Antihypertension and anti-cardiovascular remodeling by phenylalanine in spontaneously hypertensive rats: effectiveness and mechanisms

Objective To investigate mechanisms of anti-hypertension and anti-cardiovas cular remodeling by phenylalanine (phe) in spontaneously hypertensive rats (SHRs). Methods The comparison of blood pressure (BP) increment with the ages and c ardiovascular changes of SHRs was made between the 3% phe-intervented group (SHR-phe) and the control SHRs group. Detection of the structural changes with the VIDAS digital vedic-frequency processing technique and light and e lectron microscopy were made. The cell growth and proliferation of cultured smooth muscle cells (CSMCs) of the thoracic aortas or myocardial fibroblas ts were evaluated by measuring the H-3-thymidine counts per minute (cpm) in corporated into the new synthesized desoxyribonucleic acid (DNA) and determ ining the cell number with the crystal violet stain technique. The Ca2+ inf lux was measured in counts/min of (CaCl2)-Ca-45 after incubating it with 5 different concentrations of phenylalanine and the intracellular [Ca2+](i) b y Fura-II/Am indicator. The total messenger ribonucleic acid (mRNA) of the myocardium was extracted and Northern blot analysis was performed with the probe collagen alpha (2) ( I ) cDNA. The tyrosine hydroxylase (TH) activity was measured by high-performance liquid chromatography (HPLC) with electro chemical detector after having reacted with its substrate tyrosine and othe r reagents. The catecholamine contents in brain homogenat were detected by HPLC method. The comparison of pharmacokinetics of phenylalanine among SHR- phe, SHRs and control Wistar Kyoto (WKY) rats was made after intravenous in jection of H-3-L-phe (1 ml/kg) by PK-GRAPH Program for kinetic calculation. The H-3-L-phe uptake by CSMCs after incubating for difinite intervals was also detected and compared. Results Phenylalanine could prevent the increase of BP with ages and the he art weight (heart/body weight index). The aortic media thickness and the co llagen content in the myocardium were decreased significantly in SHR-phe. W hereas the dearranged cardiovascular structure was much improved. The mecha nisms might be direct and specific inhibition of the DNA synthesis and prol iferation of cardiovascular cells which may be related to the inhibition of collagen alpha (2) ( I ) cDNA, c-fos and c-myc expression. Other mechanism s may include decrease of intracellular [Ca2+](i) and an inhibition of cent ral sympathetic activity due to the results of higher TH activity in the ca udate nucleus and higher adrenaline content in the posterior hypothalamus. Besides, partial recovery of phenylalanine metabolic aberrants existed in S HRs seems to be another possibility for its effectiveness. Conclusions Phenylalanine intervention could exert a definite anti-hyperten sion and anti-cardiovascular remodeling effects on SHRs like seen in human essential hypertension. Its mechanisms might be related to direct inhibitio n of growth in the cardiovascular cells, decrease of central sympathetic ac tivity, the reverse of the exhibited phenylalanine metabolic aberrants in S HRs, and a decrement of intracellular [Ca2+](i).