Direct-acting agonists typically have a β-hydroxyl group, although dopamine does not. In addition to facilitating activation of adrenoceptors, this hydroxyl group may be important for storage of sympathomimetic amines in neural vesicles.
General outlines of the cellular actions of sympathomimetics are presented in Tables 6–3 and 9–3. Sympathomimetics have prominent cardiovascular effects because of widespread distribution of α and β adrenoceptors in the heart, blood vessels, and neural and hormonal systems involved in blood pressure regulation.
The effects of sympathomimetic drugs on blood pressure can be explained on the basis of their effects on heart rate, myocardial function, peripheral vascular resistance, and venous return (see Figure 6–7 and Table 9–4). The endogenous catecholamines, norepinephrine and epinephrine, have complex cardiovascular effects because they activate both α and β receptors. It is easier to understand these actions by first describing the cardiovascular effect of sympathomimetics that are selective for a given adrenoreceptor.
A. Effects of Alpha1-Receptor Activation
Alpha1 receptors are widely expressed in vascular beds, and their activation leads to arterial and venous vasoconstriction. Their direct
TABLE 9–3 Distribution of adrenoceptor subtypes.
effect on cardiac function is of relatively less importance. A relatively pure α agonist such as phenylephrine increases peripheral arterial resistance and decreases venous capacitance. The enhanced arterial resistance usually leads to a dose-dependent rise in blood pressure (Figure 9–6). In the presence of normal cardiovascular reflexes, the rise in blood pressure elicits a baroreceptor-mediated increase in vagal tone with slowing of the heart rate, which may be quite marked (Figure 9–7). However, cardiac output may not diminish in proportion to this reduction in rate, since increased venous return may increase stroke volume. Furthermore, direct α-adrenoceptor stimulation of the heart may have a modest positive inotropic action. It is important to note that any effect these agents have on blood pressure is counteracted by compensatory autonomic baroreflex mechanisms aimed at restoring homeostasis. The magnitude of the restraining effect is quite dramatic. If baroreflex function is removed by pretreatment with the ganglionic blocker trimethaphan, the pressor effect of phenylephrine is increased approximately 10-fold, and bradycardia is no longer observed (Figure 9–7), confirming that the decrease in heart rate associated with the increase in blood pressure induced by phenylephrine was reflex in nature rather than a direct effect of α1-receptor activation.
Patients who have an impairment of autonomic function (due to pure autonomic failure as in the case study or to more common conditions such as diabetic autonomic neuropathy) exhibit this extreme hypersensitivity to most pressor and depressor stimuli, including medications. This is to a large extent due to failure of baroreflex buffering. Such patients may have exaggerated increases in heart rate or blood pressure when taking sympathomimetics with βand α-adrenergic activity, respectively. This, however, can be used as an advantage in their treatment. The α agonist midodrine is commonly used to ameliorate orthostatic hypotension in these patients.
There are major differences in receptor types predominantly expressed in the various vascular beds (Table 9–4). The skin vessels have predominantly α receptors and constrict in response to epinephrine and norepinephrine, as do the splanchnic vessels. Vessels in skeletal muscle may constrict or dilate depending on whether α or β receptors are activated. The blood vessels of the nasal mucosa express α receptors, and local vasoconstriction induced by sympathomimetics explains their decongestant action (see Therapeutic Uses of Sympathomimetic Drugs).
B. Effects of Alpha2-Receptor Activation