L and T type Ca2+ channel blocker, diltiazem, appeared to inhibit the positive inotropic response to oCOm-21. The results also suggest the involvement of Ca2+ sensitive K+ channels (BKCa) as iberiotoxin reduced the inotropic response to oCOm-21. This positive inotropic response to oCOm-21 also appeared to be inhibited by L-NAME administration therefore it is likely to involve the production of NO from NOS. However, ODQ did not have a significant impact on the direct increase in the force of contraction therefore does not involve sGC activation of cGMP. This study found oCOm-21 had no significant chronotropic effect and did not increase the risk of arrhythmia development. The findings of these studies support the therapeutic use of low dose carbon monoxide as a positive inotropic agent for prophylactic use during cardiac surgery.