Wednesday, 24 June 2020

Angina pectoris and Glyceryl Trinitrate


     Angina pectoris is a pain in the chest, usually attendant on exercise. It is widely said that stable Angina pectoris is a result of Ischaemic heart disease [1], itself a result of excess ingestion of cholesterol, causing reduced flow of oxygenated blood in the coronary arteries (which form a 'crown-shaped' network round the heart).
     If you go to your doctor with chest pain in the UK (currently, i.e. 2017-2020) you will probably be investigated by a nurse (rather than a General Practitioner or cardiac surgeon). If you show curiosity about how bad your condition is, you will be told about various dangerous-sounding procedures that can examine how blocked your coronary arteries are, and where the blockage lies.  If you suggest improving blood-flow by lowering your intake of cholersterol the nurse pulls a long face, and you go away with a prescription for Statins (see Statins), and the impression that only a surgical reaming to scrape away the greasy plaques will restore your cardiac health. 
     However, because there are so many variables, it is very difficult for a nurse to say anything certain about your particular case, though she may be well versed in the average case. Your cholesterol may come down simply with diet. You may be among the 30% of caucasians who have a truncated form of the β subunit of the G-protein that confers hypersensitivity to adrenergic-constriction of coronary arteries [2]. Likewise, you may be a carrier of a polymorphism in the IL-6 gene. (It seems that patients carrying the 174C allele showed a 2-fold increased risk for angina pectoris (P = .036) over those carrying the 174G allele [3].)
     In August 2017 a specialist cardiac nurse confidently diagnosed my chest pain  as 'stable Angina pectoris' using a sloping treadmill while I was wired to an ecg-machine. My first clue that it was not exercise alone that caused my chest pain was my experience of what is called "walk through Angina" [4]; slowing my walking at the onset of pain I often found the pain lessening, even when I returned to my normal speed.  This observation is widely known in the literature, but inadequately explained. 
     Next, my interest was taken by the almost miraculous effect of the little pills containing 0.3 mg of glyceryl trinitrate (GTN), known since 1879 [5] to alleviate the exercise-induced chest pain known as stable angina pectoris. GTN was known to cause muscle relaxation, but its precise mode of action was not known for over a century; did it dilate the coronaries (allowing improved oxygenation of the ventricle), or did it dilate the systemic arteries (thus lessening the work-load and oxygen-requirement of the heart); or both? What did seem very unlikely is that GTN could unblock coronary arteries blocked by fatty plaques. And indeed, it is occasionally reported that GTN is without beneficial effect in such cases [6].
     It is now known that glyceryl trinitrate is broken down by enzymes in the body to release NO (the nitric oxide free-radical). Since 1986, we have learned that NO  is a wide-ranging physiological regulator of extraordinary simplicity, mobility, and short half-life [7]. It binds to the haem group in guanyl cyclase increasing its production of cyclic GMP (cGMP) with consequent smooth-muscle relaxation. GTN seems the perfect drug, as it is extremely cheap, fast acting in tiny doses and its effects seem more-or-less confined to this relief of ischaemic chest pain. With GTN pills in my pocket I did not feel my angina was a problem, and I began to wondered if stable angina is little more than a failure of the ageing body to produce sufficient endogenous NO. 

Mechanisms involved in the actions of nitrates

     After finding that NO relaxes smooth muscle, it was assumed that the main effect of NO on angina was in lowering the work that the ventricle had to perform against peripheral resistance [8], but it is now clear that coronary arteries are also relaxed [9]; so perhaps both more oxygen available, and less needed. 
    It seems that NO is largely generated (from arginine) by enzymes in the endothelium of blood vessels. It binds to a haem group of guanyl cyclase, stimulating that to produce more cyclic GMP (cGMP). That in turn stimulates protein kinase G (PKG) which phosphorylates (on serine or threonine residues) a number of protein targets depending on cell type. PKGs (of which there are several) are big players in the regulation of cytoplasmic calcium ion concentration (Ca2+), and it is here that the striking effects of GTN on the heart are evoked, for activated PKGs inhibit L-type Ca-channels and open Ca-dependent K+ channels, causing muscle relaxation. 
     Aspects of this NO-activated pathway parallel, and may overlap with, that of the the so-called adrenergic systems, i.e. the sympathetic nervous and hormonal systems that are known to cause large and rapid effects on blood flow.  Thus, there is evidence that catecholamines (adrenaline and noradrenaline) raise blood pressure by cAMP rather than cGMP [10]. Further aspects of the adrenergic control of blood flow will be considered in the next section [11].
    I end this section by concluding that NO from the tiny GTN pill, relaxes coronary and peripheral vessels by a mechanism involving cGMP and cytoplasmic Ca2+,  which is similar to, but not identical to, the mechanisms involved in adrenergic control. 

[2] Circ Res..1999; 85:965–969.
[3]  Fernanda Amorim, Bianca P Campagnaro,  Clarissa L Tonini, Silvana S Meyrelles. Angiology 62:549-53 (2011) Association of Interleukin-6 Gene Polymorphism With Angina Pectoris.
[5] William E Boden, Santosh K Padala, Katherine P Cabral, Ivo R Buschmann, and Mandeep S Sidhu; Drug Des Devel Ther. 2015; 9: 4793–4805.
[6] Bernstein, L., Friesinger, G. C., Lichtlen, P. R., and Ross, R. S. (1966). The effect of nitroglycerin on the systemic and coronary circulation in man and dogs. Myocardial blood flow measured with xenon133. Circulation, 33, 107.
[8] Kawakami H, Sumimoto T, Hamada M, Mukai M, Shigematsu Y, Matsuoka H, Abe M, Hiwada K.; Angiology. (1995), 46:151-6.; "Acute effect of glyceryl trinitrate on systolic blood pressure and other hemodynamic variables.".
[9] Nabel EG, Ganz P, et al. (1988) Circulation, 77, 43-52
[10] Strosberg, A.D. (1993) Protein Science, 2, 1198-1209., Circulation. (2018); 138: 1974–87.
[11] The next post in this blog.

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