Can hypoinsulinemia induced by calcium channel blockers be associated with cardiac events?

Among antihypertensive agents, calcium channel blockers (CCBs) are considered as one of the most common medicines. CCBs prevent the opening of voltage-gated calcium channels and reduce the entrance of calcium into the cells during the second phase of the action potential. ¹ Voltage-gated calcium channels are found in myocytes, smooth muscles, and β-cells in the pancreas. ¹

CCBs are bound to the α1 subunit available on the L-type calcium channel to exert their role. There are different binding sites of α1c subunit for various types of CCBs. ²

Muscle concentration can occur by a rise in the intracellular concentration of calcium, thereby triggering a cascade, which is observed in cardiac myocytes or smooth muscle cells. ²

A fall in peripheral vascular resistance, depression of conduction in the atrioventricular node, and a reduction in myocardial contractility have been reported to occur by Verapamil and to a lesser extent by Diltiazem as a non-dihydropyridine. So, they compromise inotropy and chronotropy in myocardial tissues. Reduced inotropy is due to a lack of intracellular calcium within the cardiac myocytes. Eventually, the impaired conduction and impulse generation in the sinoatrial and atrioventricular nodes may lead to bradycardia or atrioventricular block. ³

As discussed above, CCBs poisoning may cause cardiovascular consequences or even cardiogenic shock. ⁴

It is generally believed that all cardiovascular consequences are due to the blockage of calcium channels in the heart. In this letter, it is discussed that whether blocking calcium channels in the pancreas is associated with cardiovascular consequences in CCBs poisoning.

CCBs via L-type CCBs in the pancreas have proved to inhibit insulin secretion effectively. ⁵ Theoretically, the lack of insulin in the circulation possibly induces inappropriate usage of carbohydrate by myocardium, hyperglycemia, and acidosis. ⁵ Note that CCB intoxication associated with hyperglycemia, especially with non-dihydropyridines, is correlated with the severity of poisoning. It has also been documented that there is an association between hypoglycemia induced by CCB poisoning and in-hospital deaths, temporary demand pacing, and administration of vasopressor requirements. ⁶ Hyperglycemia is known as a marker of this poisoning. It may help to differentiate CCBs poisoning from other similar intoxications, such as β-blockers or clonidine poisoning.

It seems that in CCBs poisoning, insulin release is significantly low, leading to a sudden and significant fall in insulin concentration in the blood and tissues as well. Meanwhile, CCB toxicity results in acute resistance to insulin.

These conditions are similar to type 1 diabetes; however, in type 1 or 2 diabetes, the process is far longer than CCBs poisoning. So, these circumstances may raise a question: Can lack of insulin induce cardiac events?

Several observations have suggested that the lack of insulin has a direct impact on cardiovascular function. ⁷ Insulin has a primary role in vascular and cardiac physiological functions. ⁷ In diabetes, insulin resistance disturbs endothelium-dependent vasodilation, mainly through a reduction in the nitric oxide (NO) bioavailability. ⁸ However, acute reduction of insulin can provoke the activation of nitric oxide synthases (iNOS) which temporarily increases NO levels and disturbs the balance between endothelin-1 (ET1) as a potent vasoconstrictor, leading to vasodilation and eventually hypotension. ⁹ Under physiological conditions, insulin binds to its receptor, including IRS and Shc, and activates PI3K-Akt and the Ras/Raf/MAP kinase pathways. The activation of the PI3K-Akt pathway results in stimulation of eNOS and NO production. On the other hand, the activation of the Ras/Raf/MAP kinase pathway causes ET1 formation. Although the production of NO and ET-1 through these pathways is impaired in acute insulin reduction, the sharp fall of insulin concentrations is accompanied usually by acute hyperglycemia stimulating iNOS enzyme and temporarily elevating NO levels. ¹⁰ Therefore, insulin reduction can act as an influential factor in CCBs-induced hypotension at the beginning of poisoning. ⁹

Additionally, insulin helps in redistribution of cardiac output to insulin-sensitive tissues. All these changes are more effective in insulin-sensitive subjects than in insulin-resistant individuals. Insulin resistance has also exhibited a significant decline in cardiac output, ejection fraction, and end-diastolic volume. Further, it has been shown that insulin increases the sympathetic nervous system (SNS) activity. ¹¹

The SNS may act as a possible link between the reduction in insulin and hypotension. Insulin is the primary mediator of drug-caused alterations in sympathetic activity. ¹² Insulin can stimulate the SNS and modulate metabolic rate. The link between acute lack of insulin and hypotension leads to this hypothesis that the decreased insulin-mediated sympathetic activation can result in diminished metabolic rate and disturbed balance of energy, and eventually lowered blood pressure. ¹¹

Theoretically, in a patient with CCB poisoning with hypoinsulinemia and shock, the myocardium might change its substrate preference from free fatty acids to glucose. ^13,14 Glucose uptake in the heart can negatively be affected by hypoinsulinemia, which may play a vital role in energy demand in such conditions. ¹⁵

Administration of insulin is interestingly one of the effective treatments in CCB poisoning. Although the mechanism of action involved in this method is still unknown, in CCB poisoning, the energy source for the myocardium is possibly switched from free fatty acids to carbohydrates. High-dose insulin euglycemic therapy has been found to improve the usage of carbohydrate and lactate clearance while also ameliorating the myocardial contractility in CCB poisoning. ⁵

Under normal physiological conditions, insulin binds to the insulin receptor and provokes a cascade of pathways, which eventually increases the uptake and metabolism of glucose in the myocardium. ¹⁶ However, glucose oxidation drops during the impairment of these insulin-mediated pathways. ¹⁶ This impairment of glucose oxidation is accompanied by elevated oxygen utilization in the myocardium, due to higher ATP consumption in glucose oxidation versus oxidation of fatty acids. It is also associated with diminished left ventricular mechanical efficiency. ¹⁷

Accordingly, this approach is supported by a significant hemodynamic improvement after insulin administration in CCB poisoning. We encourage researchers to evaluate cardiac effects of hypoinsulinemia in CCB poisoning.