I came across a question in Uworld. Question was easy. Although while reading explanation I came across the concept of ACh Provocative Test in Vasospastic Angina which I was unable to understand. Especially the part where Vagal tone causes Vasoconstriction. Not even with the explanation given by Uworld. Can you explain me a bit more clearly?
<div>M3 works through a Gq receptor when there is no endothelial NO released due to dysfunction. This means that it acts through increased intracellular calcium, leading to vasoconstriction. Some blood vessels in the body are innervated by parasympathetic cholinergic fibers (e.g., coronary vessels). These nerves release ACh, which binds to muscarinic receptors on the smooth muscle and/or endothelium. It has been shown in many arterial vessels that M3 receptors located on the vascular endothelium are coupled to the formation of nitric oxide (NO), which causes vasodilation; however, ACh causes smooth muscle contraction through a smooth muscle M3 receptors (coupled to Gq-proteins and increased IP3) and M2 receptors (coupled to Gi-proteins and decreased cAMP) when formation of NO is blocked. This latter finding has been used to assess coronary vascular dysfunction in humans in which NO production is diminished in diseased coronary arteries. In contrast to other arteries, cerebral arteries appear to have M5 muscarinic receptors that produce vasodilation in response to ACh. (Source: https://www.cvphysiology.com/Blood%20Pressure/BP011b)</div>
It’s still confusing me. ACh normally causes vasodilation via M3 receptors(activation of M3 on vascular endothelial cells causes increased synthesis of nitric oxide, which diffuses to adjacent vascular smooth muscle cells and causes their relaxation and vasodilation). So if there is dysfunction with NO production, then why does increased vagal tone cause Vasoconstriction. It should rather cause nothing. And even if it causes Vasoconstriction, then which receptors are involved now because M3 causes vasodilation.<div>
<div>That is a good insight on your part. It really is a poor explanation isn’t it? Here is my explanation:
§ Blood flow is a balance of forces. Sympathetic stimulation typically has an α<sub>1</sub> receptor effect greater than the β<sub>1</sub> receptor effect, causing vasoconstriction. Muscarinic stimulation will also cause vasoconstriction. ANS stimulation is balanced by the local endothelial cell release of NO, prostaglandins and other substances giving overall vasodilation with an increase in heart rate.
<div>§ With endothelial dysfunction, there is impaired release of local vasodilators, leading to unopposed α<sub>1</sub> receptor effect, or in this case muscarinic stimulation, resulting in vasoconstriction and angina.
<div>· This is the explanation of vasospastic angina (i.e. Prinzmetal angina), which is commonly associated with non-occlusive atherosclerosis.