Abstract
Peripheral norepinephrine release is facilitated by presynaptic β-adrenoceptors, believed to involve the β2-subtype exclusively. However, β1-selective blockers are the most commonly used β-blockers in hypertension. Here the author tested the hypothesis that β1AR may function as presynaptic, release-facilitating auto-receptors. Since β1AR-blockers are injected during myocardial infarction, their influence on the cardiovascular response to acute norepinephrine release was also studied. By a newly established method, using tyramine-stimulated release through the norepinephrine transporter (NET), presynaptic control of catecholamine release was studied in normotensive and spontaneously hypertensive rats. β1AR-selective antagonists (CGP20712A, atenolol, metoprolol) reduced norepinephrine overflow to plasma equally efficient as β2AR-selective (ICI-118551) and β1+2AR (nadolol) antagonists in both strains. Neither antagonist lowered epinephrine secretion. Atenolol, which does not cross the blood–brain barrier, reduced norepinephrine overflow after adrenalectomy (AdrX), AdrX + ganglion blockade, losartan, or nephrectomy. Atenolol and metoprolol reduced resting cardiac work load. During tyramine-stimulated norepinephrine release, they had little effect on work load, and increased the transient rise in total peripheral vascular resistance, particularly atenolol when combined with losartan. In conclusion, β1AR, like β2AR, stimulated norepinephrine but not epinephrine release, independent of adrenal catecholamines, ganglion transmission, or renal renin release/angiotensin AT1 receptor activation. β1AR therefore functioned as a peripheral, presynaptic, facilitating auto-receptor. Like tyramine, hypoxia may induce NET-mediated release. Augmented tyramine-induced vasoconstriction, as observed after injection of β1AR-blocker, particularly atenolol combined with losartan, may hamper organ perfusion, and may have clinical relevance in hypoxic conditions such as myocardial infarction.
Highlights
Beta-blockers have been first-line drugs in the treatment of hypertension for half a century
Since β2AR are by far more effectively activated by epinephrine than norepinephrine, it has been suggested that they are activated by circulating epinephrine, or epinephrine co-released with norepinephrine after re-uptake through the norepinephrine transporter (NET) [5]
This overflow was reduced after pre-treatment with atenolol (β1), Table 2 | The effect of pre-treatment on cardiac work load (SBP × heart rate (HR)) during rest and during the response to tyramine
Summary
Beta-blockers have been first-line drugs in the treatment of hypertension for half a century. The β1-selective antagonist atenolol is the beta-blocker most frequently used in hypertension and is recommended as preventive medication after myocardial infarction. Metoprolol, another β1AR-selective antagonist, which unlike atenolol crosses the blood–brain barrier, is commonly used during acute myocardial infarction. Release of norepinephrine from peripheral sympathetic nerve terminal vesicles is stimulated or inhibited by presynaptic receptors (Figure 1). The first description of release-stimulating AR was made by Adler-Graschinsky and Langer [1]: β2AR but not β1AR agonists dose-dependently increased nerve-stimulated norepinephrine release, and the stimulating effect of isoproterenol on release was blocked by β2AR but not β1AR antagonists [2,3,4]. It has been accepted that the presynaptic, release-stimulating βAR is of the β2-subtype exclusively. Since β2AR are by far more effectively activated by epinephrine than norepinephrine, it has been suggested that they are activated by circulating epinephrine, or epinephrine co-released with norepinephrine after re-uptake through the norepinephrine transporter (NET) [5]
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