Vascular mechanisms of cyclosporin-induced hypertension in the rat

Jean Baptiste Roullet, Hong Xue, David A. McCarron, Scott Holcomb, William M. Bennett

Research output: Contribution to journalArticlepeer-review

103 Scopus citations

Abstract

Numerous studies have explored the pathogenesis of cyclosporin A (CysA)- induced hypertension; however, none has assessed the impact of CysA treatment on resistance arteries in the setting of elevated blood pressure. Therefore, we studied the chronic effect of CysA on rat mesenteric artery resistance vessels (ex vivo). CysA (25 mg/kg per d for 7 d), but not vehicle, significantly raised systolic blood pressure (13.4±2.2 mmHg, P < 0.003, n = 9 per group). The resistance vessels from CysA-treated rats showed a small but significant decrease in norepinephrine sensitivity (P < 0.03) and a pronounced decrease in endothelium-dependent and -independent relaxation (P < 0.001) compared to controls. Endothelin-1 sensitivity tended to be diminished (P = 0.07). The direct (in vitro) effect of CysA was subsequently evaluated in resistance vessels from nontreated animals (n = 8) and exposed to CysA (2 μg/ml) for 24 h. As observed in vivo, CysA significantly decreased endothelium-dependent and -independent relaxations (P < 0.05) and attenuated norepinephrine sensitivity (P = 0.06). Methylene blue, a nitric oxide quencher, significantly inhibited the acetylcholine-induced relaxation in control, but not in CysA vessels, suggesting a selective action of CysA on the nitric oxide pathway. We conclude that CysA-induced hypertension is the consequence of a primary effect on resistance vessel relaxation, not increased vasoconstriction, as previously suggested.

Original languageEnglish (US)
Pages (from-to)2244-2250
Number of pages7
JournalJournal of Clinical Investigation
Volume93
Issue number5
DOIs
StatePublished - May 1994

Keywords

  • blood pressure
  • cyclosporin A
  • ex vivo
  • in vivo
  • resistance vessels

ASJC Scopus subject areas

  • Medicine(all)

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