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Effects of experimental heart failure on the capacity of glucagon to augment myocardial contractility and activate adenyl cyclase 总被引:1,自引:2,他引:1 下载免费PDF全文
Herman K. Gold Kirk H. Prindle Gerald S. Levey Stephen E. Epstein 《The Journal of clinical investigation》1970,49(5):999-1006
Although glucagon exerts positive inotropic effects in patients with no or mild impairment of cardiac function, similar effects are not consistently observed in patients with chronic heart failure. Accordingly, the inotropic effects of glucagon on papillary muscles from normal cats and cats in which right ventricular failure had been produced for 4-145 days by pulmonary artery banding were compared. At the peak of the concentration-response curve, glucagon increased peak isometric tension (T) in normal muscles from 4.4±0.4 to 6.6±0.5 g/mm2 (P <0.001), and maximum rate of tension development (dT/dt) from 16.9±0.9 to 25.1±1.6 g/sec per mm2 (P < 0.001). In contrast, glucagon produced no significant increases in T or dT/dt in failure muscles. The percentage increases in T and dT/dt caused by norepinephrine were the same in muscles from normal and failing hearts. Since the cardiac effects of glucagon and norepinephrine may be mediated by adenyl cyclase, responsiveness of adenyl cyclase was determined in particulate fractions of the right ventricle. Glucagon activated adenyl cyclase in normal, but had no effect in failure preparations. Norepinephrine-induced activation of adenyl cyclase, however, was unaltered by failure. Thus, in contrast to norepinephrine, glucagon loses the capacity to augment myocardial contractility and activate adenyl cyclase in hearts derived from cats in chronic failure. 相似文献
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Ibrahim Yazji Chhinder P. Sodhi Elizabeth K. Lee Misty Good Charlotte E. Egan Amin Afrazi Matthew D. Neal Hongpeng Jia Joyce Lin Congrong Ma Maria F. Branca Thomas Prindle Ward M. Richardson John Ozolek Timothy R. Billiar David G. Binion Mark T. Gladwin David J. Hackam 《Proceedings of the National Academy of Sciences of the United States of America》2013,110(23):9451-9456
Necrotizing enterocolitis (NEC) is a devastating disease of premature infants characterized by severe intestinal necrosis and for which breast milk represents the most effective protective strategy. Previous studies have revealed a critical role for the lipopolysaccharide receptor toll-like receptor 4 (TLR4) in NEC development through its induction of mucosal injury, yet the reasons for which intestinal ischemia in NEC occurs in the first place remain unknown. We hypothesize that TLR4 signaling within the endothelium plays an essential role in NEC development by regulating perfusion to the small intestine via the vasodilatory molecule endothelial nitric oxide synthase (eNOS). Using a unique mouse system in which we selectively deleted TLR4 from the endothelium, we now show that endothelial TLR4 activation is required for NEC development and that endothelial TLR4 activation impairs intestinal perfusion without effects on other organs and reduces eNOS expression via activation of myeloid differentiation primary response gene 88. NEC severity was significantly increased in eNOS−/− mice and decreased upon administration of the phosphodiesterase inhibitor sildenafil, which augments eNOS function. Strikingly, compared with formula, human and mouse breast milk were enriched in sodium nitrate—a precursor for enteral generation of nitrite and nitric oxide—and repletion of formula with sodium nitrate/nitrite restored intestinal perfusion, reversed the deleterious effects of endothelial TLR4 signaling, and reduced NEC severity. These data identify that endothelial TLR4 critically regulates intestinal perfusion leading to NEC and reveal that the protective properties of breast milk involve enhanced intestinal microcirculatory integrity via augmentation of nitrate–nitrite–NO signaling. 相似文献
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