Physiology Note - Vasoactive Receptors A HICS Initiative

  
      Dr Mohan Sai Gudela

      Senior Resident, Critical Care Medicine,

      AIIMS, Jodhpur

                                                    VASOACTIVE RECEPTORS

Introduction

Vasoactive receptors are predominantly located in vascular smooth muscle, myocardium, and endothelium. Their primary role is to modulate systemic and regional hemodynamics through drug-receptor interactions. Beyond their actions on the cardiovascular system, these receptors exert significant metabolic and neuroregulatory effects as well. A thorough understanding of their distribution and functions is essential for optimizing hemodynamic and metabolic responses in the critically ill.

Few important vasoactive receptors include:

1. Adrenergic receptors
2. Vasopressin receptors
3. Angiotensin receptors
4. Endothelin receptors

Adrenergic Receptors

Raymond P. Ahlquist discovered the existence of two distinct types of adrenergic receptors – alpha and beta (⍺ and β).¹ Further studies revealed the presence of two alpha receptor subtypes (⍺₁ and ⍺₂) and three beta receptor subtypes (β₁, β₂ and β₃). The two alpha receptor subtypes each have three subclasses (⍺_1A, ⍺_1B, ⍺_1D and ⍺_2A, ⍺_2B, ⍺_2C) as well. Adrenergic receptors belong to the G protein-coupled receptor family. The differential responses of adrenergic receptors to various agonists and antagonists are secondary to their distribution and interaction with second messenger systems (Table 1).

 

Table 1: Adrenergic Receptors

	⍺1 receptors	⍺2 receptors	β1 receptors	β2 receptors	β3 receptors
Type of G protein receptor	Gq	Gi	Gs	Gs	Gs
Second messengers	Activates phospholipase C	Inhibit adenylyl cyclase	Stimulate adenylyl cyclase	Stimulate adenylyl cyclase	Stimulate adenylyl cyclase
Location of receptor	1.Visceral and vascular smooth muscle	1.Vascular smooth muscle 2.Nerve terminals	Myocardium	1.Visceral smooth muscle 2.Myocardium 3.Skeletal muscle 4.Nerve terminals	1.Bladder detrusor 2.Skeletal muscle 3.adipocytes
Agonist potency	NAdr > Adr >> Iso	Adr > NAdr >> Iso	Iso > NAdr > Adr	Iso > Adr > NAdr	Iso > NAdr = Adr
Selective agonist	Phenylephrine       Methoxamine	Clonidine	Dobutamine   Xamoterol	Salbutamol   Terbutaline	Mirabegron
Selective antagonist	Prazosin                 Doxazocin	Yohimbine         Idazoxan	Atenolol        Metoprolol	Butoxamine	N/A
Clinical effects	1.Vasoconstriction 2.Relaxation of GI smooth muscle 3.Salivary secretion 4.Hepatic glycogenolysis	1.Inhibition of NAdr and ACh from nerve terminals 2.Platelet aggregation 3.Decrease insulin release	Increase in inotropy and chronotropy	1.Increase in inotropy and chronotropy 2.Bronchodilation 3.Vasodilation 4.Relaxation of visceral smooth muscle 5.Hepatic glycogenolysis	1.Relaxation of bladder detrusor muscle 2.Lipolysis 3.Thermogenesis

ACh - Acetylcholine, Adr - Adrenaline, Iso - Isoprenaline, NAdr - Noradrenaline

SNIPPETS

1. Noradrenaline, at lower doses, stimulates α-receptors in the venous vascular bed, causing venoconstriction. This converts unstressed blood volume into stressed blood volume, thereby increasing preload and subsequently improving cardiac output.²
2. As the doses of noradrenaline increase, α-receptors in the arterial vascular bed are stimulated as well, leading to vasoconstriction. This results in an increase in afterload, thereby increasing cardiac output.
3. In progressive septic shock, sustained activation of the adrenal medulla by cytokines results in excessive catecholamine secretion. Such a response becomes maladaptive, and one of the reasons is adrenergic receptor desensitization. The result is a catecholamine-refractory shock. In such situations, adjunctive steroids restore vascular responsiveness to catecholamines by curbing inflammation and increasing alpha-adrenergic receptor gene expression.

Vasopressin Receptors

Similar to adrenergic receptors, vasopressin receptors belong to the G protein-coupled receptor family. Vasopressin receptors are subdivided into two types – V₁ and V₂ receptors. The V1 receptors are further classified into V_1A and V_1B subtypes (Table 2). Arginine Vasopressin (AVP), also known as anti-diuretic hormone, modulates volume status and hemodynamics through these receptors.

 

 

Table 2: Vasopressin Receptors

	V1A receptors	V1B receptors	V2 receptors
Type of G protein receptor	Gq	Gq	Gs
Second messengers	Activates phospholipase C	Activates phospholipase C	Stimulate adenylyl cyclase
Location of the receptor	1.Vascular smooth muscle                 2.Platelets                         3.Renal mesangial cells 4.Myometrium 5.Stria terminalis and hypothalamus	1.Anterior Pituitary 2.Pancreas	1.Basolateral surface of the distal tubule and the collecting ducts 2.Vascular endothelium
Agonist	Vasopressin Terlipressin Selepressin (Selective)	Vasopressin Terlipressin	Vasopressin Terlipressin Desmopressin (Selective)
Antagonist	Conivaptan Relcovaptan (Experimental)	Nelivaptan (Experimental)	Conivaptan Tolvaptan (Selective)
Clinical effects	1.Vasoconstriction 2.Platelet aggregation 3.Uterine contraction 4.Efferent arteriolar vasoconstriction in kidney	1.Adrenocorticotropic (ACTH) hormone release 2.Insulin release	1.Increases the insertion of aquaporin-2 into the luminal membrane of renal tubules, thereby increasing free water absorption 2.Increase sodium absorption 3.Afferent arteriolar vasodilation in kidney 4.Release of Von Willibrand factor

 

 

 

SNIPPETS

1. In physiological states, vasopressin released from the posterior pituitary has lower affinity for V_1A receptors compared to V₂ receptors. Compared to its anti-diuretic action, higher than normal levels of vasopressin are required to produce vasoconstriction.
2. During the initial phase of septic shock, circulating vasopressin typically surges several-fold. In the later phase, approximately one-third of patients exhibit a relative vasopressin deficiency, contributing to refractory vasoplegia.³
3. Contrary to popular belief, Terlipressin is a non-selective agonist of V₁ and V₂ receptors. Terlipressin is a prodrug that undergoes enzymatic cleavage by endothelial peptidases, providing a gradual release of its active form, lysine-vasopressin, over approximately 4 to 6 hours.

Angiotensin Receptors

Angiotensin receptors play a key role in the Renin-Angiotensin-Aldosterone System (RAAS) and modulate hemodynamics, fluids and electrolyte balance. There are two major angiotensin receptors - Angiotensin II receptor type 1 (AT₁) and Angiotensin II receptor type 2 (AT₂). Both are G protein-coupled receptors.

AT₁ receptors are expressed predominantly in glomeruli, renal tubules, efferent arterioles, heart, liver and adrenals. Angiotensin II interacts with AT₁ receptors to cause vasoconstriction, inflammation, vasopressin and aldosterone release.

AT₂ receptors are located primarily in afferent arterioles in the kidney.  Angiotensin II of the classical RAAS pathway and Angiotensin-(1-9) of the alternate RAAS pathway stimulate AT₂ receptors to produce vasodilation and anti-inflammatory effects (Figure 1).⁴ These receptors also mediate vasodilation through the production of bradykinins.⁵

Figure 1: Classical and alternative pathways of Renin-Angiotensin-Aldosterone pathway in sepsis.

ACE – Angiotensin converting enzyme, AT1-R - Angiotensin II receptor type 1, AT2-R - Angiotensin II receptor type 2, DPP-3 – Dipeptidyl peptidase 3, Mas-R – Mas receptor

The image is adapted from Legrand et al.⁴

 

 

 

SNIPPETS

1. Angiotensin II receptor blockers (ARBs) are selective for AT₁ receptors and not AT₂ receptors. On the other hand, Angiotensin-converting enzyme (ACE) inhibitors affect both AT₁ and AT₂ receptors by reducing Angiotensin II levels.
2. In sepsis, a relative deficit of AT₁ receptors appears to be one of the major reasons for vasoplegia.

Endothelin Receptors

Endothelin (ET-1, ET-2 and ET-3) cause vasoconstriction by interacting with endothelin receptors (Figure 2). There are two major endothelin receptors – ET_A and ET_B (Table 3).

                                            

Figure 2: Endothelin-1 and its actions

IL-1 – Interleukin 1, LDL – Low-density lipoprotein, MAPK – Mitogen activated protein kinase, NO - Nitric oxide, PGI2 - Prostaglandin I₂

The image is adapted from Rang & Dale's Pharmacology. 9th ed.

Table 3: Endothelin Receptors

	ETA receptor	ETB receptor
Type of G protein receptor	Gq	Gq
Second messengers	Activates phospholipase C	Activates phospholipase C
Location of the receptor	1.Vascular smooth muscle 2.Heart 3.Lung 4.Kidney	1.Cerebral cortex & cerebellum 2.Vascular endothelium 3.Vascular smooth muscle 4.Heart 5.Lung 6.Kidney
Affinity of Endothelin	ET-1 = ET-2 > ET-3	ET-1 = ET-2 = ET-3
Clinical effects	1.Vasoconstriction 2.Bronchoconstriction 3.Aldosterone secretion	1.Vasodilation 2.Inhibition of platelet aggregation
Antagonist	Bosentan Ambrisentan (Selective)	Bosentan

 

Conclusion

Vasoactive receptors form the molecular framework governing cardiovascular homeostasis and shock physiology. A receptor-level understanding allows clinicians to rationally select agents based on the underlying pathophysiology—whether it is distributive, cardiogenic, or mixed shock. Future research targeting receptor desensitization, intracellular signaling modulation, and selective agonism may refine vasopressor therapy, improving survival while minimizing adverse effects.

 

Recommended Reading

1. Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan D, Rang HP. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2019
2. Belfiore J, Taddei R, Biancofiore G. Catecholamines in sepsis: pharmacological insights and clinical applications – a narrative review. J Anesth Analg Crit Care. 2025 Apr 3;5(1):17. doi: 10.1186/s44158-025-00241-2. PMID: 40176108; PMCID: PMC11966821.
3. Levy B, Fritz C, Tahon E, Jacquot A, Auchet T, Kimmoun A. Vasoplegia treatments: the past, the present, and the future. Crit Care. 2018 Feb 27;22(1):52. doi: 10.1186/s13054-018-1967-3. PMID: 29486781; PMCID: PMC6389278.
4. Legrand M, Khanna AK, Ostermann M, Kotani Y, Ferrer R, Girardis M, Leone M, DePascale G, Pickkers P, Tissieres P, Annoni F, Kotfis K, Landoni G, Zarbock A, Wieruszewski PM, De Backer D, Vincent JL, Bellomo R. The renin-angiotensin-aldosterone-system in sepsis and its clinical modulation with exogenous angiotensin II. Crit Care. 2024 Nov 26;28(1):389. doi: 10.1186/s13054-024-05123-7. PMID: 39593182; PMCID: PMC11590289.
5. Garcia B, Zarbock A, Bellomo R, Legrand M. The alternative renin-angiotensin system in critically ill patients: pathophysiology and therapeutic implications. Crit Care. 2023 Nov 20;27(1):453. doi: 10.1186/s13054-023-04739-5. PMID: 37986086; PMCID: PMC10662652.