Prevention of Hypertensive Crises in Rats Induced by Acute and Chronic Norepinephrine Excess

Abstract

Calcium Channel Blockers (CCBs), competitive α-adrenoceptor blockers, and phenoxybenzamine (POB) are used for preoperative treatment of pheochromocytomas. We analyzed the protection from hypertensive crisis provided by these drugs during acute and chronic norepinephrine excess. To ensure adaptive changes during chronic norepinephrine (NE) excess, we continuously exposed male Wistar rats to NE for 3 weeks (osmotic pumps). Afterwards, blood pressure (BP) was continuously measured while NE boli (0–1 000 μg/kg, i. v.) were administered before and after antihypertensive treatment in anesthetized and catheterized rats. A single dose of urapidil (10 mg/kg), nitrendipine (600 μg/kg) and POB (10 mg/kg) lowered BP from 212±12 mmHg by 52±7%, 31±9%, and 50±6%, respectively. With NE boli a maximum BP of 235±29, 240±30 and 138±3 mmHg was measured in urapidil, nitrendipine, and POB treated animals (p<0.05). The number of hypertensive episodes (delta BP >30 mmHg) was 3 (3), 1.5 (0–3), and 0 (0–1) (p<0.05). Because of inferiority, urapidil was excluded from further testing. Chronically NE exposed rats were treated with POB (10 mg/kg/d), nifedipine (10 mg/kg/d), or vehicle for 7 days. Marked BP elevations were observed at baseline (167±7, 210±7, and 217±7 mmHg, p<0.01) and maximum blood pressure was 220±32, 282±26, and 268±40 mmHg (p<0.001) with NE boli. Further stabilization was achieved combining POB pretreatment with a continuous nifedipine infusion, which effectively prevented BP elevations during NE excess. POB was the most effective drug used in monotherapy, but BP stabilization was superior using a combination of POB pretreatment with a continuous nifedipine infusion in this model.

Key words

pheochromocytoma - catecholamine excess - hypertensive crisis - pretreatment - phenoxybenzamine - nifedipine - urapidil

References

• 1 Kinney MA, Narr BJ, Warner MA. Perioperative management of pheochromocytoma.  J Cardiothorac Vasc Anesth. 2002;  16 359-369
• 2 Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma.  Lancet. 2005;  366 665-675
• 3 Weismann D, Fassnacht M, Weinberger F, Hamelmann W, Diehl S, Lorenz K, Baerlehner E, Reincke M, Beuschlein F, Knoefel W, Nies C, Hahner S, Allolio B. Intraoperative haemodynamic stability in patients with phaeochromocytoma – minimally invasive vs. conventional open surgery.  Clin Endocrinol (Oxf). 2006;  65 352-358
• 4 Boutros AR, Bravo EL, Zanettin G, Straffon RA. Perioperative management of 63 patients with pheochromocytoma.  Cleve Clin J Med. 1990;  57 613-617
• 5 Walz MK, Alesina PF, Wenger FA, Koch JA, Neumann HP, Petersenn S, Schmid KW, Mann K. Laparoscopic and retroperitoneoscopic treatment of pheochromocytomas and retroperitoneal paragangliomas: results of 161 tumors in 126 patients.  World J Surg. 2006;  30 899-908
• 6 Lebuffe G, Dosseh ED, Tek G, Tytgat H, Moreno S, Tavernier B, Vallet B, Proye CA. The effect of calcium channel blockers on outcome following the surgical treatment of phaeochromocytomas and paragangliomas.  Anaesthesia. 2005;  60 439-444
• 7 Boulkina LS, Newton CA, Drake AJ, Tanenberg RJ 3rd. Acute myocardial infarction attributable to adrenergic crises in a patient with pheochromocytoma and neurofibromatosis 1.  Endocr Pract. 2007;  13 269-273
• 8 Taylor MJ, McIndoe A. Unresponsive asystolic cardiac arrest responding to external cardiac pacing in a patient with phaeochromocytoma.  Anaesthesia. 2007;  62 838-841
• 9 Myklejord DJ. Undiagnosed pheochromocytoma: the anesthesiologist nightmare.  Clin Med Res. 2004;  2 59-62
• 10 Weismann D, Fassnacht M, Schubert B, Bonfig R, Tschammler A, Timm S, Hahner S, Wunder C, Allolio B. A dangerous liaison – pheochromocytoma in patients with malignant disease.  Ann Surg Oncol. 2006;  13 1696-1701
• 11 Tokuda H, Hosoi T, Hayasaka K, Okamura K, Yoshimi N, Kozawa O. Overexpression of protein kinase C-delta plays a crucial role in interleukin-6-producing pheochromocytoma presenting with acute inflammatory syndrome: a case report.  Horm Metab Res. 2009;  41 333-338
• 12 Platts JK, Drew PJ, Harvey JN. Death from phaeochromocytoma: lessons from a post-mortem survey.  J R Coll Physicians Lond. 1995;  29 299-306
• 13 Primhak RA, Spicer RD, Variend S. Sudden death after minor abdominal trauma: an unusual presentation of phaeochromocytoma.  Br Med J (Clin Res Ed). 1986;  292 95-96
• 14 Carruthers SG. Adverse effects of alpha 1-adrenergic blocking drugs.  Drug Saf. 1994;  11 12-20
• 15 Cubeddu LX, Zarate NA, Rosales CB, Zschaeck DW. Prazosin and propranolol in preoperative management of pheochromocytoma.  Clin Pharmacol Ther. 1982;  32 156-160
• 16 Nicholson Jr JP, Vaughn Jr ED, Pickering TG, Resnick LM, Artusio J, Kleinert HD, Lopez-Overjero JA, Laragh JH. Pheochromocytoma and prazosin.  Ann Intern Med. 1983;  99 477-479
• 17 Miura Y, Yoshinaga K. Doxazosin: a newly developed, selective alpha 1-inhibitor in the management of patients with pheochromocytoma.  Am Heart J. 1988;  116 1785-1789
• 18 Prys-Roberts C, Farndon JR. Efficacy and safety of doxazosin for perioperative management of patients with pheochromocytoma.  World J Surg. 2002;  26 1037-1042
• 19 Colson P, Ryckwaert F, Ribstein J, Mann C, Dareau S. Haemodynamic heterogeneity and treatment with the calcium channel blocker nicardipine during phaeochromocytoma surgery.  Acta Anaesthesiol Scand. 1998;  42 1114-1119
• 20 Proye C, Thevenin D, Cecat P, Petillot P, Carnaille B, Verin P, Sautier M, Racadot N. Exclusive use of calcium channel blockers in preoperative and intraoperative control of pheochromocytomas: hemodynamics and free catecholamine assays in 10 consecutive patients.  Surgery. 1989;  106 1149-1154
• 21 Adjalle R, Plouin PF, Pacak K, Lehnert H. Treatment of malignant pheochromocytoma.  Horm Metab Res. 2009;  41 687-696
• 22 Pacak K, Eisenhofer G, Ahlman H, Bornstein SR, Gimenez-Roqueplo AP, Grossman AB, Kimura N, Mannelli M, McNicol AM, Tischler AS. Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005.  Nat Clin Pract Endocrinol Metab. 2007;  3 92-102
• 23 Pelzer T, Jazbutyte V, Hu K, Segerer S, Nahrendorf M, Nordbeck P, Bonz AW, Muck J, Fritzemeier KH, Hegele-Hartung C, Ertl G, Neyses L. The estrogen receptor-alpha agonist 16alpha-LE2 inhibits cardiac hypertrophy and improves hemodynamic function in estrogen-deficient spontaneously hypertensive rats.  Cardiovasc Res. 2005;  67 604-612
• 24 Team RDC. R: A language and environment for statistical computing. In. R version 2.5.0 (2007-04-23) ed. Vienna, Austria: R Foundation for Statistical Computing; 2007
• 25 Prys-Roberts C. Phaeochromocytoma – recent progress in its management.  Br J Anaesth. 2000;  85 44-57
• 26 Pacak K, Ilias I, Adams KT, Eisenhofer G. Biochemical diagnosis, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour.  J Intern Med. 2005;  257 60-68
• 27 Bruynzeel H, Feelders RA, Groenland TH, van den Meiracker AH, van Eijck CH, Lange JF, de Herder WW, Kazemier G. Risk Factors for Hemodynamic Instability during Surgery for Pheochromocytoma.  J Clin Endocrinol Metab. 2010;  95 678-685
• 28 Pacak K. Preoperative management of the pheochromocytoma patient.  J Clin Endocrinol Metab. 2007;  92 4069-4079
• 29 Joris JL, Hamoir EE, Hartstein GM, Meurisse MR, Hubert BM, Charlier CJ, Lamy ML. Hemodynamic changes and catecholamine release during laparoscopic adrenalectomy for pheochromocytoma.  Anesth Analg. 1999;  88 16-21
• 30 Michelotti GA, Price DT, Schwinn DA. Alpha 1-adrenergic receptor regulation: basic science and clinical implications.  Pharmacol Ther. 2000;  88 281-309
• 31 Vazquez E, Coronel I, Bautista R, Romo E, Villalon CM, Avila-Casado MC, Soto V, Escalante B. Angiotensin II-dependent induction of AT(2) receptor expression after renal ablation.  Am J Physiol Renal Physiol. 2005;  288 F207-F213

Correspondence