PubMed · 7887369
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E C McGuffey. 1995. Treating hot flashes.. https://doi.org/10.1016/s0160-3450(16)33860-0
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BACKGROUND: Accumulating evidence suggests that the local synthesis of endothelin-1 (ET-1) plays a role in the development of heart failure in vivo. We investigated the role of endothelin-converting enzyme-1 (ECE-1), which mediates the conversion of big ET-1 to mature ET-1, in the development of alpha1-adrenergic-stimulated hypertrophy in cultured neonatal rat cardiac myocytes. METHODS AND RESULTS: Phenylephrine (PE) induced the expression of ET-1 in rat cardiac myocytes and accelerated the conversion of big ET-1 to ET-1. The ECE-1 mRNA levels were markedly increased 3 hours after PE stimulation (3.6-fold compared with saline stimulation, P<0.005). A specific ECE-1 antagonist, FR901533, inhibited the PE-stimulated increase in protein synthesis rate by 45% (P<0.05). As genetic markers for the hypertrophic response, FR901533 inhibited the PE-stimulated transcriptional activities of the 3.5-kb beta-myosin heavy chain promoter by 79% (P<0.01) but did not affect that of the 3.4-kb atrial natriuretic factor (ANF) promoter. In Bio14.6 Syrian cardiomyopathic hamsters, ventricular ET-1 and ANF mRNA levels did not correlate at 2 different stages. CONCLUSIONS: ET-1-independent pathways may mediate activation of the ANF gene program in ventricular myocytes both in vitro and in vivo. These results also indicate that the conversion of big ET-1 to ET-1 in rat cardiac myocytes is required for the development of alpha1-adrenergic-stimulated hypertrophy and beta-myosin heavy chain gene transcription.
Peroxynitrite is produced by vascular endothelial and smooth muscle cells in response to inflammation, induces vascular relaxation, and alters vascular responses to endothelial-derived relaxing factors. The present study examined the changes in mean arterial pressure and hindquarter, renal, and mesenteric vascular resistances produced by the systemic administration of (i) the catecholamines epinephrine or norepinephrine, (ii) the alpha1-adrenoceptor agonist phenylephrine, (iii) the beta-adrenoceptor agonist isoproterenol or (iv) [Arg delta] vasopressin in pentobarbital-anesthetized rats prior to and following the systemic administration of peroxynitrite. The systemic administration of peroxynitrite significantly inhibited (i) epinephrine-induced pressor and renal and mesenteric vasoconstrictor responses, (ii) norepinephrine-induced pressor and hindquarter, renal, and mesenteric vasoconstrictor responses, (iii) phenylephrine-induced hindquarter and mesenteric vasoconstrictor responses, and (iv) isoproterenol-induced depressor and hindquarter and renal vasodilator responses. In comparison, the systemic administration of peroxynitrite had no effect on arginine vasopressin-induced pressor or vasoconstrictor responses. These results demonstrate selective and consequential attenuation of the hemodynamic effects produced by alpha- and beta-adrenoceptor agonists, suggesting that selective impairment of adrenoceptors by peroxynitrite may play a critical role in the hemodynamic dysfunction associated with inflammatory conditions.
Ergot alkaloids (EA) such as the ergopeptine alkaloid ergotamine (ET) are adrenergic, dopaminergic, and serotonergic agents. The objective of this experiment was to investigate regional brain neurotransmitter alterations caused by EA. Male BALB/c mice were treated s.c. daily with ergotamine tartrate for 10 d at 0 (saline), 0.4, 2, 10, or 50 mg/kg body weight. Twenty-four hours after the last treatment, animals were sacrificed and brains dissected. Regional concentrations of norepinephrine (NE), dopamine (DA), serotonin (5-HT), and metabolites 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindole-3-acetic acid (5-HIAA) were measured by high-performance liquid chromatography (HPLC). Moreover, selected organ weights and plasma prolactin (PRL) were determined. Dopamine concentration was significantly reduced by ET at all doses in the striatal and hypothalamic regions. A reduction of the DA metabolite HVA occurred in striatum at only the highest dose, whereas in the hypothalamus both HVA and DOPAC were markedly reduced. Concentrations of NE, MHPG, 5-HT, and 5-HIAA were not affected by treatment in these regions. In the cerebellum, MHPG was significantly elevated at the 50 mg/kg dose. No effect of treatment was observed in the cerebrum, medulla, and midbrain. Further, no treatment-related differences in plasma PRL and organ weights other than a significant liver weight decrease at intermediate doses were found. Therefore, the effects of ET were predominantly upon DA metabolism in the corpus striatum and hypothalamus. The reductions in DA, HVA, and DOPAC indicate decreased DA synthesis.