Catecholamine storage vesicle protein expression in genetic hypertension

Chromogranin A expression is heritable in humans, and both plasma chromogra nin A concentration and its releasable adrenal and sympathetic neuronal poo ls are augmented in established essential (hereditary) hypertension. To eva luate chromogranin A further as a simpler or "intermediate phenotype" in th e complex trait of hypertension, we studied chromogranin A expression in th e spontaneously hypertensive rat (SHR), a rodent model of essential hyperte nsion. Both plasma (p < 0.0001) and adrenal medullary (p = 0.003 to p < 0.0 001) chromogranin A were elevated in the SHR, even at the earliest stages ( 3-4 weeks of age). In the adult adrenal gland, both chromogranin A (p = 0.0 05) and norepinephrine (p =0.011) were increased in the SHR, while dopamine beta-hydroxylase activity was diminished (p < 0.0001). Chromogranin A mRNA expression was also elevated in the SHR adrenal medulla (p = 0.017). Diffe rences in chromogranin A processing were not noted between SHR and Wistar K yoto control (WKY) rats. In an SHR x WKY genetic intercross, control of the adrenal chromogranin A phenotype by a single major locus was suggested by comparison of phenotypic variance of the F2 vs F1 generations, and by bimod al frequency histogram (3:1 ratio), confirmed by maximum likelihood analysi s (X-2 = 74.6, p < 0.000001) in the F2 generation. However, microsatellite alleles at a surrogate locus (Ighe) 12.7 cM from chromogranin A (Chga), on rat chromosome 6, failed to co-segregate with brood pressure in an F2 gener ation (F = 0.06, p = 0.94). In another rodent model of hereditary hypertens ion, the genetically hypertensive mouse (BPH/2), adrenal chromogranin A (p = 0.018) and norepinephrine (p = 0.004) were actually diminished. We conclu de that over-expression of chromogranin A is a variable feature of mammalia n genetic hypertension. In one rodent model (the SHR), over-expression of c hromogranin A is largely controlled by a single genetic locus, but the chro mogranin A locus itself is not directly linked to determination of the bloo d pressure elevation of the SHR.