Cellular Mechanism Underlying The Cardiovascular Actions Of Agmatine

In 1994, Li et al isolated agmatine from cow brain. Like clonidine, agmatine is an endogenous agonist at imidazoline receptors (IR) and a noncatecholamine ligand at (ai-adrenergic receptors ((X2-AR). It has been identified as an endogenous clonidine-displacing substance (CDS) in mammalian brain and may serve as a neurotransmitter/neuromodulator in the central nervous system. Agmatine is a primary amine formed by the decarboxylation of L-arginine by the enzyme arginine decarboxylase. It has been known that agmatine was widely distributed in cardiovascular system of mammalian tissues, suggesting that agmatine could act on cardiovascular system. Our previous studies demonstrated that agmatine not only reduced the amplitude of action potential (APA), maximal rate of depolarization (Vmax), velocity of diastolic (phase 4) depolarization (VDD), and rate of pacemaker firing (RPF), but also prolonged 90% duration of action potential (APD90) in a concentration-dependent manner. And agmatine also decreased APA, VmaX) VDD, RPF and APD50,9o in a concentration-dependent manner in human atrial fibers and guinea pig papillary muscles. However, little is known about cellular mechanism underlying the cardiovascular actions of agmatine. The purposes of the present study were to investigate (1) the hemodynamic effects of agmatine in anaesthetized Dahl salt-sensitive (DS) hypertensive and Dahl salt-resistant (DR) rats; (2) the effect of agmatine on vascular tension in the isolated aortic artery of rats and the underlying receptor mechanism; (3) the effects of local injection of agmatine on femoral, renal, and mesenteric vascular beds by constant flow perfusion method; (4) the effect of agmatineon L-type calcium current (/ca-t) in rat ventricular myocytes withwhole-cell configuration of the patch-clamp technique; (5) the effects ofagmatine on free intracellular calcium concentration (Ca2+D of isolatedrat ventricular myocytes. The experimental projects and results were asfollows.1. Hemodynamic effects of agmatine in Dahl salt-sensitive hypertensiveand Dahl salt-resistant ratsThe hemodynamic effects of agmatine were investigated in anaesthetized Dahl salt-sensitive (DS ) hypertensive and Dahl salt-resistant ( DR ) rats. The results are as follows: (1) Agmatine ( 1, 10, 20 mg/kg, iv.) decreased heart rate (HR), mean arterial pressure (MAP), left ventricular blood pressure ( LVP ), the first derivative of LVP ( LV dp/dt), cardiac index (CI) and total peripheral resistance index (TPRI) in dose-dependent manner in both DS and DR rats, and the decreases in MAP, LVP, +LV dp/dtmax and TPRI at the same dose of agmatine in DR rats were less than those in DS hypertensive rats. Specifically, agmatine at high dose ( 20 mg/kg ) induced a delayed increment of hemodynamic parameters in DS hypertensive rats but not in DR rats. (2 ) Idazoxan ( 2.5 mg/kg ), an antagonist for I2 over Irimidazoline receptors and oi2-adrenoceptor receptors (a2-AR ), only partially blocked the effects of agmatine ( 10 mg /kg). (3) Yohimbine ( 4 mg/kg ), a selective a2-AR antagonist, also partially attenuated the effects of agmatine. ( 4 ) Efaroxan ( 2f5 mg/kg ), a selective antagonist for Ii over I2-imidazoline receptors and a2-AR, could completely blocked the effects of agmatine. Taken together, the results indicate that agmatine can dose-dependently decrease HR, MAP, LVP,+LV dp/dtmax, CI and TPRI in DS hypertensive and DR normotensive rats. The hemodynamic effects of agmatine are mediated mainly by IrIR with the participation of I2-IR and a2-AR.2 Action of agmatine on tension of isolated aortic artery and its receptor mechanism in ratsThe effect of agmatine on vascular tension and the underlying receptor mechanism were investigated in the isolated aortic artery of rats. The results are as follows. (1) Agmatine (10-7-10-2mol/L) relaxed aortic rings in a concentration-dependent manner under the condition of precontraction induced by phenylephrine (PE) at a concentration of 10~6 mol/L. (2) Either in the intact or the endothel...