a-lactorphin and h-lactorphin improve arterial function in spontaneously hypertensive rats Marika Sipola a, * , Piet Finckenberg a , Heikki Vapaatalo a , Anne Pihlanto-Leppa ¨la ¨ b , Hannu Korhonen b , Riitta Korpela c , Marja-Leena Nurminen a a Institute of Biomedicine, Pharmacology, BIOMEDICUM HELSINKI, P.O. Box 63, FIN-00014 University of Helsinki, Finland b Agrifood Research Finland, Myllytie 1, FIN-31600 Jokioinen, Finland c Foundation for Nutrition Research, P.O. Box 30, FIN-00039 Helsinki, Finland Received 20 June 2001; accepted 4 February 2002 Abstract a-lactorphin (Tyr-Gly-Leu-Phe) lowers blood pressure in conscious adult SHR. This tetrapeptide is originally released from milk protein a-lactalbumin by enzymatic hydrolysis. In order to evaluate the antihypertensive mechanisms of a-lactorphin, the effects of the tetrapeptide on vascular function were investigated in (30À35 weeks old) spontaneously hypertensive rats (SHR) with established hypertension and age-matched normotensive Wistar-Kyoto (WKY) rats in vitro. In addition, we studied the vascular effects of another structurally related tetrapeptide, h-lactorphin (Tyr-Leu-Leu-Phe), which originates from milk protein h-lactoglobulin. Endothelium- dependent relaxation to acetylcholine (ACh) was reduced in mesenteric arterial preparations of SHR as compared to those of WKY. In SHR, the ACh-induced relaxation was augmented by a-lactorphin or h-lactorphin. The role of nitric oxide (NO) is suggested, since this improvement was abolished by the NO synthase (NOS) inhibitor N G - nitro-L-arginine methyl ester (L-NAME). Simultaneous potassium channel inhibitor tetraethylammonium (TEA) elicited no additional effect on the ACh-induced relaxation. The cyclooxygenase inhibitor diclofenac did not attenuate the augmented ACh relaxation induced by a-lactorphin or h-lactorphin, suggesting that endothelial vasodilatory prostanoids were not involved in the effect of the tetrapeptides. Endothelium-independent relaxation to the NO donor sodium nitroprusside (SNP) was augmented in mesenteric arterial preparations of SHR by simultaneous h-lactorphin. The tetrapeptides did not alter vascular responses in mesenteric arteries from WKY. In conclusion, both a-lactorphin and h-lactorphin improved vascular relaxation in adult SHR in vitro. The beneficial effect of a-lactorphin was directed towards endothelial function, whereas h-lactorphin also enhanced endothelium- independent relaxation. D 2002 Elsevier Science Inc. All rights reserved. Keywords: a-lactorphin; h-lactorphin; Vascular function; SHR; NO 0024-3205/02/$ - see front matter D 2002 Elsevier Science Inc. All rights reserved. PII:S0024-3205(02)01793-9 * Corresponding author. Tel.: +358-9-191-25351; fax: +358-9-191-25364. E-mail address: marika.sipola@helsinki.fi (M. Sipola). www.elsevier.com/locate/lifescie Life Sciences 71 (2002) 1245 – 1253