Vascular β-adrenergic receptor system is dysfunctional after myocardial infarction

Abstract

We identified abnormalities in the vascular β-adrenergic receptor (β-AR) signaling pathway in heart failure after myocardial infarction (MI). To examine these abnormalities, we measured β-AR-mediated hemodynamics, vascular reactivity, and the vascular β-AR molecular signaling components in rats with heart failure after MI. Six weeks after MI, these rats had an increased left ventricular (LV) end-diastolic pressure, decreased LV systolic pressure, and decreased rate of LV pressure change (dP/d t). LV dP/d t responses to isoproterenol were shifted downward, although the responses for systemic vascular resistance were shifted upward in heart failure rats ( P < 0.05). Isoproterenol- and IBMX-induced vasorelaxations were blunted in heart failure rats ( P< 0.05) with no change in the forskolin-mediated vasorelaxation. These changes were associated with the following alterations in β-AR signaling ( P < 0.05): decreases in β-AR density (aorta: 58.7 ± 6.0 vs. 35.7 ± 1.9 fmol/mg membrane protein; carotid: 29.6 ± 5.6 vs. 18.0 ± 3.9 fmol/mg membrane protein, n = 5), increases in G protein-coupled receptor kinase activity levels (relative phosphorimage counts of 191 ± 39 vs. 259 ± 26 in the aorta and 115 ± 30 vs. 202 ± 7 in the carotid artery, n = 5), and decreases in cGMP and cAMP in the carotid artery (0.85 ± 0.10 vs. 0.31 ± 0.06 pmol/mg protein and 2.3 ± 0.3 vs. 1.2 ± 0.1 pmol/mg protein, n = 5) with no change in Gαs or Gαi in the aorta. Thus in heart failure there are abnormalities in the vascular β-AR system that are similar to those seen in the myocardium. This suggests a common neurohormonal mechanism and raises the possibility that treatment in heart failure focused on the myocardium may also affect the vasculature.