Role of β _1–3 -Adrenoceptors in Blood Pressure Control at Rest and During Tyramine-Induced Norepinephrine Release in Spontaneously Hypertensive Rats

Abstract

beta-Adrenoceptors contribute to hypertension in spite of the fact that beta-adrenoceptor agonists lower blood pressure. We aimed to differentiate between these functions and to identify differences between spontaneously hypertensive and normotensive rats. beta-Adrenoceptor antagonists with different subtype selectivity or the ability to cross the blood-brain barrier were used to demonstrate beta-adrenoceptor involvement in resting blood pressure and the response to tyramine-induced peripheral norepinephrine release. The centrally acting propranolol (beta(1+2[+3])), CGP20712A (beta(1)), ICI-118551 (beta(2)), and SR59230A (beta(3)), as well as peripherally restricted nadolol (beta(1+2)) and atenolol (beta(1)), were administered intravenously, separately, or in combinations. Blood pressure, cardiac output, heart rate, total peripheral vascular resistance, and plasma catecholamine concentrations were evaluated. beta-Adrenoceptor antagonists had little effect on cardiovascular baselines in normotensive rats. In hypertensive rats, antagonist-induced hypotension paralleled reductions in resistance, except for atenolol, which reduced cardiac output. The resistance reduction involved primarily neuronal catecholamine, central beta(1)-adrenoceptors, and peripheral beta(2)-adrenoceptors. Tyramine induced a transient, prazosin-sensitive vascular resistance increase. Inhibition of nerve-activated, peripheral beta(1/3)-adrenoceptors enhanced this alpha(1)-adrenoceptor-dependent vasoconstriction in normotensive but not hypertensive rats. In hypertensive rats, return to baseline was eliminated after inhibition of the central beta(1)-adrenoceptor, epinephrine release (acute adrenalectomy), and peripheral beta(2/3)-adrenoceptors. Adrenalectomy eliminated beta-adrenoceptor-mediated vasodilation in hypertensive rats, and tyramine induced a prazosin-sensitive vasoconstriction, which was inhibited by combined blockade of central beta(1)- and peripheral beta(2)-adrenoceptors. In conclusion, nerve-activated beta(1)- and beta(3)-adrenoceptor-mediated vasodilation was not present in hypertensive rats, whereas epinephrine-activated beta(2)- and beta(3)-adrenoceptor-mediated vasodilation was upregulated. There was also a hypertensive, nerve-activated vasoconstrictory mechanism present in hypertensive rats, involving central beta(1)- and peripheral beta(2)-adrenoceptors combined.

Expression and functions of β1- and β2-adrenergic receptors on the bulbospinal neurons in the rostral ventrolateral medulla

“…b 2 -AR agonists are generally known to dilate blood vessels and decrease BP. 46 The existence of b 2 -ARs in the bulbospinal RVLM neurons was demonstrated in this study, and b 2 -AR agonists are considered to reduce BP partially through decreasing bulbospinal RVLM neuron activity.…”

Beta-3 Adrenoceptors as New Therapeutic Targets for Cardiovascular Pathologies

“…However, in spite of enhanced epinephrine secretion and subsequent augmented norepinephrine release in SHR, epinephrine functioned as an antihypertensive agent by upregulating ß 2 -and ß 3 -AR-mediated vasodilation [42]. In this model, the previously described [43] ß 3 -AR upregulation was confirmed and associated to G protein-coupled receptor kinase 2 (GRK2) increase [26], which seems to be the main factor involved in diminishing ß-AR signaling in hypertension [44].…”

β- and α2-Adrenoceptor Control of Vascular Tension and Catecholamine Release in Female Normotensive and Spontaneously Hypertensive Rats

“…In male rats, βAR opposed the TPR response throughout the tyramine-infusion period in WKY but downregulated the TPR response only during the late part of the infusion period in SHR (15). Thus, βAR-mediated vasodilatation played an important role in modulating the TPR response throughout the tyramine-infusion period in both genders in WKY and also in female SHR but played a delayed role in downregulating NE-induced vasoconstriction and TPR in male SHR.…”

“…Control rats were pretreated with PBS, and the tyramine infusion was started 10 min later. To answer the questions if β 1 AR and/or β 2 AR stimulated catecholamine release and/or opposed the NE-induced rise in TPR, the PBS sham injection was substituted with either β 1 AR-selective antagonists, i.e., the peripherally restricted atenolol (5.6 μmol/kg) or the not restricted metoprolol (8.8 μmol/kg, β 1 ), or the β 2 AR-selective antagonist ICI-118551 (initial dose of 1 μmol/kg, followed by 0.3 μmol/kg/min throughout the experiment) (15). To test for an additive effect of the β 1 AR and the β 2 AR, the rats were pretreated with the peripherally restricted β 1+2 AR-selective antagonist nadolol (8.5 μmol/kg) (15).…”