Adrenergic Angina Pectoris

Introduction

     Angina pectoris is a pain in the chest, usually attendant on exercise. It is widely thought that stable Angina pectoris is a result of Ischaemic heart disease [1]. For this there are said to be a number of 'risk' or pre-disposing factors [2]:

• increasing age, 
• smoking, 
• high-fat diet, 
• lack of exercise, 
• overweight, 
• excessive alcohol consumption, 
• (other conditions, including high blood pressure, high cholesterol and diabetes, a family history of CVD, being of south Asian, African or African-Caribbean descent.)

     I shall assume that the rational man will neither smoke nor eat nor drink too much. Clearly, you cannot do anything about your increasing age, or your ethnic or familial inheritance. But I think it is highly interesting to know more about how all these factors impinge on the heart and its coronary blood supply (i.e. oxygen supply.)
    In my own case I was able to get my blood pressure and cholesterol values into the 'healthy' range by taking a low does of a statin for a few months (supplemented with CoQ to offset one of the deleterious effects of inhibiting HMGCoA synthase. [See my blog post]), and by eschewing completely the double-cream I liked to pour over my dessert. In addition I tweaked my consumption of alcohol down by 20%, and exercise up by 20% (aiming at ≧60 minutes walking per day, and running up and down stairs when a trip was required). As for 'long acting nitrates', after reading up the literature I never touched the packet of tablets I had been prescribed,  for it was clear that they cause desensitisation, and gratuitously mess with your glutathione (and all -SH groups in general). I used to carry a little vial of 'short acting' glyceryl trinitrate (GTN) tablets [see blog post 'Angina and GTN'] (as my father did, to his dying day aged 86); but I now find I can leave them behind without regret. The 'low dose aspirin' seemed counter-indicated in my case as there is no evidence of clotting [3]. 
     That I was prescribed a synthetic β1-blocker (Bisoprolol) interested me. What does adrenaline or noradrenaline have to do with blood flow?  They are the "fight or flight" hormones after all? As I am a minimalist when it comes to interventions, and because I had discontinued all the other pills, I first asked the doctor to halve the dose then quartered it by snapping the tiny pills in half, then stopped altogether my daily β-blocker. I was intent on lowering my adrenergic stimulation by more natural means, if at all possible.
      On the other hand, I had clear evidence that mental stress could cause me the ischaemic pain of angina in the absence of increased exercise-related oxygen demand. Resentment, aprehension, and fear all caused ischaemic chest pain even when I was physically at rest. Once, when playing the fiddle in a pub I realised that I had forgotten the second half of the tune. Suddenly, the familiar tightness in the chest; and I had to stop playing and sit down. Of course:  "the fight-or-flight response"! So, I have to look into mental stress as a cause (or even the cause) of my angina; for I can sometimes walk energetically without trouble from my heart.
     First, let us note that there are two rather similar adrenergic chemicals, adrenaline and noradrenaline; the former released into the bloodstream by the adrenal glands (and thus a 'hormone'), the latter released by nerves (and thus a 'neurotransmitter'). Both are catecholamines, both are referred to as 'adrenergic', and their activieties greatly overlap. 
    Next, let us note that there is an array of 9 (or more) closely related adrenergic receptors, all being 7-helix transmembrane proteins of the rhodopsin family, and GTP-binding-protein-linked receptors. They were divided into two basic types by Ahlquist in 1948 on the basis of affinity (alpha and beta). However, since then, a combination of gene sequencing and pharmacological analysis in transfected cells has led to the distinction of three main types: α1, α2, and β, with the identification  of  three  subtypes for each of them [4]. See table.

TABLE

Name Action Typical site

α1A       ↑Ca2+Ch artery
α1B        IP3/DAG heart
α1C        IP3/DAG (Not human)
α2A       ↓cAMP, ↑K+Ch,↓Ca2+Ch platlet, brain
α2B       ↓cAMP,↓Ca2+Ch
α2C       ↓cAMP, spleen
β1       ↑cAMP heart
β2       ↑cAMP lung
β3       ↑cAMP fat

Experiments using Endogenous Catecholamines and Pharmacological Agents.

     (1) Plunging the hand and wrist into icy water for 90 s (the 'cold pressor test') causes release of both adrenaline and noradrenaline. In healthy subjects, blood pressure rises markedly during immersion, but falls as steadily afterwards.   [5]
    (2)  In similar experiments, Monahan et al. found that, besides the increase in blood pressure, the catecholamines released by the icy-water caused pronounced vasodilatation in healthy young men (to supply the extra oxygen needed by the heart muscle), but that this effect was lost with age. Moreover, in young men, blocking α- and β-adrenergic responses mimics the effect of ageing, suggesting a critical role for an adrenergic mechanism in this ageing effect. [6] 
    (3) Nabel et al. (1988) applied the cold pressor test to healthy controls and patients with varying degrees of atherotic damage; group I healthy, group II mildly sclerotic with some smooth vessels and some damaged vessels, group III heavily sclerotic.  The catecholamine release produced vasodilation in group I. In group II the smooth segments dilated, while the damaged segments contracted. In group III only 2 smooth segments were found, but they dilated. The authors speculate that this constricting effect may represent 'altered catecholamine sensitivity' and/or a defect in 'endothelial vasodilator function'. [7]. 
    (4)  Heusch et al. (2000) review a number of indication that there is α-adrenergic coronary constriction whether evoked by cold water, exercise or emotional stress (a public speaking ordeal). Such α-adrenergic coronary constriction, augmented  by coronary endothelial dysfunction and atherosclerosis, is "powerful enough to induce myocardial ischaemia and limit myocardial function". [8]. 
    (5)  Recent studies indicate a genetic determination of α2-adrenergic coronary constriction. Apparently, a C to T polymorphism at nucleotide 825 in the gene coding for the Gβ3 subunit of G protein leads to shortening the protein by 41 amino acids and is associated with enhanced signal transduction, and hypertension, and also with pronounced sensitivity to α2-adrenergic coronary constriction.[9] Such individuals comprise 30% in caucasian populations [10].
   (6)  Experimentally, it is found that β-blockers blunt or ameliorate the pain of stable angina in 70% of cases. But not 100%.  [11]

Conclusions

     It is tempting to think that one's inherited genotype is at least partly to blame for one's angina, and that it is not entirely due to idleness and over-eating. My father had very similar angina at a similar age, and his mother also; both were lean and active people. 
     I am familiar with the autonomic nervous system going wonky in older people [12], such as sluggishness in the auto-regulation of cerebral blood pressure, and the the intense desire to urinate that leaves you as soon as you start walking. However, it seems possible that, when it comes to adrenergic effects on cardiovascular function, ageing might always mean 'sclerotic damage to endothelium', when you have the means to look for it. 
     Note [my post] that the endothelium seems to be the site of NO release from endogenous arginine, and that 'Heusch et al invoked an 'endothelial vasodilator function'. Is it the endogenous production of NO that is damaged in atherosclerosis?
     Note also [my post] that GTN seems to work by cGMP rather than cAMP, It is also the case that NO from GTN can (usually) relax coronaries even when catecholamines cease to cause coronary dilation and cause only contraction?  

References:

1. https://www.heart.org/en/health-topics/heart-attack/angina-chest-pain/angina-pectoris-stable-angina 
2. https://www.nhs.uk/conditions/atherosclerosis/
3. https://www.nhs.uk/news/medication/aspirin-bleeding-risk-balances-out-lower-heart-attack-risk-worried-well/
4. Strosberg, A.D. (1993) Protein Science, 2, 1198-1209.
5. Silverthorn, DU, and J. Michael (2013) "Cold stress and the cold pressor test"; Advances in Physiology Education Vol. 37, 93-96.
6. Monahan, KD., RP Feehan, et al. (2013) J Physiol. 2013; 591: 2937–2947.
7. Nabel EG, Ganz P, et al. (1988) Circulation, 77, 43-52
8. Heusch, G. et al. Circulation. 2000;101:689–694
9. Circ Res..1999; 85:965–969.
10. C. K. Naber, R. Erbel, W. Siffert.  Current Genomics (2003) Vol. 4, 337-342.
11. Elliott, WC., JM. Stone, (1969) Progress in Cardiovascular Diseases Vol. 12, 83-98.
12. Parashar, R., M. Amiret al. (2016) J Clin Diagn Res. 2016: CC11–CC15. "Age Related Changes in Autonomic Functions"

(Please comment direct to Cawstein@gmail.com)

Angina pectoris and Glyceryl Trinitrate

Introduction

     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. 

References:
[1] https://www.heart.org/en/health-topics/heart-attack/angina-chest-pain/angina-pectoris-stable-angina
[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.
[4] https://www.wikidoc.org/index.php/Walk_through_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.
[7] https://www.nobelprize.org/prizes/medicine/1998/summary/

[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.