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(Hypertension. 2002;39:815.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Exaggerated Hypotensive Effect of Vascular Endothelial Growth Factor in Spontaneously Hypertensive Rats

Renhui Yang; Annie K. Ogasawara; Thomas F. Zioncheck; Zhen Ren; Guo-Wei He; Geralyn G. DeGuzman; Nicolas Pelletier; Ben-Quan Shen; Stuart Bunting; Hongkui Jin

From the Departments of Cardiovascular Research (R.Y., A.K.O., S.B., H.J.) and Clinical and Experimental Pharmacology (T.F.Z., G.G.D., N.P., B-Q.S.), Genentech Inc, South San Francisco, Cal; Cardiovascular Research, Starr Academic Center, St Vincent Hospital (Z.R., G-W.H.), Portland, Org; and Department of Surgery, The Chinese University of Hong Kong (G-W.H.), Hong Kong.

Correspondence to Hongkui Jin, MD, Department of Cardiovascular Research, Genentech Inc, 1 DNA Way, South San Francisco, CA 94080. E-mail hkj{at}gene.com

Vascular endothelial growth factor (VEGF) induces hypotension in normotensive subjects, which is considered to be a major side effect for treatment of ischemic diseases. However, the hypotensive effect of VEGF has not been investigated in the setting of hypertension. This study determined effects of VEGF on hemodynamics, pharmacokinetics, and release of NO and prostaglandin I₂ (PGI₂) in vivo and on vasorelaxation of mesentery artery rings in vitro in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY). Intravenous infusion of VEGF for 2 hours produced a dose-related decrease in arterial pressure, which was enhanced in conscious SHR compared with WKY (P<0.01), and an increase in heart rate in WKY but not in SHR. In response to similar doses of VEGF, compared with WKY, SHR had a higher plasma VEGF level and lower VEGF clearance (P<0.01). Circulating NO and PGI₂ levels after VEGF administration were not increased in SHR versus WKY, and VEGF-induced vasorelaxation was blunted in SHR versus WKY in vitro, suggesting endothelial dysfunction in SHR. One-week VEGF infusion also caused greater hypotension (P<0.05) in the absence of tachycardia in SHR compared with WKY controls. Thus, despite blunted vasorelaxation in vitro because of endothelial dysfunction, SHR exhibited exaggerated hypotension without tachycardia in response to VEGF, which was independent of NO and PGI₂. The exaggerated hypotensive response to VEGF in SHR may be owing to impaired baroreflex function and reduced VEGF clearance. The data may also suggest that more caution should be taken when VEGF is administered in patients with hypertension.

Key Words: growth substances • rats, spontaneously hypertensive • hemodynamics • hypotension • blood pressure

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