Ventricular PKC-ε and humoral signaling in DOCA-salt rats treated with labedipinedilol-A

Effects of oral antihypertensive monotherapy with labedipinedilol-A, labetalol, atenolol, amlodipine, prazosin (20 mg kg^-1 day^-1), and short-acting nifedipine (3 mg kg^-1 day^-1) on DOCA-salt-induced translocation of ventricular protein kinase C-ε(PKC-ε), humoral signaling, and the cardiovascular system were investigated in rats for 4 weeks. The triple blocking activities of labedipinedilol-A (α/β-adrenoceptor blockade and calcium entry blockade) were compared with single blocking activities of selective drugs. Cytosolic PKC-ε: immunoreactivity was decreased by labedipinedilol-A, short-acting nifedipine, amlodipine, prazosin, labetalol, atenolol, and losartan. Membranous PKC-ε: immunoreactivity was significantly decreased by labedipinedilol-A, amlodipine, prazosin, labetalol, and atenolol. Labedipinedilol-A and prazosin more potently decreased membranous than cytosolic PKC-ε: expression. Labedipinedilol-A, labetalol, and atenolol effectively inhibited DOCA-salt-induced increases in angiotensin II (Ang II). All antihypertensive agents reduced endothelin-1 (ET-1) levels in urine and cardiac weight growth. Treatments with labedipinedilol-A, labetalol, atenolol, and amlodipine normalized DOCA-salt-induced ANP increases. Prazosin did not decrease ANP. Short-acting nifedipine elevated ANP. During long-term antihypertensive therapy in DOCA-salt hypertensive rats, single blockade drugs did not fully inhibit ventricular PKC-ε translocation or Ang II, ET-1, and ANP humoral signaling. However, triple blockade labedipinedilol-A therapy had a wide range of α/β-adrenergic receptor and calcium channel inhibitory activities, including diminished reflux tachycardia, inhibition of PKC-ε translocation, and reduction of Ang II, ET-1, and ANP formation.