Alpha-Adrenergic Mechanisms in the Cardiovascular Hyperreactivity to Norepinephrine-Infusion in Essential Hypertension

Abstract

Aims: Essential hypertension (EHT) is characterized by cardiovascular hyperreactivity to stress but underlying mechanism are not fully understood. Here, we investigated the role of α-adrenergic receptors (α-AR) in the cardiovascular reactivity to a norepinephrine (NE)-stress reactivity-mimicking NE-infusion in essential hypertensive individuals (HT) as compared to normotensive individuals (NT).

Methods: 24 male HT and 24 male NT participated in three experimental trials on three separate days with a 1-min infusion followed by a 15-min infusion. Trials varied in infusion-substances: placebo saline (Sal)-infusions (trial-1:Sal+Sal), NE-infusion without (trial-2:Sal+NE) or with non-selective α-AR blockade by phentolamine (PHE) (trial-3:PHE+NE). NE-infusion dosage (5µg/ml/min) and duration were chosen to mimic duration and physiological effects of NE-release in reaction to established stress induction protocols. We repeatedly measured systolic (SBP) and diastolic blood pressure (DBP) as well as heart rate before, during, and after infusions.

Results: SBP and DBP reactivity to the three infusion-trials differed between HT and NT (p's≤.014). HT exhibited greater BP reactivity to NE-infusion alone compared to NT (trial-2-vs-trial-1: p's≤.033). Group differences in DBP reactivity to NE disappeared with prior PHE blockade (trial-3: p=.26), while SBP reactivity differences remained (trial-3: p=.016). Heart rate reactivity to infusion-trials did not differ between HT and NT (p=.73).

Conclusion: Our findings suggest a mediating role of α-AR in DBP hyperreactivity to NE-infusion in EHT. However, in SBP hyperreactivity to NE-infusion in EHT, the functioning of α-AR seems impaired suggesting that the SBP hyperreactivity in hypertension is not mediated by α-AR.

Keywords: alpha-adrenergic receptor blockade; cardiovascular reactivity; essential hypertension; norepinephrine-infusion; phentolamine.

Figure 1

Participant flow chart. BP, blood pressure; HT, hypertensive participants; HR, heart rate; n, sample size; NT, normotensive participants.

Figure 2

Infusion procedure and measurements. Infusion dosages: Norepinephrine: 75 µg (5 µg/ml/min); PHE: 2.5 mg. CVM, cardiovascular measurement; i.e. blood pressure and heart rate assessment; CAT, catecholamine assessment; PHE, phentolamine; post, post infusion 2.

Figure 3

Systolic blood pressure (SBP) reactivity to the three different substance infusion-trials (trial 1: Sal+Sal, circles; trial 2: Sal+NE, triangles; trial 3: PHE+NE, rectangles) in hypertensive participants (HT; black symbols; n = 23) and normotensive controls (NT; white symbols; n = 24) (mean ± SEM). SBP reactivity differed across the three trials between HT and NT as revealed by the calculated general linear model (interaction trials-by-group-by-time: p = .002). Pairwise trial comparisons by means of general linear models: In comparison to NT, HT displayed higher SBP reactivity to Sal+NE as compared to Sal+Sal (p = .033). Moreover, HT and NT differed in their SBP reactivity to PHE+NE as compared to Sal+Sal (p = .015) and to Sal+NE (p = .007): In NT, SBP reactivity to PHE+NE was markedly reduced as compared to Sal+NE, whereas HT showed a similar reactivity to Sal+NE and PHE+NE. Within each trial by means of repeated measures ANCOVAs: HT showed higher SBP reactivity to Sal+NE and PHE+NE (p’s ≤.038) but not to Sal+Sal (p = .21).

Figure 4

Diastolic blood pressure (DBP) reactivity to the three different substance infusion-trials (trial 1: Sal+Sal, circles; trial 2: Sal+NE, triangles; trial 3: PHE+NE, rectangles) in hypertensive participants (HT; black symbols; n = 23) and normotensive controls (NT; white symbols; n = 24) (mean ± SEM). DBP reactivity differed across the three trials between HT and NT as revealed by the calculated general linear model (interaction trials-by-group-by-time: p = .014). Pairwise trial comparisons by means of general linear models: In comparison to NT, HT displayed higher DBP reactivity to Sal+NE as compared to Sal+Sal (p = .007). PHE-induced α-adrenergic receptor blockade dampened reactivity to NE in both, HT and NT, resulting in similar reactivity to Sal+Sal and PHE+NE (Sal+Sal vs. PHE+NE: p = .55; Sal+NE vs. PHE+NE: p = .024). Within each trial by means of repeated measures ANCOVAs: DBP reactivity of HT and NT to did not differ to Sal+Sal and PHE+NE (p’s ≥.26) but to Sal+NE where HT exhibited higher reactivity as compared to NT (p = .034).

Figure 5

Heart rate (HR) reactivity to the three different substance infusion-trials (trial 1: Sal+Sal, circles; trial 2: Sal+NE, triangles; trial 3: PHE+NE, rectangles) in hypertensive participants (HT; black symbols; n = 23) and normotensive controls (NT; white symbols; n = 23) (mean ± SEM). HR reactivity across the three trials did not differ between HT and NT as revealed by the calculated general linear model (interaction trials-by-group-by-time: p = .73).