Vascular Tone, Vasoplegia, and Catecholamine Responsiveness

Vascular smooth muscle changes the diameter and capacity of blood vessels. These changes influence arterial pressure, venous return, and the distribution of flow. Understanding a vasopressor response therefore requires following what happens to the heart and organs as well as to the pressure reading.

21.1 Vascular Tone Is More Than a Resistance Number

Vascular tone is the active tension produced by smooth muscle in a vessel wall. When that muscle contracts, it tends to narrow the vessel. The resulting diameter also depends on the pressure stretching the wall, the surrounding tissue pressure, and the wall's passive elasticity. A change in diameter is therefore not a direct measurement of a change in muscle activation.

Small arteries and arterioles provide much of the adjustable resistance to systemic flow. Narrowing these vessels usually increases the pressure difference needed to drive a given flow. Veins have a different role. By changing their capacity, they can hold more blood in a reservoir or redistribute it toward the heart. These arterial and venous actions can occur together, but they affect circulation through different mechanisms.

Systemic vascular resistance, or SVR, summarizes the relationship between systemic flow and its arterial-to-venous pressure difference. Mean arterial pressure is the upstream pressure used in this calculation. Central venous pressure approximates the downstream pressure, and cardiac output is the volume flowing through the circulation each minute.

Enter both pressures in mm Hg and cardiac output in L/min. The factor 80 converts the answer to dyn·s·cm⁻⁵. For an illustrative mean arterial pressure of 65 mm Hg and central venous pressure of 10 mm Hg, the pressure difference is 65 − 10 = 55 mm Hg. If cardiac output is 8 L/min, SVR = 80 × 55 / 8 = 550 dyn·s·cm⁻⁵. If output is instead 4 L/min at the same pressures, SVR = 80 × 55 / 4 = 1100 dyn·s·cm⁻⁵.

The two examples have the same arterial pressure but very different flow and calculated resistance. They show why hypotension alone cannot establish that a patient has low SVR. They do not define a universal threshold for vasoplegia or identify the cause of either circulation.

SVR is calculated from measured pressures and output. Errors in any of those measurements affect the answer. The calculation also combines many vascular beds into one value. A low overall resistance can coexist with restricted flow in a kidney, limb, or intestinal region. It cannot reveal microvascular obstruction or uneven capillary perfusion.

Use SVR to describe the pressure–flow relationship, then examine the mechanism. The same number may accompany different degrees of venous dilation, ventricular dysfunction, and regional maldistribution. Those differences influence what happens when vascular tone is increased.

21.2 Smooth-Muscle Contraction Depends on Calcium and Its Sensitivity

Vascular smooth muscle generates force when myosin interacts with actin. Calcium helps control whether that interaction can occur. Unlike cardiac muscle, smooth muscle regulates contraction largely by changing the phosphorylation of the myosin light chain.

When intracellular calcium rises, calcium binds to the protein calmodulin. The calcium–calmodulin complex activates myosin light-chain kinase. This enzyme adds a phosphate group to the myosin light chain, allowing myosin to interact more effectively with actin and generate force. Myosin light-chain phosphatase removes that phosphate group and favors relaxation. The balance between these enzymes helps determine the force produced.

Calcium can enter through channels in the cell membrane or be released from intracellular stores. Some membrane channels respond to electrical depolarization. Receptors can also activate signaling pathways that release stored calcium or alter calcium entry. A constrictor hormone therefore needs a functioning sequence from receptor activation to calcium handling and myosin activation.

Calcium concentration is only part of the explanation. At the same calcium concentration, the muscle can produce more force if myosin phosphatase is inhibited. This is calcium sensitization: the contractile system generates greater force for a given calcium signal. Rho-associated kinase is one pathway that can reduce phosphatase activity and sustain myosin phosphorylation.

Uehata and colleagues used an inhibitor of Rho-associated kinase to study calcium sensitization in experimental smooth muscle and hypertensive animals. Their findings support this additional control of force generation. They do not establish that manipulating the pathway treats septic vasoplegia. 1

Relaxation can interrupt the sequence at several points. Less calcium may enter the cell, more may be removed from the cytoplasm, or phosphatase activity may become more effective relative to kinase activity. A strong receptor stimulus can therefore produce little contraction when the processes downstream favor relaxation.

This explains why a weak response to a vasopressor does not necessarily mean that too little drug reached the receptor. The receptor may bind the drug while the cell fails to translate that signal into force. At the bedside, the measured pressure response adds further influences from the heart and circulating volume, so it cannot isolate which cellular step is impaired.

21.3 The Endothelium Regulates the Muscle Beneath It

Endothelial cells line the vessel lumen and respond to blood-borne substances and mechanical forces such as shear stress. They release signals that alter the smooth muscle beneath them. This allows a local vascular bed to adjust its diameter while participating in wider control of blood flow.

The classic experiments of Furchgott and Zawadzki made this function visible. Acetylcholine relaxed isolated arterial preparations when the endothelium was intact. Removing the endothelial layer prevented that relaxation. The experiment established that the endothelial cells supplied an essential relaxing signal in that preparation. It preceded the identification of nitric oxide as a major endothelial relaxing mediator. 2

Nitric oxide diffuses from its site of production into nearby smooth-muscle cells. It activates soluble guanylate cyclase, which increases the intracellular signaling molecule cyclic guanosine monophosphate, or cGMP. Subsequent signaling changes calcium handling and contractile regulation in ways that favor relaxation. Arnold and colleagues demonstrated nitric-oxide activation of guanylate cyclase and increased cGMP in tissue preparations, providing a key biochemical link in this sequence. 3

The endothelium uses several other signals. Prostacyclin and endothelial influences on membrane potential can also promote relaxation. Constrictor mediators participate in the balance. The relative contribution of each pathway differs between organs, vessel sizes, and physiological conditions.

Inflammation can increase vasodilator production while also damaging normal local vascular control. These effects need not occur uniformly. Excessive dilation in one region can coexist with endothelial dysfunction, microvascular obstruction, or poor flow in another. A low calculated SVR therefore does not mean that every small vessel is open or that tissue perfusion is adequate.

A treatment that blocks a relaxing pathway may raise systemic pressure by increasing vascular resistance. The same treatment may remove local signals needed to maintain flow or alter the load on the heart. This is why the demonstration that a pathway contributes to hypotension does not by itself establish that globally blocking it will benefit the patient.

21.4 Receptors Translate Different Signals into Different Effects

A receptor links a circulating signal to a cellular response. The response depends on the receptor subtype and on the signaling machinery in that cell. The same family of messengers can therefore stimulate the heart while relaxing smooth muscle in some vessels.

Alpha-1 adrenergic receptors commonly activate the Gq signaling protein and phospholipase C. The resulting intracellular messengers release stored calcium and help promote vascular contraction. Alpha-2 receptors have both presynaptic roles in regulating transmitter release and direct vascular effects. Their location and signaling differ from those of alpha-1 receptors, so the term alpha stimulation does not describe one uniform mechanism.

Beta-1 receptors are important in cardiomyocytes. Their cAMP-linked signaling increases the calcium signals that support contraction and can increase heart rate. Beta-2 receptors in vascular smooth muscle also use cAMP-linked signaling, but the cellular targets favor relaxation. The messenger's effect depends on what the receiving cell does with it.

Vasopressin and angiotensin II provide nonadrenergic routes to contraction. Vascular V1a receptors mediate important constrictor effects of vasopressin. AT1 receptors mediate important vasoconstrictor effects of angiotensin II. These pathways overlap with parts of intracellular calcium signaling without producing identical whole-body responses.

The table identifies predominant effects rather than exclusive receptor locations or complete drug profiles. The observed response also depends on receptor density, endogenous hormones, dose, and the patient's baseline vascular and cardiac state.

For example, norepinephrine has arterial, venous, and cardiac actions. Its venous action can redistribute existing blood toward the heart, while beta-1 stimulation can support contraction. Its arterial action simultaneously increases the load against which the ventricle ejects. A receptor label cannot predict which of these effects will dominate in an individual patient.

21.5 Vasoplegia Is a Failure of Appropriate Vascular Tone

Vasoplegia describes pathologically reduced vascular tone that contributes to inadequate arterial pressure. It often produces a low systemic resistance despite an output that is normal or high. Definitions differ between clinical settings, so no single SVR value or vasopressor dose establishes the syndrome in every patient.

Sepsis is a common cause. Similar patterns occur after cardiopulmonary bypass and in other inflammatory or drug-related conditions. The term identifies a vascular component of circulatory failure. It does not exclude simultaneous hypovolemia, ventricular dysfunction, or mechanical obstruction.

Several cellular changes can reduce the response to constrictor signals. Inflammatory mediators may increase relaxing signals or interfere with receptor coupling. Altered calcium handling can reduce the force generated after receptor stimulation. Changes in potassium-channel activity can also shift the membrane toward a state that opposes contraction.

When potassium channels open, potassium movement tends to make the cell interior more negative. This hyperpolarization reduces activation of voltage-dependent calcium channels. Less calcium entry then favors relaxation. ATP-sensitive potassium channels connect metabolic conditions to this electrical control of vascular tone.

Landry and Oliver studied these channels in dogs with endotoxemia or hypoxic lactic acidosis. Blocking the channels with glyburide restored pressure in those experimental conditions. The result supports a role for the channels in that model; it does not establish their blockade as routine treatment for human septic shock. 4

Loss of venous tone adds another mechanism. A more capacious venous system can accommodate more blood without generating the same pressure that drives venous return. Effective stressed volume can fall even when total blood volume has not fallen. If the heart receives less useful preload, cardiac output may decrease despite a large extracellular-fluid volume and visible edema.

The bedside problem is therefore often mixed. Vasodilation can lower pressure while impaired venous return or myocardial dysfunction limits flow. Additional fluid may help one component while raising venous pressure and worsening edema in another. Identifying the vascular component should lead to examination of the rest of the circulation, rather than end that assessment.

21.6 Catecholamine Responsiveness Changes During Critical Illness

Responsiveness describes the effect produced by a drug exposure. A reduction in sensitivity shifts the dose–response relationship: a larger exposure is needed for a similar effect. A reduction in maximal responsiveness is different. Even a large exposure cannot produce the previous maximum effect. A patient's rising infusion rate does not distinguish these possibilities by itself.

Continued receptor stimulation can change receptor phosphorylation, coupling to intracellular proteins, movement into the cell, and expression at the membrane. Inflammation can also impair signaling beyond the receptor. These processes explain why the phrase receptor exhaustion is too imprecise to account for every increasing vasopressor requirement.

Bernardin and colleagues studied beta-adrenergic signaling in circulating human immune cells during critical illness. They found impairment in receptor-linked cAMP responses and additional downstream defects in the septic group. These findings demonstrate altered signal transmission in the studied cells. They do not measure alpha-adrenergic contraction in a patient's arteries or establish that every vascular bed changes in the same way. 5

Acidemia can further alter the response by affecting receptors, membrane channels, contractile proteins, and cardiac performance. The effects differ across pathways and tissues. There is no universal pH at which all vasopressors abruptly cease to work.

Medgett and colleagues lowered pH in two isolated arterial preparations. Noradrenaline-induced constriction was markedly inhibited in the cat cerebral artery, where alpha-2 responses predominated, but was preserved in the rabbit pulmonary artery, where alpha-1 responses predominated. The comparison demonstrates that acidosis need not affect different preparations equally. Because receptor subtype, vascular bed, and species differed together, it cannot establish a universal clinical rule about one receptor subtype. 6

These experiments also do not prove that administering an alkalinizing drug restores organ perfusion. Correcting the cause of acidemia and testing a particular buffer intervention are separate clinical questions.

The measured response includes the rest of the circulation. A worsening ventricle may generate less output despite effective vasoconstriction. Continuing blood loss or increased venous capacity may reduce filling. An interrupted infusion may reduce exposure even though the pump displays an unchanged rate. Reassessment should therefore include drug delivery, the evolving shock mechanism, cardiac function, acid–base conditions, and perfusion.

21.7 Norepinephrine Can Change Pressure, Preload, and Output

Norepinephrine commonly raises arterial pressure by constricting resistance vessels. It can also constrict venous reservoirs. When venous capacity falls, some blood that previously filled the reservoir contributes more to the pressure driving venous return. This recruits effective stressed volume without adding blood to the body.

Recruitment can increase ventricular filling and stroke volume when the heart is preload responsive. Cardiac beta-1 stimulation can also support contraction. At the same time, arterial constriction increases ventricular afterload. The net output response reflects the balance between improved filling, contractile stimulation, and the increased load on ejection.

Hamzaoui and colleagues observed increased preload and cardiac output after early norepinephrine administration in severely hypotensive septic patients. This physiological study shows that norepinephrine can increase flow as well as pressure. Its design and selected population do not establish the same response in every phase of sepsis or isolate one mechanism as the cause of all observed changes. 7

A poorly functioning ventricle may not turn additional filling into a useful increase in ejection. Filling pressures can then rise. If the additional arterial load outweighs the benefit of recruitment and stimulation, stroke volume can fall. A higher pressure in that situation may coexist with more congestion and less forward flow.

CENSER tested early low-dose norepinephrine in a single-center randomized phase II trial. More patients achieved its prespecified six-hour shock-control outcome, which combined a pressure requirement with evidence of adequate urine output or lactate improvement. Twenty-eight-day mortality did not differ significantly. The trial supports the studied early resuscitation strategy's effect on shock control; it does not establish a universal survival benefit. 8

Changes in vascular tone can also alter arterial waveform analysis. A pulse-contour estimate may change partly because the relationship between the waveform and actual flow has changed. When a modest output difference determines interpretation, consider the monitor's assumptions and whether another assessment supports it.

Follow the combined response. A rise in pressure with maintained or increased stroke volume and improving perfusion differs from a rise accompanied by reduced output and increasing filling pressures. The drug name and dose alone cannot identify which response occurred.

21.8 Nonadrenergic Pathways Can Support Pressure Through Other Receptors

Vasopressin and angiotensin II stimulate constrictor pathways through receptors distinct from adrenergic receptors. Adding one may restore pressure with less catecholamine exposure. Using another receptor does not remove the need to assess ventricular load and regional perfusion.

Vasopressin's vascular V1a effects promote smooth-muscle contraction. Its V2 effects in the kidney promote water retention and are a separate part of its physiology. The net circulatory response depends on the dose, baseline tone, and the heart's ability to eject against the increased arterial load.

In VASST, low-dose vasopressin was compared with additional norepinephrine in patients already receiving catecholamine support for septic shock. Vasopressin reduced norepinephrine requirements while maintaining pressure, but overall 28-day mortality was not significantly different. A favorable result in a severity subgroup does not establish a survival indication for all patients. 9

Angiotensin II acts principally through AT1 receptors for its vasoconstrictor effects. The renin–angiotensin system also influences renal vascular behavior and hormonal responses. Consequently, the systemic pressure reading cannot tell whether perfusion in each organ has improved.

ATHOS-3 tested angiotensin II against placebo added to background support in catecholamine-resistant vasodilatory shock. Its primary endpoint was a defined pressure response three hours after starting the infusion without increasing background vasopressors. Angiotensin II increased the proportion achieving that endpoint. Overall 28-day mortality was not significantly reduced. 10

A successful pressure response demonstrates that the intervention changed the pressure-support requirement under the studied conditions. It does not establish that cardiac output improved, that regional ischemia decreased, or that the patient is more likely to survive. Each of those claims requires its own evidence.

The same distinction applies to catecholamine sparing. Reducing norepinephrine exposure may be a useful treatment aim, but the lower infusion rate is an intermediate result. Follow whether the new combination maintains circulation and changes arrhythmias, ischemic complications, congestion, or organ function. Treatment decisions require both this observed response and evidence applicable to the clinical population.

21.9 Correcting a Mechanism Is Not the Same as Improving Outcomes

A mechanism can explain hypotension without identifying a beneficial treatment. Blocking an excessive relaxing signal may increase resistance and raise pressure. If that same signal helps maintain local flow or limits cardiac loading, global blockade can produce harmful effects elsewhere.

The nitric oxide synthase inhibitor 546C88 illustrates this problem. The randomized trial reported by López and colleagues was stopped early because mortality was higher with the inhibitor. Cardiovascular adverse events contributed to the difference between groups. A pathway implicated in vasodilation therefore became a harmful treatment target when inhibited through this strategy. 11

The result does not negate nitric oxide's contribution to vasoplegia. It separates two questions: whether a signal participates in hypotension and whether manipulating it in a particular way improves patient outcomes. The second question must account for the pathway's other functions and the intervention's effects across the circulation.

Corticosteroids also act beyond one constrictor receptor. They alter inflammatory signaling and can support vascular responsiveness. These actions take place alongside effects on other tissues, so shock reversal and survival must be evaluated rather than inferred from the proposed mechanism.

In ADRENAL, hydrocortisone shortened the time to shock resolution in ventilated adults with septic shock. It did not significantly reduce the primary outcome of 90-day mortality. This is the result for that trial's population and regimen; it does not establish that every corticosteroid regimen has identical effects. 12

Current guidance integrates evidence beyond one trial. The 2026 Surviving Sepsis Campaign conditionally favors norepinephrine over vasopressin or angiotensin II as the initial vasopressor in usual septic shock. It conditionally suggests adding vasopressin when norepinephrine doses are escalating, with moderate-certainty evidence for that recommendation. Concomitant cardiac dysfunction has a separate first-line recommendation that allows either norepinephrine or epinephrine. The guideline also conditionally suggests IV corticosteroids for septic shock, with low-certainty evidence. 13

These distinctions keep the therapeutic claim matched to its evidence. Receptor activation explains an action. Pressure control demonstrates one physiological effect. Shock resolution, organ recovery, and survival are further outcomes that need direct evaluation. None should be substituted for another merely because the mechanistic sequence appears plausible.

21.10 Interpret the Trajectory of Pressure, Flow, and Perfusion

Before changing vasoactive support, identify the problem the intervention is meant to correct. It may be inadequate arterial pressure, insufficient output, or a combination. Confirm the actual drug exposure and compare the circulation over a defined interval so that the response can be related to the change.

As tone increases, output can rise, remain stable, or fall. Venous recruitment may improve filling, and cardiac stimulation may improve ejection. Increased afterload may instead limit ejection. Ventricular interaction and the pulmonary circulation can further modify these effects, especially when the right ventricle is failing.

A pressure rise with falling cardiac output can reduce global oxygen delivery if arterial oxygen content is unchanged. This does not mean the pressure rise has no value; a critically low perfusion pressure may itself limit organ flow. It means that the benefit and the accompanying loss of flow must be assessed together.

Regional findings add information that global output cannot provide. Peripheral perfusion, mental status when assessable, urine output, and metabolic trends can help identify whether organ conditions are improving. Resistance within each organ, venous drainage pressure, and tissue swelling can cause different organs to respond differently to the same systemic intervention.

Each observation also has other determinants. Urine output may lag or remain low because of intrinsic kidney injury. Lactate can change through altered production or clearance without a simple global-flow deficit. Sedation can prevent meaningful neurological assessment. Interpret the pattern and its timing rather than demanding that one marker explain the entire circulation.

New tachyarrhythmia can reduce filling time and increase myocardial oxygen demand. Excessive regional constriction can impair flow to vulnerable tissues. When pressure improves but perfusion worsens, these possibilities deserve attention alongside reduced output, venous congestion, and progression of the underlying illness.

Unexpected responses also require checking the measurements and delivery. An incorrectly leveled transducer can create an apparent pressure change. A damped waveform can distort derived values. Extravasation or an interrupted infusion can reduce delivered drug despite an unchanged pump setting.

Responsiveness changes during recovery as well as deterioration. A dose that was previously needed may produce excessive constriction when vascular function recovers. Reducing support therefore requires the same attention to pressure, flow, and organ response as increasing it.

21.11 Applying the Mechanisms to Persistent Hypotension

Consider an illustrative patient with sepsis, persistent hypotension, warm extremities, and a high measured cardiac output. A preload assessment suggests little useful increase in flow from additional volume. Venous congestion is beginning to appear.

The combination supports an important loss of vascular tone. The heart is generating substantial flow, yet the arterial pressure remains low. Warm skin is consistent with peripheral dilation, but it does not establish adequate perfusion in every organ. Verify the measurements and review cardiac function, infection control, drug exposures, and regional findings before assigning the entire problem to vasoplegia.

Suppose a vasoconstrictor raises arterial pressure while output remains adequate and peripheral perfusion improves. This response is consistent with restoring useful tone without an observed loss of forward flow. Continue following the trajectory because the same dose may have different effects as preload, cardiac function, and vascular responsiveness change.

Now consider a different response. Pressure rises, but output falls, filling pressures increase, and the extremities become poorly perfused. The arterial load may have exceeded the ventricle's capacity to maintain ejection. Venous recruitment may also have raised filling pressure beyond the range that improves stroke volume. Review ventricular function and congestion, and confirm that the apparent output change is reliable.

If the same apparent drug exposure later produces less pressure, inspect delivery first and reassess the shock state. Worsening inflammation, acidemia, myocardial dysfunction, ongoing fluid loss, and altered signaling may coexist. A rising infusion requirement establishes that more support is being used; it does not identify the dominant cause.

Adding another receptor pathway creates another physiological experiment, but interpretation still depends on the whole circulation. A lower norepinephrine dose is evidence of changed support. Sustained pressure with maintained flow and improving organ findings is stronger evidence that the combination is meeting its purpose. New ischemia, arrhythmia, or worsening congestion changes that assessment.

This chapter completes the section on microvascular and fluid physiology. The next part examines respiratory mechanics, where resistance, compliance, and pressure continue to influence both ventilation and the circulation.

References

1. Uehata M, Ishizaki T, Satoh H, et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997;389:990–994. doi:10.1038/40187

2. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373–376. doi:10.1038/288373a0

3. Arnold WP, Mittal CK, Katsuki S, Murad F. Nitric oxide activates guanylate cyclase and increases guanosine 3′:5′-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci U S A. 1977;74(8):3203–3207. doi:10.1073/pnas.74.8.3203

4. Landry DW, Oliver JA. The ATP-sensitive K+ channel mediates hypotension in endotoxemia and hypoxic lactic acidosis in dog. J Clin Invest. 1992;89(6):2071–2074. doi:10.1172/JCI115820

5. Bernardin G, Strosberg AD, Bernard A, Mattei M, Marullo S. Beta-adrenergic receptor-dependent and -independent stimulation of adenylate cyclase is impaired during severe sepsis in humans. Intensive Care Med. 1998;24(12):1315–1322. doi:10.1007/s001340050768

6. Medgett IC, Hicks PE, Langer SZ. Effect of acidosis on alpha 1- and alpha 2-adrenoceptor-mediated vasoconstrictor responses in isolated arteries. Eur J Pharmacol. 1987;135(3):443–447. doi:10.1016/0014-2999(87)90698-4

7. Hamzaoui O, Georger JF, Monnet X, et al. Early administration of norepinephrine increases cardiac preload and cardiac output in septic patients with life-threatening hypotension. Crit Care. 2010;14:R142. doi:10.1186/cc9207

8. Permpikul C, Tongyoo S, Viarasilpa T, Trainarongsakul T, Chakorn T, Udompanturak S. Early use of norepinephrine in septic shock resuscitation (CENSER). A randomized trial. Am J Respir Crit Care Med. 2019;199(9):1097–1105. doi:10.1164/rccm.201806-1034OC

9. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358(9):877–887. doi:10.1056/NEJMoa067373

10. Khanna A, English SW, Wang XS, et al. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med. 2017;377(5):419–430. doi:10.1056/NEJMoa1704154

11. López A, Lorente JA, Steingrub J, et al. Multiple-center, randomized, placebo-controlled, double-blind study of the nitric oxide synthase inhibitor 546C88: effect on survival in patients with septic shock. Crit Care Med. 2004;32(1):21–30. PubMed

12. Venkatesh B, Finfer S, Cohen J, et al. Adjunctive glucocorticoid therapy in patients with septic shock. N Engl J Med. 2018;378(9):797–808. doi:10.1056/NEJMoa1705835

13. Society of Critical Care Medicine and European Society of Intensive Care Medicine. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2026. Official recommendations