As the cornerstone effector peptide of the renin-angiotensin-aldosterone system, angiotensin operates as an indispensable endocrine and paracrine regulator of cardiovascular hemodynamics, electrolyte balance, and systemic arterial pressure. Its physiological orchestration bridges renal filtration dynamics with neurohormonal tone, ensuring circulatory homeostasis across vertebrate organisms. Unraveling the biochemical intricacies of angiotensin has reshaped modern cardiology, nephrology, and pharmacology, offering foundational paradigms for the clinical management of hypertension, heart failure, and chronic renal disease.
Angiotensin
1. Concise Definition
Angiotensin refers to a family of biologically active, oligopeptide hormones derived from the enzymatic cleavage of the hepatically synthesized precursor globulin, angiotensinogen. Principally functioning via its octapeptide isoform, angiotensin II, this biochemical agent produces potent systemic vasoconstriction, stimulates aldosterone secretion from the adrenal cortex, promotes tubular sodium and water retention in the kidneys, and modulates central sympathetic nervous system outflow to preserve effective arterial blood volume.
Beyond its classical role as an endocrine pressor agent, contemporary molecular physiology recognizes angiotensin as an autocrine and paracrine signaling molecule with pervasive actions across diverse organ beds. The peptide interacts with specialized transmembrane G protein-coupled receptors to initiate downstream intracellular phosphorylation cascades, transcriptional programs, and cellular remodeling processes. Consequently, dysregulated or chronically elevated levels of angiotensin are fundamentally implicated in the pathogenesis of vascular hypertrophy, myocardial fibrosis, endothelial dysfunction, and the progression of inflammatory tissue injury.
2. Etymology & Linguistic Origin
The term angiotensin is a neoclassical hybrid portmanteau coined in the mid-twentieth century to resolve a transcontinental scientific naming dispute. It fuses the ancient Greek noun angeion (αγγεῖον), signifying “vessel” or “duct,” with the Latin noun tensio, derived from the verb tendere, meaning “to stretch,” “extend,” or “exert tension.”
During the late 1930s and 1940s, two independent research groups discovered the vasoconstrictive peptide: Eduardo Braun-Menéndez and his colleagues in Argentina isolated the substance and named it hypertensin, whereas Irvine Page and Arda Green in the United States isolated it concurrently and designated it angiotonin. In 1957, both investigative teams mutually agreed to reconcile the conflicting nomenclature by synthesizing the prefix from angiotonin and the suffix from hypertensin, thus establishing the standardized international moniker angiotensin.
3. Pronunciation & Grammatical Form
In standard scientific and phonetic English, the term is pronounced /ˌæn.dʒi.oʊˈtɛn.sɪn/ (an-jee-oh-TEN-sin). Grammatically, it functions exclusively as an uncountable singular common noun, though it regularly occurs in pluralized forms (such as angiotensins) when denoting the collective family of peptide fragments spanning angiotensin I through VII. In medical and biochemical prose, it frequently acts as an attributive noun or modifier, generating standard diagnostic and pharmacological compounds such as angiotensin receptor, angiotensin pathway, and angiotensin-converting enzyme.
4. Detailed Conceptual Explanation
The conceptual framework of angiotensin centers upon an enzymatic biochemical cascade termed the renin-angiotensin-aldosterone system (RAAS). The sequence initiates in the liver, which constitutively synthesizes and secretes angiotensinogen, a heavy alpha-2-globulin consisting of 452 amino acids in humans. When the juxtaglomerular apparatus of the renal cortex detects decreased renal perfusion pressure, reduced sodium delivery to the macula densa, or beta-adrenergic sympathetic stimulation, it discharges the aspartyl protease enzyme renin into systemic circulation.
Circulating renin cleaves the N-terminal decapeptide sequence of angiotensinogen between the leucine and valine residues, liberating angiotensin I (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu). Angiotensin I represents an inactive prohormone possessing negligible inherent physiological reactivity. As angiotensin I navigates the microvasculature, predominantly within the pulmonary endothelial capillary beds, it encounters angiotensin-converting enzyme (ACE), a membrane-bound zinc metallopeptidase. ACE cleaves the C-terminal dipeptide histidyl-leucine from angiotensin I, generating the primary active octapeptide, angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe).
Once synthesized, angiotensin II exerts multifaceted physiological actions by binding primarily to two distinct cell-surface receptor subtypes: the Angiotensin II Type 1 (AT1) receptor and the Angiotensin II Type 2 (AT2) receptor. Activation of the AT1 receptor, which couples predominantly to Gq/11 proteins, initiates phospholipase C activation, generating inositol trisphosphate (IP3) and diacylglycerol (DAG). This pathway triggers an immediate mobilization of intracellular calcium stores within vascular smooth muscle cells, generating profound systemic vasoconstriction and acutely elevating total peripheral resistance.
Concurrently, AT1 receptor stimulation in the zona glomerulosa of the adrenal cortex accelerates the transcription of aldosterone synthase, culminating in the secretion of aldosterone. Aldosterone acts downstream on the principal cells of the renal collecting ducts to upregulate epithelial sodium channels (ENaC) and sodium-potassium ATPase pumps, driving sodium conservation, water retention, and kaliuresis. Concurrently, angiotensin II stimulates the thirst center within the hypothalamic subfornical organ and triggers neurohypophyseal discharge of arginine vasopressin, synergistically expanding intravascular volume.
In contrast to the classical ACE-Angiotensin II-AT1 axis, modern physiological models incorporate the counter-regulatory non-canonical arm consisting of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7), and the Mas receptor. ACE2 cleaves a single amino acid from angiotensin II to produce angiotensin-(1-7), a heptapeptide that binds the G protein-coupled receptor Mas. Signaling through this alternative pathway promotes vasodilation, anti-inflammatory cascades, anti-fibrotic remodeling, and natriuresis, thereby maintaining a homeostatic brake against excessive AT1 receptor-mediated tissue damage.
5. Historical Development
The history of angiotensin spans more than a century of physiological inquiry into the humoral control of blood pressure. The groundwork was laid in 1898 at the Karolinska Institute by Finnish physiologist Robert Tigerstedt and his student Per Bergman, who demonstrated that crude rabbit renal cortical extracts contained a heat-labile substance capable of eliciting marked and sustained pressor responses when injected into recipient animals. They christened this renal extract renin, though their pioneering work was largely overlooked for over three decades.
Renewed interest in the renal humoral mechanism emerged in 1934, when Harry Goldblatt published his landmark animal experiments showing that constricting the main renal arteries of dogs produced chronic, sustained arterial hypertension mimicking human benign essential hypertension. This proved that renal ischemia stimulated the systemic release of a pressor substance. In 1939, two groups working simultaneously on different continents deciphered that renin was not itself an active pressor agent, but rather an enzyme acting on a blood precursor: Eduardo Braun-Menéndez, Juan Carlos Fasciolo, Luis Leloir, and Alberto Muñoz in Buenos Aires, and Irvine Page and Arda Green at the Cleveland Clinic.
In the mid-1950s, Leonard Skeggs and his collaborators made foundational biochemical breakthroughs by isolating, purifying, and sequencing the peptide fragments. Skeggs demonstrated that the substance existed in two forms: the inactive decapeptide (angiotensin I) and the active octapeptide (angiotensin II), and he identified the essential role of the converting enzyme responsible for this post-translational cleavage. The complete chemical synthesis of angiotensin II was achieved in 1957 by Robert Schwyzer and colleagues in Switzerland, and independently by F. Merlin Bumpus and associates in the United States, catalyzing the modern pharmacological era.
6. Theoretical Foundations
The conceptual evolution of angiotensin integrates three major physiological and systems-biology frameworks: the whole-body autoregulation framework, the local-tissue micro-environment paradigm, and the dual-axis counter-regulatory equilibrium model.
Under the classic hemodynamic model established by Arthur Guyton in the 1970s, the renin-angiotensin-aldosterone axis represents a premier negative-feedback homeostatic servomechanism. Guytonian systems physiology posits that long-term blood pressure control is governed by the renal pressure-natriuresis relationship. Within this theoretical paradigm, angiotensin shifts the pressure-natriuresis curve to the right: by stimulating direct renal arteriolar constriction and aldosterone-dependent tubular transport, angiotensin prevents catastrophic hemodynamic collapse in settings of hypovolemia, salt depletion, or postural change.
A critical shift occurred in the late 1980s with the establishment of the local or “tissue” renin-angiotensin system concept. Rather than viewing angiotensin exclusively as an endocrine hormone transported via systemic circulation, researchers recognized that all biochemical components of the cascade are synthesized locally within specialized microenvironments, including the myocardium, brain, vascular wall, adipose tissue, and kidneys. In these tissues, locally generated angiotensin II serves paracrine and autocrine functions, regulating local capillary perfusion, cellular proliferation, cytokine synthesis, and phenotypic transformation independent of systemic circulating renin levels.
The third theoretical framework is the Yin-Yang or counter-regulatory balance hypothesis, crystallized following the discovery of ACE2 in 2000. Under this paradigm, vascular and tissue health reflects dynamic tension between two antagonistic pathways: the injurious, pro-constrictive, pro-inflammatory ACE-Angiotensin II-AT1 axis, and the protective, pro-dilatory, anti-inflammatory ACE2-Angiotensin-(1-7)-Mas axis. Disease pathogenesis is understood not merely as the hyperactivation of angiotensin II, but as an uncoupling or exhaustion of this counter-regulatory balance.
7. Key Components, Types & Dimensions
The angiotensin cascade encompasses an array of peptide fragments, cleavage enzymes, and specialized membrane receptors that collectively govern its downstream biological consequences:
- Angiotensinogen: The hepatically derived 452-amino-acid alpha-2-globulin substrate constitutively released into the circulation, providing the structural scaffold for subsequent proteolytic processing.
- Angiotensin I (Ang I): A decapeptide (amino acid sequence: Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu) generated by the catalytic action of renin on angiotensinogen; acts as an inactive precursor with no primary pressor capacity.
- Angiotensin II (Ang II): The primary physiological octapeptide (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), cleaved from Ang I by ACE; acts as an exceptionally potent systemic vasoconstrictor, secretagogue for aldosterone, and mediator of tissue remodeling.
- Angiotensin III (Ang [2-8]): A heptapeptide derived from Ang II via aminopeptidase A cleavage; exhibits 100% of the aldosterone-stimulating activity of Ang II and approximately 40% of its systemic pressor activity, exerting significant neuroendocrine influence within the central nervous system.
- Angiotensin IV (Ang [3-8]): A hexapeptide produced through the enzymatic cleavage of Ang III by aminopeptidase N; binds with high affinity to the AT4 receptor (identified as insulin-regulated aminopeptidase, IRAP), playing putative roles in synaptic plasticity, memory consolidation, and regional blood flow regulation.
- Angiotensin-(1-7): A protective heptapeptide generated directly from Ang II by ACE2, or from Ang I by neutral endopeptidases; induces vasodilation, mitigates fibrosis, reduces oxidative stress, and dampens inflammation through Mas receptor signaling.
- Angiotensin II Type 1 (AT1) Receptor: A seven-transmembrane G protein-coupled receptor mediating vasoconstriction, aldosterone release, vascular smooth muscle proliferation, sympathetic activation, oxidative stress, and myocardial remodeling.
- Angiotensin II Type 2 (AT2) Receptor: A distinct GPCR exhibiting actions generally antagonistic to the AT1 receptor, driving nitric oxide production, vasodilation, cellular differentiation, and tissue reparative processes.
8. Examples & Illustrative Cases
To grasp the clinical impact of angiotensin kinetics, consider the classical presentation of Renovascular Hypertension secondary to unilateral renal artery stenosis. In an illustrative patient with an atherosclerotic plaque narrowing the right renal artery, the downstream right juxtaglomerular apparatus perceives marked hypoperfusion and pressure drop. In response, it unloads substantial quantities of renin into the systemic circulation. Circulating renin cleaves angiotensinogen into angiotensin I, which is converted in the lungs to high levels of angiotensin II. The resulting widespread peripheral vasoconstriction and sodium retention produce refractory systemic hypertension, while the healthy contralateral kidney undergoes hyperfiltration and secondary hypertensive nephrosclerosis. Correcting the stenosis via revascularization or administering an ACE inhibitor or angiotensin receptor blocker dramatically halts the hyperactivation of the cascade.
A second illustrative example occurs during Decompensated Systolic Heart Failure. As cardiac output diminishes, effective circulating arterial volume plummets, triggering baroreceptors and sympathetic outflow to activate the renal renin cascade. Angiotensin II generation surges in a compensatory effort to sustain blood pressure through vasoconstriction and fluid retention. Over time, however, sustained AT1 receptor stimulation drives pathological cardiomyocyte hypertrophy, interstitial collagen deposition, and progressive ventricular remodeling. The excessive afterload and fluid overload accelerate cardiac decompensation, creating a lethal positive feedback loop that is therapeutically broken by pharmacological inhibition of the angiotensin pathway.
9. Measurement & Assessment
Quantifying the activity of the angiotensin cascade requires precise biochemical assays due to the picomolar circulating concentrations and fleeting half-lives (often under two minutes) of the peptides. Standard clinical and laboratory evaluation protocols include:
- Plasma Renin Activity (PRA) and Direct Renin Concentration (DRC): Assayed via radioimmunoassay (RIA) or chemiluminescence to quantify the functional rate of Ang I generation from endogenous angiotensinogen per unit time, serving as an indirect surrogate for overall cascade activation.
- Direct Angiotensin II Quantification: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and competitive radioimmunoassays measure absolute circulating levels of Ang II, demanding rapid blood collection into chilled tubes containing enzyme inhibitors to halt ongoing ex vivo peptide degradation.
- Aldosterone-to-Renin Ratio (ARR): A fundamental clinical screening parameter for primary aldosteronism; high aldosterone in the presence of suppressed renin or angiotensin indicates autonomous adrenal production, whereas concurrent elevation reflects secondary hyperreninemic hyperaldosteronism.
- Serum Angiotensin-Converting Enzyme (ACE) Activity: Spectrophotometric and fluorometric assays measuring the cleavage of synthetic substrates (such as hippuryl-histidyl-leucine) in serum, frequently deployed in the diagnostic evaluation and monitoring of pulmonary sarcoidosis.
- Equilibrium RAAS Peptide Profiling: Advanced mass spectrometry platforms capable of concurrently quantifying multiple peptide metabolites (Ang I, Ang II, Ang III, Ang IV, Ang 1-7, and Ang 1-5), providing a complete biochemical snapshot of circulating and local tissue protease networks.
10. Applications & Practical Significance
The pharmacological manipulation of angiotensin pathways represents one of the greatest triumphs in modern pharmacotherapy. Therapeutic interventions modulating this system have drastically reduced global cardiovascular morbidity and mortality across multiple disease categories.
Angiotensin-Converting Enzyme (ACE) Inhibitors: Synthetic agents such as captopril, enalapril, and lisinopril competitively inhibit ACE, preventing the conversion of Ang I to Ang II while simultaneously retarding the degradation of the vasodilatory peptide bradykinin. These drugs form the backbone of guideline-directed medical therapy for essential hypertension, heart failure with reduced ejection fraction (HFrEF), and post-myocardial infarction care.
Angiotensin II Receptor Blockers (ARBs): Non-peptide antagonists including losartan, valsartan, and telmisartan selectively bind and block the AT1 receptor subtype, blunting the pathological effects of Ang II while leaving the bradykinin degradation pathway uninhibited (avoiding the dry cough characteristic of ACE inhibitors). In addition to treating hypertension, ARBs provide robust nephroprotection in diabetic kidney disease by lowering intraglomerular pressure and mitigating podocyte effacement.
Angiotensin Receptor-Neprilysin Inhibitors (ARNIs): The innovative drug class combining an ARB with a neprilysin inhibitor (e.g., sacubitril/valsartan) simultaneously inhibits AT1 receptors and blocks the degradation of beneficial natriuretic peptides. This dual mechanism substantially reduces cardiovascular death and hospitalizations in patients with chronic heart failure compared to traditional ACE inhibitor monotherapy.
Synthetic Angiotensin II in Critical Care: In 2017, the U.S. Food and Drug Administration approved synthetic human angiotensin II (Giapreza) as an intravenous vasopressor for the management of distributive and septic shock refractory to high-dose catecholamines, leveraging the peptide’s primary vasoconstrictive potency to restore systemic perfusion pressure.
11. Research & Empirical Evidence
Over four decades of randomized clinical trials have established the definitive prognostic benefits of modulating the angiotensin system. Landmark investigations such as the CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study, 1987) and SOLVD (Studies of Left Ventricular Dysfunction, 1991) trials proved conclusively that inhibiting Ang II generation reduced mortality and slowed heart failure progression. Later, the HOPE (Heart Outcomes Prevention Evaluation, 2000) trial established that ACE inhibition afforded profound cardioprotective and vasculoprotective benefits in high-risk patients independent of blood pressure reduction alone.
Similarly, the clinical efficacy of AT1 receptor blockade in renal medicine was validated by the RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan, 2001) and IDNT (Irbesartan Diabetic Nephropathy Trial, 2001) studies, which demonstrated significant reductions in the doubling of serum creatinine and progression to end-stage renal disease (ESRD) in diabetic patients. More recently, the PARADIGM-HF trial (2014) showed a 20% relative risk reduction in the composite endpoint of cardiovascular death or heart failure hospitalization with ARNI therapy over enalapril, demonstrating the clinical superiority of combined angiotensin blockade and natriuretic peptide enhancement.
Basic science investigations led by researchers such as Marc de Gasparo, Victor Dzau, and Rhian Touyz have unraveled the molecular mechanisms of AT1-induced tissue pathology. Their work demonstrated that Ang II directly activates NADPH oxidase (NOX), generating massive cascades of intracellular reactive oxygen species (ROS) that uncouple endothelial nitric oxide synthase (eNOS), trigger nuclear factor-kappa B (NF-κB) inflammatory signaling, and promote transforming growth factor-beta (TGF-β)-mediated organ fibrosis.
12. Cultural & Cross-Cultural Considerations
Epidemiological and pharmacogenomic research has revealed profound population-level variations in the reactivity and genetic architecture of the angiotensin system. Clinical trials and international observational cohorts indicate that individuals of African descent frequently exhibit a phenotype characterized by low-renin, volume-sensitive hypertension. Consequently, clinical guidelines emphasize that monotherapy with ACE inhibitors or ARBs often results in smaller reductions in systemic blood pressure in Black patients compared to Caucasian populations, necessitating combination therapies featuring thiazide diuretics or calcium channel blockers to achieve equivalent efficacy.
Furthermore, genetic polymorphism distributions across global populations markedly influence individual susceptibility to cardiovascular pathologies. The ACE insertion/deletion (I/D) polymorphism, located in intron 16 of the ACE gene, shows differing allelic frequencies across ethnic groups. The D allele, linked with higher circulating and tissue ACE activity, has been correlated with increased risk of left ventricular hypertrophy, diabetic nephropathy, and preeclampsia in varied regional cohorts, illustrating how evolutionary ancestral divergence affects peptide signaling dynamics and pharmacotherapeutic responsiveness.
13. Criticisms, Debates & Limitations
Despite the immense therapeutic success of targeting angiotensin, several fundamental pharmacological debates and biological paradoxes endure:
The ACE Escape Phenomenon: Long-term treatment with ACE inhibitors frequently leads to a secondary resurgence of circulating Ang II levels back toward pre-treatment baselines. This occurs because alternative non-ACE serine proteases, predominantly chymase, can bypass the blocked enzyme and directly convert Ang I to Ang II within cardiac and vascular tissues, blunting the durable efficacy of ACE inhibitor monotherapy.
The Failure of Dual RAAS Blockade: A major pharmacological hypothesis suggested that simultaneously combining ACE inhibitors and ARBs, or adding direct renin inhibitors (such as aliskiren), would completely extinguish the system and yield superior clinical outcomes. However, large multicenter trials including ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, 2008) and ALTITUDE (2012) proved that dual blockade significantly increased adverse events—specifically hyperkalemia, acute kidney injury, and hypotension—without adding meaningful clinical benefit.
The COVID-19 / ACE2 Paradox: During the SARS-CoV-2 pandemic, a fierce global debate erupted regarding the clinical use of ACE inhibitors and ARBs. Because SARS-CoV-2 exploits membrane-bound ACE2 as its entry receptor, early theoretical concerns suggested that RAAS inhibitors might upregulate ACE2 expression, potentially facilitating viral entry and increasing infection severity. Subsequent rigorous multinational observational studies and randomized trials (such as the BRACE CORONA study) decisively demonstrated that continuing RAAS inhibitors was safe and carried protective trends against catastrophic pulmonary inflammation.
14. Related Terms & Distinctions
- Renin: An aspartyl protease enzyme secreted by the kidneys that possesses no intrinsic pressor action itself; its sole primary biochemical function is to cleave angiotensinogen into angiotensin I.
- Angiotensinogen: The large glycoprotein precursor produced by hepatocytes; unlike its cleaved derivative angiotensin II, it does not bind to G protein-coupled receptors or induce vasoconstriction.
- Aldosterone: A downstream mineralocorticoid steroid hormone synthesized by the adrenal cortex under the stimulation of angiotensin II; unlike the rapid, acute vasoconstrictive actions of angiotensin II, aldosterone regulates fluid retention over hours to days through genomic transcription of renal ion transport channels.
- Bradykinin: A vasodilatory and pro-inflammatory peptide cleaved by tissue and plasma kallikreins; it is degraded directly by ACE, meaning that pharmacological ACE inhibition leads to an accumulation of bradykinin, which causes characteristic side effects like dry cough and angioedema.
- Endothelin-1: Another exceptionally potent endogenous vasoconstrictor peptide; however, endothelin-1 is synthesized directly by endothelial cells and acts via ETA and ETB receptors, operating through distinct upstream pathways from the renin-angiotensin cascade.
15. Summary / Key Takeaways
Angiotensin represents the primary functional peptide orchestrating systemic circulatory pressure, volume balance, and vascular architecture throughout the mammalian body. Through the coordinated sequential activity of renin and ACE, the hepatically derived substrate angiotensinogen is cleaved into the bioactive octapeptide angiotensin II. By signaling through the AT1 receptor, angiotensin II drives arteriolar vasoconstriction, adrenal aldosterone secretion, and renal fluid conservation, while the counter-regulatory ACE2-Ang-(1-7)-Mas axis provides homeostatic protection against excessive remodeling and tissue inflammation. Pharmacological modulation of this axis through ACE inhibitors, ARBs, and ARNIs constitutes the absolute cornerstone of contemporary therapeutic management for hypertension, congestive heart failure, and chronic renal disease worldwide.
Ultimately, the continuous scientific redefinition of angiotensin—from an acute circulating pressor factor to an intricate autocrine, paracrine, and counter-regulatory signaling network—highlights its fundamental place in human physiology and translational medicine.
References
- Braun-Menéndez, E., Fasciolo, J. C., Leloir, L. F., & Muñoz, J. M. (1940). The substance causing renal hypertension. The Journal of Physiology, 98(3), 283–298.
- Guyton, A. C. (1991). Blood pressure control—special role of the kidneys and body fluids. Science, 252(5014), 1813–1816.
- McMurray, J. J., Packer, M., Desai, A. S., Gong, J., Lefkowitz, M. P., Rizkala, A. R., Rouleau, J. L., Shi, V. C., Solomon, S. D., Swedberg, K., & Zile, M. R. (2014). Angiotensin-neprilysin inhibition versus enalapril in heart failure. The New England Journal of Medicine, 371(11), 993–1004. https://www.nejm.org/doi/10.1056/NEJMoa1409077
- Page, I. H., & Helmer, O. M. (1940). A crystalline pressor substance (angiotonin) resulting from the reaction between renin and renin-activator. The Journal of Experimental Medicine, 71(1), 29–42. https://rupress.org/jem/article/71/1/29/4266/A-CRYSTALLINE-PRESSOR-SUBSTANCE-ANGIOTONIN
- Santos, R. A. S., Sampaio, W. O., Alzamora, A. C., Motta-Santos, D., Alenina, N., Bader, M., & Wang, H. (2018). The ACE2/angiotensin-(1-7)/MAS axis of the renin-angiotensin system: Focus on angiotensin-(1-7). Physiological Reviews, 98(1), 505–553. https://journals.physiology.org/doi/full/10.1152/physrev.00023.2016