Substantial evidence from animal studies suggests that enhanced memory associated with emotional arousal results from an activation of beta-adrenergic stress hormone systems during and after an emotional experience. To examine this implication in human subjects, we investigated the effect of the beta-adrenergic receptor antagonist propranolol hydrochloride on long-term memory for an emotionally arousing short story, or a closely matched but more emotionally neutral story. We report here that propranolol significantly impaired memory of the emotionally arousing story but did not affect memory of the emotionally neutral story. The impairing effect of propranolol on memory of the emotional story was not due either to reduced emotional responsiveness or to nonspecific sedative or attentional effects. The results support the hypothesis that enhanced memory associated with emotional experiences involves activation of the beta-adrenergic system.

Estrogen (E) has been identified in epidemiologic and prospective studies to protect against the development of cardiovascular disease in women. It is unclear whether progesterone (P) is similarly beneficial. The mechanisms by which E or P might act are incompletely defined. One possibility is that sex steroids inhibit the proliferation of vascular smooth muscle, an early/important event in vascular pathology. We examined the ability of E and P to inhibit the growth of human umbilical vein smooth muscle cells (hUVSMC) in culture, when stimulated by serum or the mitogen, endothelin-1 (ET-1). Serum and ET-1 stimulated hVSMC cell numbers by approximately 110% and 43% respectively, compared with control, after 3 days in culture. This stimulation was maximally reversed 75% by E and 64% by P. No synergistic or additive effects of the two steroids were found. ET-1 and serum stimulated mitogen-activated protein kinase (MAP-K) and MAP-kinase kinase activities, and these were critical for mitogenesis. Mitogen-stimulated MAP-kinase kinase and MAP-K activities were significantly inhibited by either E or P. The steroids also inhibited mitogen-stimulated c-fos and c-myc, downstream targets for MAP-K action. Critical signaling and molecular events through which mitogens stimulate VSMC proliferation can be significantly inhibited by E or P, providing a potential cellular mechanism for their vascular protective actions.

The results of this study confirm that low lead (0.01%) but not high lead (0.5%) administration results in increased blood pressure in rats treated for up to 12 months. This effect appeared to be related to an imbalance of endothelially-derived vasoconstrictor and vasodilator compounds in low lead-treated animals but not in high lead-treated animals. In low lead-treated rats, measurement of plasma endothelins 1 and 3 (ET-1 and ET-3) revealed that ET-3 concentration increased significantly after both 3 months (Experimental, 92.1 +/- 9.7 v Control, 46.7 +/- 12.0 pmol/mL; P < .001) and 12 months (Experimental, 105.0 +/- 9.3 v Control, 94.1 +/- 5.0 pmol/mL; P < .01) while ET-1 was unaffected. Plasma and urinary cGMP concentrations (as a reflection of endothelium-derived relaxing factor (EDRF)) decreased significantly at 3 months (plasma, Experimental, 1.8 +/- 0.9 v Control, 4.2 +/- 1.6 pmol/mL; P < .001) and 12 months (plasma, Experimental, 2.2 +/- 0.7 v Control, 4.2 +/- 0.9 pmol/mL; P < .001). Thus, the path to development of hypertension in low lead rats may be through an increase in the concentration of the vasoconstrictor hormone, ET-3, and a decrease in the vasodilator hormone, EDRF. High levels of lead exposure did not result in hypertension, perhaps because plasma concentrations of ET-1, ET-3 and cGMP were unaltered at 3 months, while ET-1, ET-3 and cGMP concentrations were coordinately and significantly decreased at 12 months.

The modulation of the activity of mitogen-activated protein kinase (MAPK) by endogenous growth factors or growth inhibitors provides a potential means of regulating cell proliferation. We determined the effect of the endogenous anti-proliferative peptide, atrial natriuretic peptide (ANP), on the ability of MAPK to phosphorylate myelin basic protein. In astrocytes, MAPK activity was significantly stimulated (up to 3-fold) by three known glial mitogens, endothelin-3, platelet-derived growth factor, or phorbol 12-myristate 13-acetate. ANP inhibited by 55-70% the ability of each of these mitogens to activate MAPK. The effects of ANP were equipotent to those caused by C-ANP 4-23, a peptide that specifically binds to the natriuretic peptide clearance receptor. Additionally, both natriuretic peptides caused a 70-80% inhibition of the sodium vanadate-stimulated MAPK activity, complete inhibition of the okadaic acid-stimulated activity, and inhibition of the mitogen-stimulated phosphorylation of MAPK. To understand the potential mechanism by which the natriuretic peptides act, we found that both ANP and C-ANP inhibited the mitogen-stimulated activity of the immediate upstream kinase in the cascade, MAPK kinase (MEK). C-ANP also strongly inhibited the endothelin-3-, platelet-derived growth factor-, and phorbol 12-myristate 13-acetate-induced stimulation of DNA synthesis in the astrocytes, while both okadaic acid and sodium vanadate significantly reversed these anti-proliferative actions. Our results identify ANP as a peptide hormone that inhibits growth factor-stimulated MAPK. These data suggest that the ability of the natriuretic peptides to inhibit MAPK may be important for their anti-growth actions. This effect likely occurs via the inhibition of upstream kinase(s), including MEK, uniquely resulting from ligand binding to the natriuretic peptide clearance receptor.

C-type natriuretic peptide (CNP) is a member of the natriuretic peptide family which is produced in vascular endothelial cells and may play an important paracrine role in the vasaculature. We sought to determine the regulation of CNP production by other vasoactive peptides from cultured aortic endothelial cells. The vasoconstrictors endothelin-1 and angiotensin II had little effect on the basal secretion of CNP. In contrast, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) strongly stimulated the secretion of CNP. BNP caused as much as a 400-fold enhancement above the basal accumulated secretion of CNP over 24 h at a concentration of 1 ,IM; this was 20 times greater than the stimulatory effect of ANP. BNP and ANP also significantly enhanced the production of new CNP protein (translation) and mRNA expressed in the BAEC. In contrast, C-ANP-4-23, a truncated form of ANP which selectively binds to the natriuretic peptide clearance receptor, did not stimulate CNP secretion. The enhanced production and secretion of CNP, caused by either ANP or BNP, was significantly prevented by LY 83583, an inhibitor of cGMP generation, and was also attenuated by KT 5823, an inhibitor of cGMPdependent protein kinase. Our results indicate that ANP and BNP can stimulate CNP production through a guanylate cyclase receptor on endothelial cells. BNP is a much more potent stimulator of CNP secretion, compared to ANP. Our findings suggest that the vasodilatory, and anti-mitogenic effects of ANP and BNP in the vasculature could occur in part through CNP production and subsequent action if these interactions occur in vivo. (J. Clin. Invest. 1995.

The concentration of HDL in the blood inversely correlates with the incidence of cardiovascular disease, probably related to the ability of these lipoproteins to efflux cholesterol from vascular cells. It is also possible that HDL affect the production or action of vasoactive peptides implicated in the development of vascular diseases. Therefore, we determined the effects of human HDL on the production and secretion of endothelin-1 (ET-1 ) from cultured bovine aortic endothelial cells. HDL produced a highly significant stimulation of endothelin secretion (maximum 240% of control), even at very low levels of lipoproteins (1 ,gg/ml). HDL also stimulated the translation of by twofold in the bovine aortic endothelial cells. In contrast, HDL had no significant effect on steady state mRNA levels, transcript degradation, or transcription. Stimulation of ET-1 secretion by HDL was dependent on protein kinase C activation. Purified apo A-I, the major apoprotein of HDL, increased ET-1 secretion and translation -85% as potently as HDL. Our results indicate that low concentrations of human HDL strongly stimulate the production of ET-1, a powerful vasoconstrictor and mitogen for the vascular smooth muscle cell. We propose that HDL may participate in the regulation of vasomotor tone through this potentially important effect in the vasculature. (J. Clin. Invest. 1994. 93:1056-1062

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