Phenoxybenzamine, urapidil and nitrendipine for prevention of hypertensive crisis in a rat model for acute and chronic norepinephrine excess

Objectives: Reversible alpha-adrenoceptor antagonists and L-type calcium-channel blockers have been proposed as alternatives to phenoxybenzamine (POB) for preoperative treatment in pheochromocytoma, but evidence is incomplete regarding the prevention of hypertensive crisis during sudden catecholamine excess. We studied the ability of high doses of urapidil, nitrendipine and POB to prevent hypertensive crisis in a rat model for chronic and acute norepinephrine (NE) excess.

Methods: Male whistar rats were treated by continuous subcutaneous application of NE (50µg/h; implantable osmotic pump) over a period of 3 weeks. Animals were anesthetized and an arterial and venous line was placed. Animals were then randomly assigned to receive urapidil 10mg/kg body weight [BW]) (n=3), nitrendipine 600µg/kg BW (n=5) and POB 10mg/kg BW (n=3) as a single intravenous dose. Afterwards, increasing doses of NE (1, 10, 100 and 1000µg/kg BW) were given to mimick acute intraoperative catecholamine release. Blood pressure (BP) was monitored continuously.

Results: Continuous NE infusion enhanced BP by 64±47% (p<0.001). BP decreased following administration of urapidil (52±8.6%, p<0.01), nitrendipine (31±8.9%, p<0.01) and POB (50±5.9%, p<0.005), respectively, and remained stable at this level. However, NE bolus resulted in a marked increase of BP after urapidil and nitrendipine, but not POB injection: 100µg/kg BW NE: 92±7.9%, 16±18% and –4.5±4.4%, resp.; p<0.001; 1000µg/kg BW NE: 144±25%, 22±40% and -12±7%, resp.; p<0.001.

Conclusion: Only POB treatment efficiently prevents hypertensive crisis caused by acute catecholamine excess. Urapidil was the least effective drug, which may be explained by competitive displacement with increasing norepinephrine doses. With nitrendipine treatment severe hypertension was observed in individual cases, also indicating incomplete safety. Thus, our findings indicate that POB is the drug of choice for preoperative treatment of patients with pheochromocytoma.