A 78-year-old woman is admitted to the hospital due to altered mental status. Medical history is significant for pyelonephritis, type 2 diabetes mellitus, coronary artery disease, and heart failure with reduced ejection fraction. Temperature is 36.2 C (97.2 F), blood pressure is 80/50 mm Hg, pulse is 120/min, and respirations are 24/min. Oxygen saturation is 90% on room air. Examination shows bilateral crackles. After she is started on appropriate treatment, including initiation of norepinephrine infusion, her blood pressure increases and her heart rate slightly decreases. This patient's change in heart rate is most likely due to norepinephrine's effect on which of the following receptors?
Cardiovascular effects of adrenergic agonists | |||
| |||
Agonist | Receptor | Blood | Heart |
Dobutamine | β1 > β2 | –/↓ | ↑ |
Dopamine | D1 > β1 > α1 | –/↓ | ↑ |
α1 > β1 > D1 | ↑ | –/↓* | |
Epinephrine | β1 > β2 > α1 | –/↓ | ↑ |
α1 > β1 > β2 | ↑ | –/↓* | |
Isoproterenol | β1 = β2 | –/↓ | ↑ |
Norepinephrine | α1 > β1 > β2 | ↑ | –/↓* |
Phenylephrine | α1 | ↑ | ↓* |
*Reflex-mediated decrease. SVR = systemic vascular resistance. | |||
Norepinephrine has both vasopressor and inotropic effects and is commonly used in patients with shock. It directly and potently stimulates alpha-1 receptors to trigger peripheral vasoconstriction, causing increased systemic vascular resistance (SVR) and increased blood pressure. Norepinephrine also directly stimulates beta-1 receptors to facilitate increased heart rate, myocardial contractility, and cardiac output (Choice C).
In addition to the direct effects of norepinephrine, the alpha-1–mediated increase in SVR triggers indirect effects via the baroreceptor reflex. Increased blood pressure stimulates increased firing of the aortic and carotid baroreceptors. In response, the CNS increases parasympathetic output and decreases sympathetic output, decreasing heart rate and contractility. These reflexive effects on the heart oppose the effects of direct beta-1–receptor stimulation. Because of the marked increase in SVR with norepinephrine, the reflexive decrease in heart rate usually completely offsets or overrides the directly-mediated increase in heart rate, resulting in an unchanged or slightly decreased heart rate.
A similar offsetting effect occurs with high-dose dopamine and high-dose epinephrine due to baroreceptor-mediated feedback from predominant alpha-1 receptor stimulation.
(Choices B and E) Stimulation of alpha-2 receptors in the CNS (eg, with clonidine) decreases sympathetic output, causing peripheral vasodilation, decreased heart rate, and reduced blood pressure. Stimulation of dopamine-1 receptors (eg, with dopamine) causes renal arteriolar vasodilation and increases renal blood flow. Norepinephrine has no significant effect on either dopamine-1 or central alpha-2 receptors (does not cross blood brain barrier).
(Choice D) Although norepinephrine also causes mild, direct stimulation of vasodilatory beta-2 receptors, its peripheral vasoconstrictive effect (mediated by alpha-1 receptors) predominates, making it a very potent vasopressor.
Educational objective:
Norepinephrine potently stimulates alpha-1 receptors to cause peripheral vasoconstriction, increasing systemic vascular resistance and blood pressure. This triggers a baroreceptor–mediated reflexive decrease in heart rate that completely offsets or overrides the direct beta-1–mediated increase in heart rate caused by norepinephrine, resulting in overall unchanged or slightly decreased heart rate.