Uptake-1 and cutaneous vascular sensitivity to norepinephrine in human hypertension

Vascular sensitivity to exogenous norepinephrine (NE) has been reported to be increased in hypertension. To elucidate the mechanism of this increase, we used bretylium tosylate (BT) to competitively inhibit pre-synaptic noradrenergic uptake-1. 11 hypertensive subjects (HTN), one week off anti-hypertensive medications, and 16 normotensives (NT) were studied. Subjects received 6 ascending doses of NE by iontophoresis (current*time: 100-24300 μA*sec) at each of 2 forearm skin sites. One site was pre-treated with iontophoretically applied BT; the second site served as a control. Skin blood flow at both sites was indexed by laser-Doppler flowmetry (LDF) during NE iontophoresis. Mean arterial pressure (MAP) was monitored continuously (Finapres) and cutaneous vascular conductance calculated (CVC=LDF/MAP). Dose response curves (DRC's, CVC vs. NE) were constructed. At the control site, the mean threshold NE dose was much lower (1027±713 μA*sec) in HTN than in NT (3750±1504 μA*sec). At the BT site the mean threshold NE dose was 227±73 μA*sec for HTN and was 125±17 μA*sec for NT. Thus, when uptake-1 function is intact vascular sensitivity to NE is greater in HTN than NT. Competitive inhibition of uptake-1 potentiates the vascular sensitivity to exogenous NE in both groups; however, this potentiation is greater in NT than in HTN so that NT are more sensitive to NE than HTN. These findings indicate that the effectiveness of pre-synaptic uptake-1 in clearing NE is reduced in HTN. (Supported by American Heart Assoc., Texas Affiliate).