This chapter makes brave attempts to understand Section G5(iv) of the 2017 CICM Primary Syllabus, in which the Court of Examiners expects the exam candidate to "explain the humoral regulation of blood volume and flow". And of course when they say "flow", surely they also mean "pressure" and "resistance". An when they chose the term "humoral", these sagely elders were probably referring to the endocrine control mechanisms which maintain the extracellular fluid volume and vascular tone, rather than the effects of phlegm and yellow bile on the patient's activity and temperament. Restating this syllabus item in a way which facilitates understanding, this chapter will briefly cover the hormonal systems which influence the circulation.
Though some of these systems have been mentioned individually in the college exams (eg. the RAAS, in Question 6 from the second paper of 2011), thankfully nobody has so far been asked to put it all together into a summary statement. There are several systems involved and most people know them all very well by the end of their exam preparation, which makes questions like that very dangerous - without preparation, one may waste their time writing every possible thing they know. Clearly some sort of system is called for.
For lack of a better system:
Humoral systems which regulate volume and flow:
- These are regulatory feedback mechanisms which use circulating hormones to make ajustments to circulatory parameters
- The goal is to maintain a stable intravascular volume, stable blood pressure, stable osmolality and serum sodium content (as it influences extracellular fluid volume)
- These systems involve the nervous system usually as sensors, and use the endocrine system as effectors.
- End targets are vascular smooth muscle, renal tubule channels and behavioural triggers (eg. increased thirst)
- Stimulus: hypotension, hypovolemia, descending central stimuli (emotion)
- Sensor: various baroreceptors in the carotid sinus, aorta and atria
- Afferent: glossopharyngeal and vagus nerves, thalami, cerebral cortex
- Efferent: sympathetic nervous system (medulla, spinal cord, sympathetic ganglia)
- Effector: Adrenal chromaffin cells which secrete catecholamines into blood
- Effect: vasoconstriction of peripheral circulation, redistribution of blood flow
- Stimulus: hypotension, hypovolemia, salt depletion
- Sensor: arterial and renal baroreceptors
- Afferent: glossopharyngeal and vagus nerves, renal sensors (macula densa?)
- Efferent: enzymatic steps (renin, ACE) which produce angiotensin-II, which in turn mediates release of vasopressin and aldosterone
- Effectors: A2 receptors, adrenal glomerulosa, pituitary gland, renal tubule
- Effect: vasoconstriction of peripheral circulation, salt and water retention
- Stimulus: hypovolemia, sodium depletion, hyperkalemia
- Sensor: zona glomerulosa cells of the adrenal cortex
- Afferent: RAAS (via angiotensin), pituitary (via ACTH) and directly (potassium)
- Efferent: aldosterone secretion and binding to widespread intracellular receptors
- Effectors: Numerous targets, but mainly vessel smooth muscle and renal tubule
- Effect: vasoconstriction, salt and water retention, potassium excretion
- Stimulus: hypovolemia, hyperosmolarity
- Sensor: baroreceptors and hypothalamic osmoreceptors (OVLT)
- Afferent: fibres from nucleus of the solitary tract and from osmoreceptors
- Efferent: vasopressin secretion and binding to renal and vascular receptors
- Effectors: vessel smooth muscle and cortical collecting duct cells
- Effect: vasoconstriction, water retention, thirst
- Stimulus: cardiac chamber distension
- Sensor: cardiac chambers themselves (mechanoreceptor mechanism unknown)
- Efferent: ANP and BNP secretion, binding to numerous targets (mainly kidney)
- Effectors: Renal tubule, renal afferent arteriole, multiple others
- Effect: Increased renal blood flow, increased urinary water and sodium excretion
Other endocrine systems:
- Released in response to stress of various forms, including haemodynamic stress
- Act on the myocardium and peripheral circulation to increase catecholamine sensitivity
- Cross-reacti with mineralocorticoid receptors to increase water and sodium retention
- Thyroid hormone:
- Causes vasodilation and therefore reflex increase in cardiac output
- Increases blood volume
- Increases catecholamine sensitivity and the release of renin
The best sources for this sort of thing are actually endocrinology textbooks. For example, an excellent chapter from the 2018 Principles of Endocrinology and Hormone Action by Mannelli et al (Ch.23, p.611-625) would by itself be enough to answer anything they could possibly ask on this topic, and that whole book appears to somehow be available for free in its entirety. In case of some sort of brutal crackdown by Springer-Verlag, Chopra (2011) will probably remain available through PubMed. For each hormone system here, some individual references are listed in the text, and there is also a short summary available in the Body Fluids section which compiles everything specifically relevant to the control of extracellular fluid volume.
As the cardiac reflexes and vasomotor centres have already been discussed elsewhere, the neuro part of this neurohormonal system will only be discussed in passing here. The hormonal element here refers to the release of adrenaline from the adrenal glands. The vasomotor centre (specifically the rostral ventrolateral medulla) sends projections to preganglionic sympathetic neurons in the intermediolateral column of the spinal cord. These neurons, in turn, innervate the chromaffin cells of the renal medulla, so called because they contain dye-absorbant granules full of acidic peptides and catecholamines. The whole medulla can therefore be described as a highly modified sympathetic ganglion, as these chromaffin cells are basically neurons which release their catecholamine neurotransmitters directly into the circulation instead of into the waiting receptors of a neighbouring neuron. In a way, this is still "neurotransmission", except the "synaptic cleft" separating the synapses is the entire extracellular fluid.
Cardiovascular reflexes which trigger the activation of these sympathetic efferents, the effects of adrenaline and the subtypes of different adrenergic receptors are discussed in greater detail elsewhere, and so it would be pointless to revisit that material here unless something substantially new was being discussed. To simplify revision, this brief summary will suffice:
In addition to catecholamines, the adrenal medulla secretes all sorts of other bioactive molecules, which are described in glorious detail by Eiden & Jiang (2018). Without going down that particular rabbit hole, the author will instead tease you with the names of these substances (pancreastatin, vasostatin, catestatin, adrenomedullin, and BAM-22P, which stands for "bovine adrenal medulla docosapeptide"). Their endocrine functions are so numerous and diverse that even usually reserved endocrinology authors tend to use the term "protean" multiple times in the same paragraph while discussing these molecules (for one example, BAM-22P is a potent opioid receptor agonist). There is, of course, no possible way for any of this to ever be examinable, and to write anything more about it would be to squander the reader's time.
Like with the rest of the sympathetic nervous system, the adrenal glands maintain a constant baseline level of adrenaline and noradrenaline secretion (in fact usually there's more noradrenaline being produced than adrenaline). With stimulation, for example exercise or stress, this secretion can be ramped up significantly. Kjær et al (1987) determined that the serum levels of circulating catecholamines increase exponentially with work intensity. The authors convinced a group of healthy young subjects to madly pedal on a cycle ergometer while having their subclavian blood tested for serum catecholamines. The original data are exciting enough to be reproduced here in (more or less) their original state:
As one might imagine, the secretory function of each adrenal gland is going to be a pretty unique and individual thing, and so it is unremarkable that the results were very varied between individuals. Also the "healthy volunteers" recruited by Kjær et al were intentionally a rather diverse group, some of whom were trained athletes and others were sedentary randoms (as you can see, one wuss dropped out after literally 2 minutes of pedalling). What is remarkable is that the serum catecholamine levels skyrocketed within minutes and reached extremely high levels, up to 32 nmol/L for noradrenaline.
Of course, ICU patients are usually not trained athletes, nor are they usually exercising maximally on cycle ergometers. More often, they are just calmly dying of shock. What of their catecholamine secretion? Kajihara et al (1977) had to test this in haemorrhaging dogs, who literally bled to death. As the end approached, serum adrenaline levels increased tenfold, and postmortem analysis of chromaffin cells showed only empty vesicles and autophagic vacuoles, a record of the sympathetic nervous system emptying its reserves in desperation.
In humans, the neuroendocrine response to shock is harder to study, as one would have to withhold lifesaving noradrenaline from them in order to measure its endogenous secretion. Benedict et al (1978) had to sidestep this issue by enrolling only shocked patients who did not require vasopressors following their ICU admission, which admittedly selects for relatively "healthy" shock. Unfortunately their method of presenting data was rather messy, including all the patient's data points and using different graphical scales, and so the original data could not be reproduced here, but with some effort a couple of representative patient data sets could be extracted and reproduced here across the same coordinates for comparison:
As you can see, the brief adrenaline peak in haemorrhagic shock was approximately 60 times the normal level (for the record, the normal ranges would be 0.25 and 1.0 ng/ml for adrenaline and noradrenaline). As haemorrhagic shock resolves more rapidly with the replacement of lost blood volume, normality is quickly restored, whereas septic shock simmers over a slow fire.
With all these serum concentration values being thrown around, one cannot help but wonder - how does this adrenal catecholamine secretion compare to the dose of noradrenaline usually administered to septic patients? Turns out, rather favourably. In a study by Qualha et al (2014), the investigators gave a decent dose of noradrenaline (0.50 mcg/kg/min) to septic children and measured the serum levels for purposes of calculating clearance. Serum noradrenaline increased from a baseline value of 0.54 ng/ml up to 3.75 ng/ml on average, i.e. achieving roughly the same concentration as the septic patients from Benedict et al (1978) were generating on their own. The reader is reminded that the patients from Benedict et al were rather unremarkable haemodynamically, i.e. in order to be enrolled into that study they had to have been admitted to ICU for monitoring but never required noradrenaline. In other words, in septic shock, your adrenal glands can produce enough noradrenaline to match a drug infusion pump going at 35ml/hr, for a standard 6mg/100ml prescription.
There will probably be no better time to discuss this system, as it does not appear in the CICM syllabus anywhere else, and there will probably be no point of mentioning it in the endocrine or fluid sections. It does however appear in the CICM First part exam, as Question 5 from the second paper of 2021, which was failed by 76% of the candidates. Thus, the bulk of this chapter will be dedicated to this system of "humoral regulation of blood volume and flow". Most people will have a sound grasp of it already, as it tends to be well emphasised by medical school curricula. For the same reason, you could find a satisfactory explanation of this subject by grabbing literally any physiology textbook. Or, if for some reason you didn't want to do that, you could look at Fyhrquist & Saijonmaa (2008), or Atlas (2007) who approaches the topic from the viewpoint of pharmacological targets. And though it might seem pointless to add another redundant review where there is already no shortage of peer-reviewed resources, one should be reminded that "pointless and redundant" are the words of our house.
Anyway. To go through the familiar steps of the RAAS enzymatic signalling cascade:
So, the main effect of the RAAS is to increase blood volume and blood pressure, and systemic renin release is the main trigger for this cascade. In addition to this, there is also some peripheral capacity to create angiotensin-II, which has some sort of regional paracrine effect. Atlas (2007) called this the "tissue RAS" and remarked that it probably has different effects in different organs, some of which are probably related to cell growth and differentiation (eg. in the heart).
From the above, it stands to reason that renin release should be stimulated by low blood volume and low blood pressure. That is exactly what we see. There are two main mechanisms for renin release:
Salt depletion can also act as the stimulus for renin release. About this, nobody knows nothing; or as Schweda (2015) puts it, "the understanding of the signaling pathways that transfer changes in salt intake to appropriate adjustments of renin synthesis and release is incomplete." Somehow, by some unknown mechanisms, decreased salt intake produces the release of renin, and vice versa. The macula densa is implicated, as well as several other renal vascular and parenchymal regions. It is probably not essential to unravel that thread for the readers, because ultimately after decades of research it appears to have led nowhere.
Apart from salt depletion or excess, the magnitude of the renin response is downregulated by several other factors, listed by Kurtz (2012). These are:
In summary, in case one ever needs to represent this in the form of a diagram, the simplest most minimalist form would have to be this:
This whole thing seems to play out over a very short timeframe. For example, haemorrhagic shock leads to an almost immediate reaction from the RAAS. Michailov et al (1987) extracted about 20ml/kg of blood out of anaesthetised dogs and observed that over the 30 minutes of this haemorrhage, the renin and angiotensin-II levels in the blood increased by about four times. That this machinery is powerful in its own right, sans sympathetic help, was demonstrated by Brough et al (1975). Animals rendered areflexic by spinal lignocaine were still able to mount an impressive haemodynamic response following rapid haemorrhage. In the diagram below (slightly modified from the original), haemorrhage was simulated by rapidly withdrawing blood from the carotid artery, over about 30-40 seconds. Over the subsequent 30 minutes, a rather impressive recovery occurred, all without baroreflexes or sympathetic vasoconstriction.
Considering the extremely brief serum half-life of angiotensin-II, it makes sense for this system to be rapidly reactive. However, this brings the question: what use is there for a redundant method of quickly regulating blood pressure? Surely the sympathetic nervous system does exactly the same thing? Why all these extra steps?
Well. One may answer that unlike the sympathetic nervous system (which merely redirects the flow of blood from place to place), the RAAS is able to act in the defence of volume and extracellular sodium (the milieu intérieur, as Fournier et al had put it). The autonomic nervous system has no mechanism by which to increase the retention of fluid and sodium. Moreover, the RAAS appears to be more ancient, in evolutionary terms. It is present in even the lowermost vertebrates; for example, lampreys, who do not have functional sympathetic ganglia, secrete angiotensin-II in response to haemorrhage. There are ACE homologues in flies, and renin-like proteins in leeches (who have an open circulatory system, i.e. their blood is not even in vessels). In short, the RAAS may have existed in some form for much longer than even peripheral resistance vessels, let alone sympathetic baroreflexes.
Aldosterone is really all thing to all people, and an endocrinologist would bring up different properties when asked what it does, as compared to a cardiologist, intensivist, or beautician. As the length of this discussion already exceeds the acceptable limits for online discourse, the focus will remain on the role of aldosterone in the defence of blood volume and blood pressure, rather than all the other wonderful things it does. Good reviews by Briet et al (2010) and Briet & Schifrin (2013) were used to fill and organise this section; the first is paywalled but the second is not.
In the same way as aldosterone is a huge complex topic all on its own, a discussion of vasopressin could take many directions. This one will focus purely on its effects on blood volume and blood pressure. For those in need of a deep dive into vasopressin, Holmes Landry & Granton (2003) produced two excellent papers (Part 1 and Part 2) to satisfy even the biggest vasopressin weirdo.
Vasopressin (antidiuretic hormone) is a nonapeptide secreted by the posterior pituitary. A dated article by Zimmerman & Robinson (1976) is probably still the best explanation of where and how this happens. In short, the synthesis of vasopressin actually occurs in the magnocellular neurons of the hypothalamus, specifically in the supraoptic nucleus and the paraventricular nucleus. That is where the cell bodies of the neurons lie. Vasopressin manufactured here is packaged into granules and then transported by axonal flow into the posterior pituitary, where the granules are opened and the vasopressin is secreted into the systemic circulation via the pituitary portal system, specifically via the short portal veins which connect the anterior and posterior pituitary. There are granules involved and therefore there is a small, finite store of preformed vasopressin available there, but it runs out quickly.
The stimuli for vasopressin release are hypotension and hyperosmolarity. Hypotension is sensed by arterial baroreceptors in the usual way, and when the nucleus of the solitary tract is responding to this stimulus, one of its efferent projections extends to the hypothalamus to stimulate vasopressin release. The sensing of hyperosmolarity is a little more specialised:
The sensors for hyperosmolarity-initiated vasopressin release are situated in the hypothalamus. Verbalis (2007) gives the best explanation of how they work. In short, two receptor regions mediate this function: the subfornical organ and the organum vasculosum of the lamina terminalis, thankfully abbreviated as OVLT. Vasopressin-secreting magnocellular neurons are themselves osmosensitive, but their responsiveness is somewhat blunted by their being behind the blood-brain barrier; hence the need for these other organs, which stick out into the bloodstream unprotected to sample the osmolality.
These sensors are a fascinating variation on the theme of stretch-sensitive baroreceptors, except that they are mechanosensitive at a cellular level. As osmolality increases and decreases, unprotected cells shrink and swell, which produces a change in their membrane tension. This change is detected by transient receptor potential vanilloid (TRPV) cation channel proteins, which are said to be nonselective cation channels with a preference for calcium. The exact signalling pathway from there remains unclear; all that can be safely said is that animals with OVLT lesions tend to become chronically hyperosmolar (i.e. they stop secreting vasopressin).
From the above, it follows that these sensors should be selective, i.e. the thirst and antidiuretic response should be unequal depending on which solute is used to increase the osmolality. This is in fact what is observed: the sensors seem to prioritise the solutes which are predominantly extracellular: for example, hypernatremic hyperosmolarity is a very potent stimulus, whereas a very raised urea or a massively elevated glucose does not seem to produce the same response. It is almost as if the main point of this endocrine reflex is to preserve the volume of cells rather than the volume of the circulating fluid; solutes which distribute into all compartments are not viewed as much of an osmotic threat. This makes some sense, if you consider that vasopressin-like peptides are probably the most ancient endocrine regulatory system, traced back to the precambrian Archaeometazoa around the time they developed bilateral symmetry and therefore pre-dating bourgeois novelties like the renal nervous and circulatory systems.
Effects of vasopressin on blood volume are related to the reason it is called "antidiuretic hormone". Vasopressin binding to V2 receptors at the cortical collecting duct stimulates the increased expression of aquaporin proteins on the surface of the collecting duct, concentrating the urine by allowing water to move osmotically out of the duct lumen. The result is water retention. This works nicely with the sodium retention mediated by aldosterone, and if the two systems play well together, serum sodium remains normal. Apart from this renal effect, vasopressin stimulates all sorts of other more sophisticated changes (eg. thirst) which lead to the same thing: increased water intake and decreased water loss.
One might point out that this effect could easily come into conflict with the reflexive defence of blood volume. If the patient is hypovolemic and hypoosomolar, the hypovolemia stimulus pulls the pituitary in one direction while the low osmolality pulls in the other. In such circumstances, the defence of the volume takes priority. The patient will continue to secrete vasopressin even though the retention of water will perhaps worsen their hypoosmolar state, all in an attempt to maintain a proper circulating volume. This is the basis of the "hypovolemic hyponatremia". Given enough fluid to restore their circulating volume, these people's vasopressin release will suddenly turn off, and they will rapidly self-diurese several buckets of dilute urine as their sodium autocorrects, frightening their endocrinologist with the pons-melting rate of its rise.
Effects of vasopressin on blood pressure
Vasopressin in the circulation binds to V1 receptors, which are widespread through the systemic arterial circulation (mostly sparing the pulmonary arteries). The density of their expression favours the splanchnic arteries, producing a redistribution of blood flow away from the gut which resembles what the sympathetic nervous system and catecholamines do. V1 receptors are G-protein coupled, and binding to them activates phospholipase-β which produces IP 3 and leads to the predictable increase in intracellular calcium via which every vasopressor seems to exert its vasopressor effect.
This latter effect is often exploited in the ICU, where vasopressin is used as a second agent to decreased noradrenaline requirements, and on occasion (heretically) as a sole vasopressor. It is usually prescribed as a "hormone replacement" rather than a titratable vasopressor, allowed to infuse at a stable rate over a sustained period of time. The rationale behind this way of using it is the theory of "relative vasopressin insufficiency" (Landry et al, 1997), whereby we expect that the patient with a sustained cardiovascular compromise (eg. sepsis) requires so much vasopressin that their posterior pituitary will rapidly run out of granule stores.
The recommended dose used for this "hormone replacement" is somewhere around 0.04u/min, or 0.04u/kg/hr. So, if this is supposed to be a replacement of normal function, one might ask the question: how does this infusion compare to the normal systemic secretion of vasopressin? What is a normal vasopressin level, and how is it supposed to scale with the severity of shock? A study of healthy volunteers by Mann et al (2000) found a serum level of around 5 pg/ml when they were euvolaemic, and which increased to about 30 pg/ml when they were dehydrated to an osmolality of around 304 mOsm/L.
Of course, these were relatively healthy adults, and the investigators did not let them come to harm during the course of the experiment, because this was the year 2000 and somebody would have raised an eyebrow at a study design that intentionally makes people almost die. Fortunately, Baylis & Robertson were operating in the ethical vacuum of 1979, and were entirely unconstrained by such concerns. They poisoned their volunteers with trimetaphan until their blood pressure dropped by half (we are talking SBP of 60 or so) and recorded some fairly heroic values:
This corresponds to findings by Wang et al (1988) who recorded a maximum value of about 1000 pg/ml from exsanguinating dogs (following 30ml/kg blood loss, or about 40% of the circulating volume). So, when properly stimulated, a nice healthy neuroendocrine system will crank up its secretion of vasopressin by up to a thousand times. One might expect the vasopressin requirements of critically ill ICU patients to be in this range, but as you will see this did not turn out to be the case. Sharshar et al (2003) measured the vasopressin levels of 44 patients with septic shock (their data is reproduced below), and found a rather anaemic response:
So even in septic shock, early when the granules still have plenty of pre-baked vasopressin, the serum vasopressin level is rather modest, exceeding 15 pg/ml in only one case.
How much, then, does the routine sepsis-dose exogenous vasopressin infusion contribute? Turns out, quite a lot when compared to normal septic people, but not very much compared to healthy adults, and certainly nothing compared to the doses used by some of the more adventurous investigators. For example, here's a piece of startling ICU pharmacotrivia. Ebert et al (1986) infused healthy males with 15 and 40ng/kg/min of vasopressin, increasing their serum concentration of vasopressin from 5 pg/ml to 18 and 36 pg/ml respectively, i.e. well in excess of what is usually expected under "natural" circumstances in shock. But wait: working from the assumption that 1mg of vasopressin contains 530 units, that dose they used amounts to about 30-90 units per hour. This exceeds all normal infusion standards in modern clinical practice, and even the most liberal guideline documents draw the line at 0.6units/kg/hr (which is about 42 units/hr for a 70kg person).
A more normal dose rate would be about 2-3 units power hour. During the VASST study the investigators measured vasopressin levels of septic shock patients receiving an infusion of about 0.03U/min (1.8 U/hr) and found vasopressin levels increased from a low baseline of around 3 pmol/L up to about 70-100 pmol/L (Gordon & Russell, 2010). At a baseline, in a healthy euvolaemic person, the pituitary maintains a level somewhere around 3-4 pmol/L, which means your own internal rate of vasopressin infusion is about 0.07-0.10 units per hour.
Fortunately for the victims of Ebert et al, the cardiovascular effects of vasopressin appear to be completely unrelated to its dose. And its maximal effect is only apparent in patients with shock. Those healthy young men in the 1986 experiment were completedly unharmed by their 90u/hr vasopressin binge, by the way. Their MAP increased from about 86 to about 94. Those receiving 30u/hr barely had experienced any change in their blood pressure. Dünser et al (2004), in unhealthy completely-falling-apart patients with what the authors described as "advanced vasodilatory shock" also found no relationship between the serum vasopressin level and haemodynamic effect. But at least it had a haemodynamic effect- vasopressin at "modest" doses up to 4u/hr predictably and significantly decreased the noradrenaline requirements in these patients. Clearly, something unique and wonderful happens in severe vasoplegic shock which potentiates the effects of vasopressin.
What is that unique and wonderful thing, that restores vessel wall tone in sepsis, but spares a normal circulation? Well, there are probably at least four such things. Landry & Oliver (2001) list references in support of the following hypotheses:
So, in short, rather than acting as a vasoconstrictor which brutally imposes its will upon the vascular smooth muscle in a linear dose-dependent manner, in sepsis vasopressin acts mainly to restore vessel tone and catecholamine responsiveness, basically returning vascular reactivity to a point where other vasoactive drugs can be useful in nontoxic doses.
This topic is well covered in the literature, as natriuretic peptides are turning into commercially attractive diagnostic biomarkers and drug targets. Good representation which pre-dates the corporate taint of Big Peptide can be found in Potter et al (2009) or Baxter (2004). In summary, there are three of them. ANP and BNP (atrial and brain natriuretic peptide) are the sexy interesting hormones, and CNP (C-type natriuretic peptide) is somewhat forgotten as it appears to support long bone growth and other "unappreciated functions". Nobody talks to CNP at parties.
ANP and BNP are relatively large (28- and 32-amino-acid) peptide molecules which are structurally related (they both have the same 17-aa ring). They seem to be well conserved from the evolutionary perspective, our ANP differing from the rat by just one amino acid (we preferred methionine to their isoleucine). Synthesis of these molecules takes place in atrial muscle. BNP is said to come from the ventricle and ANP is said to come from the atrium, but in fact it appears that both substances can be found in atrial granules, and both tend to be released in response to atrial stretch. In contrast, only BNP is released in response to ventricular stretch and is therefore a more sensitive biomarker for ventricular volume overload. ANP is preformed and stored in granules, whereas BNP is synthesised as needed. Of the two hormones, BNP has a longer circulating half-life (20 minutes, vs 2 minutes for ANP).
Stimulus for ANP and BNP secretion is basically myocardial stretch, which occurs in response to an increase in preload. There seems to be some baseline level, which increases with any state which puts pressure on the chamber walls (for example, the failure of an upstream chamber). The precise mechanoreceptor process involved in this remains to be explained. Apart from mechanical stretch, Fu et al (2018) list a whole bunch of other (totally predictable) release modulators, such as exercise, hypoxia, cold, angiotensin, endothelin, vasopressin catecholamines and corticosteroids. Natriuretic peptides are released into myocardial capillary blood and end up being washed into the bloodstream out of the coronary sinus.
Natriuretic peptide receptors are located mainly in the renal tubule, vascular smooth muscle, adrenal glands, the heart and the brain. These are membrane-spanning receptors attached to an intracellular guanylyl cyclase which produces cGMP as a secondary messenger. Downstream effects are then mediated by protein kinase G and phosphodiesterase.
The effect of stimulating these receptors is basically natriuresis and diuresis. ANP inhibits sodium channel function and Na/K ATPase activity in the cortical collecting duct, decreasing sodium reabsorption. It also directly inhibits renin release, interferes with vasopressin binding to its V2 receptors, and directly vasodilates the afferent arterioles of the kidney (Wong et al, 2017). In short, everything happens to increase the excretion of sodium and water, which reduces the cardiac chamber distension.
It will surprise nobody to hear that the thyroid gland interferes in the control of blood pressure, as it interferes in virtually everything. Hypothyroidism is associated with hypotension and low cardiac output, whereas hyperthyroidism gives rise to a hyperdynamic circulation with an occasional hypertensive crisis. The cardiovascular effects of thyroid hormone are well reported in Danzi & Klein (2003), and it would probably benefit nobody to get into them in any great detail here, considering especially that many of the effects are not particularly well explained and therefore do not lend themselves to a good SAQ or viva answer. In summary, it has direct and indirect effects:
Cortisol, the major human glucocorticoid, is produced by the adrenocortical zona fasciculata. The total list of their functions is massive and complex, including inter alia some influence on the maintenance of blood pressure and blood volume. Corticosteroid release is triggered by various forms of stress, a spectrum which incorporates shock and hypovolaemia. They then produce a restoration of blood pressure and blood volume by a variety of mechanisms, which are detailed in Whitworth (2005).
If no shock or hypovolemia is present, corticosteroids will produce hypertension and volume overload. When Whitworth et al (1984) famously filled healthy volunteers with cortisol, they found that after five days their blood pressure increased by about 20mmHg on average, and their bodies gained about a litre of fluid. The latter effect is owed to their cross-reactivity with mineralocorticoid receptors, which increases the renal reabsorption of sodium and decreases the renal excretion of water. The vasopressor effect is probably multimodal and indirect, i.e. mediated by an increase of catecholamine receptor sensitivity and interference with nitric oxide-mediated vasodilation.