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 journalArticle

99 Citations (Scopus)

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
StatePublished - May 1994

Fingerprint

Cyclosporine
Blood Vessels
Hypertension
Blood Pressure
Endothelium
Norepinephrine
Nitric Oxide
Mesenteric Arteries
Methylene Blue
Endothelin-1
Vasoconstriction
Acetylcholine
Arteries

Keywords

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

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Roullet, J-B., Xue, H., McCarron, D. A., Holcomb, S., & Bennett, W. M. (1994). Vascular mechanisms of cyclosporin-induced hypertension in the rat. Journal of Clinical Investigation, 93(5), 2244-2250.

Vascular mechanisms of cyclosporin-induced hypertension in the rat. / Roullet, Jean-Baptiste; Xue, Hong; McCarron, David A.; Holcomb, Scott; Bennett, William M.

In: Journal of Clinical Investigation, Vol. 93, No. 5, 05.1994, p. 2244-2250.

Research output: Contribution to journalArticle

Roullet, J-B, Xue, H, McCarron, DA, Holcomb, S & Bennett, WM 1994, 'Vascular mechanisms of cyclosporin-induced hypertension in the rat', Journal of Clinical Investigation, vol. 93, no. 5, pp. 2244-2250.
Roullet J-B, Xue H, McCarron DA, Holcomb S, Bennett WM. Vascular mechanisms of cyclosporin-induced hypertension in the rat. Journal of Clinical Investigation. 1994 May;93(5):2244-2250.
Roullet, Jean-Baptiste ; Xue, Hong ; McCarron, David A. ; Holcomb, Scott ; Bennett, William M. / Vascular mechanisms of cyclosporin-induced hypertension in the rat. In: Journal of Clinical Investigation. 1994 ; Vol. 93, No. 5. pp. 2244-2250.
@article{cda16c59718a4505a6a6018236f2f9fa,
title = "Vascular mechanisms of cyclosporin-induced hypertension in the rat",
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.",
keywords = "blood pressure, cyclosporin A, ex vivo, in vivo, resistance vessels",
author = "Jean-Baptiste Roullet and Hong Xue and McCarron, {David A.} and Scott Holcomb and Bennett, {William M.}",
year = "1994",
month = "5",
language = "English (US)",
volume = "93",
pages = "2244--2250",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "5",

}

TY - JOUR

T1 - Vascular mechanisms of cyclosporin-induced hypertension in the rat

AU - Roullet, Jean-Baptiste

AU - Xue, Hong

AU - McCarron, David A.

AU - Holcomb, Scott

AU - Bennett, William M.

PY - 1994/5

Y1 - 1994/5

N2 - 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.

AB - 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.

KW - blood pressure

KW - cyclosporin A

KW - ex vivo

KW - in vivo

KW - resistance vessels

UR - http://www.scopus.com/inward/record.url?scp=0028206918&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028206918&partnerID=8YFLogxK

M3 - Article

VL - 93

SP - 2244

EP - 2250

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 5

ER -