Relationship between the sympatholytic action of nebivolol and hypotension

Nebivolol, a chemically novel β₁-adrenoceptor antagonist, acutely lowers blood pressure in spontaneously hypertensive rats, anaesthetised nor-motensive dogs, and hypertensive patients. We have investigated the actions of dl-nebivolol in five conscious normotensive rabbits (sham, mean blood pressure (BP) of 82.2 ±; 4.1 mm Hg, mean ±; SEM) and four hypertensive rabbits (renal wrap hypertension) (wrap, mean BP of 117.6 ±; 1.5 mm Hg). Nebivolol (1 mg/kg i.v.) did not significantly lower the BP or heart rate in either group 30 min after injection. In the same rabbits, on another day, after autonomic blockade (mecamylamine), nebivolol (0.1, 0.3, and 1.0 mg/kg i.v.) right shifted the bolus i.v. isoproterenol tachycardia dose-response curves by dose ratios of 5, 18, and 90 in sham rabbits, respectively, and 5, 11, and 23 in wrap rabbits, respectively, indicating significant cardiac β1-adrenoceptor antagonism. In guinea pig isolated right atria pretreated with atropine (1 μM) and desipramine (DMI, 0.1 μM), norepinephrine concentration-response curves were antagonised competitively by nebivolol (3–100 nM), giving a pK_b of 7.90. In separate atria without DMI pretreatment, neither nebivolol (100 nM) nor propranolol (100 nM) had any significant effect on the increase in the rate of norepinephrine efflux following electrical field stimulation (0.5–2 Hz, 3 min). These findings suggest that at concentrations of nebivolol that show substantial β1-adrenoceptor antagonism, there is no evidence of hypotension or bradycardia nor additional effects on cardiac norepinephrine release. Why nebivolol lowers blood pressure in some species but not in the conscious rabbit is not known.