Epinephrine and the genesis of hypertension.

Abstract

Several lines of evidence suggest a psychophysiological link between stress, adrenomedullary activation, and the genesis of hypertension. Experimental data support four important concepts: 1) epinephrine stimulates prejunctional beta 2-adrenergic receptors that facilitate norepinephrine release from sympathetic nerve endings; 2) epinephrine can be converted into a cotransmitter by neuronal uptake and on subsequent release augment the simultaneous discharge of norepinephrine; 3) exogenous epinephrine can induce sustained hypertension in rats; and 4) there is a period of critical sensitivity to endogenous epinephrine in a genetic model of rat hypertension. Plasma epinephrine concentrations are elevated in many young subjects with borderline or mild hypertension. The hypothesis that intermittent surges in epinephrine could initiate or promote the development of primary hypertension by amplifying peripheral neurotransmission, both directly (facilitative effect) and indirectly (cotransmitter action), is supported by reports that hemodynamic and noradrenergic responses to sympathetic activation can be augmented by increases in endogenous epinephrine or by its local or systemic (up to 30 ng/kg/min) infusion. Such responses have been documented in both normotensive and hypertensive subjects and can be blocked by propranolol. Although the weight of evidence (mostly indirect) indicates that epinephrine can augment norepinephrine release in humans, the epinephrine hypothesis, itself, remains unproven. Expression of hypertension by this mechanism may be restricted to a specific epinephrine-sensitive subset of individuals with a genetic predisposition to high blood pressure.

Hypertension in women

“…24 Plasma noradrenaline levels provide a clinically useful index of sympathetic nervous system activity in human subjects. 25,26 Villecco et al 27 used a headup tilt test as a physiological stimulus to study blood pressure, heart rate, and plasma noradrenaline in women. They demonstrated that hypertensive women (both pre-and postmenopausal) had a significantly greater increase in noradrenaline secretion after physiological stimulation than normotensive women (P Ͻ 0.01) (Figure 3).…”

Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension

“…25 We demonstrated that the arteries from LPAR1-deficient mice became less responsive to phenylephrine stimulation in contraction, Figure 2. Null function of LPAR1 reduced blood pressure and inhibits sleep deprivation-induced blood pressure elevation and phenylephrine-induced vasoconstriction.…”

“…25 We demonstrated that the arteries from LPAR1-deficient mice became less responsive to phenylephrine stimulation in contraction, Two hundred seventy-eight healthy individuals were randomly recruited, and rs531001 was genotyped by direct sequencing. The individuals were divided into GG, CG, and CC groups.…”

Basal and Stimulated Sympathetic Responses After Epinephrine

“…[1][2][3][4] According to the "epinephrine hypothesis" of hypertension, epinephrine, released from the adrenal medulla during physiological stress, is taken up into sympathetic nerve terminals and later rereleased with norepinephrine (NE) as a cotransmitter. The epinephrine that has been rereleased stimulates further NE release through its action on presynaptic ␤-adrenergic receptors and in this way amplifies and prolongs sympathetic responses.…”

“…The epinephrine that has been rereleased stimulates further NE release through its action on presynaptic ␤-adrenergic receptors and in this way amplifies and prolongs sympathetic responses. 1,4,5 Therefore, a brief increase in epinephrine concentrations, such as occurs in response to stress, could, through the mechanisms of uptake, rerelease, and stimulation of NE release, amplify and prolong sympathetic responses and facilitate the development of hypertension. 1,3,4 Experimental evidence supports the existence of functional presynaptic ␤-adrenergic receptors as well as the process of uptake and rerelease of epinephrine in the nerve terminal [5][6][7][8][9][10] : mechanisms that would allow epinephrine to produce a delayed and sustained facilitatory effect on NE release.…”