Peptides derived from high voltage-gated calcium channel β subunit reduce blood pressure in rats

The β subunits of high voltage-gated calcium channels (HGCCs) are es-sential for optimal channel functions such as channel gating, activation-inactivation kinetics, and trafficking to the membrane. In this study, we report for the first time the potent blood pressure-reducing effects of peptide fragments derived from the β subunits in anesthetized and non-anesthetized rats. Intravenous administra-tion of 16-mer peptide fragments derived from the interacting regions of the β1 [cacb1(344–359)], β2 [cacb2(392–407)], β3 [cacb3(292–307)], and β4 [cacb4(333–348)] subunits with the main α-subunit of HGCC decreased arterial blood pressure in a dose-dependent manner for 5–8 min in anesthetized rats. In contrast, the peptides had no effect on the peak amplitudes of voltage-activated Ca2+ current upon their in-tracellular application into the acutely isolated trigeminal ganglion neurons. Further, a single mutated peptide of cacb1(344–359)—cacb1(344–359)K357R—showed consis-tent and potent effects and was crippled by a two-amino acid-truncation at the N-terminal or C-terminal end. By conjugating palmitic acid with the second amino acid (lysine) of cacb1(344–359)K357R (named K2-palm), we extended the blood pressure re-duction to several hours without losing potency. This prolonged effect on the arterial blood pressure was also observed in non-anesthetized rats. On the other hand, the intrathecal administration of acetylated and amidated cacb1(344–359)K357R peptide did not change acute nociceptive responses induced by the intradermal formalin in-jection in the plantar surface of rat hindpaw. Overall, these findings will be useful for developing antihypertensives.