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Activation of cardiac muscarinic receptors by vagal stimulation decreases cardiac work, which may have a protective effect against ischemic injury. To determine whether cardiac muscarinic receptors contribute to the mechanisms of preconditioning effects, we examined the effect of carbachol on ischemia/reperfusion damage and the effect of vagotomy on cardioprotection induced by ischemic preconditioning. Rats were subjected to 30 min of left coronary artery occlusion followed by 30-min reperfusion in situ. Pre-conditioning was induced by three cycles of 2-min coronary artery occlusion and, subsequently by 5 min of reperfusion. The incidence of ischemic arrhythmias, such as ventricular tachycardia (VT) and ventricular fibrillation (VF), and the development of myocardial infarction were markedly reduced by the preconditioning. Carbachol infusion (4 micrograms/kg per min) delayed the occurrence of VT and VF during ischemia and reduced the infarct size. Compared with non-ischemic left ventricle, the cyclic guanosine monophosphate (GMP) content in the ischemic region of the left ventricle was decreased by ischemia/reperfusion, whereas the cyclic adenosine monophosphate (AMP) content of this region was increased. These changes were reversed by preconditioning. Similar changes in cyclic GMP and AMP content in the ischemic region were seen in rats undergoing carbachol treatment. These results suggest the possible contribution of muscarinic receptor stimulation to preconditioning. Vagotomy prior to preconditioning diminished the antiarrhythmic effects, whereas it did not block the anti-infarct effect afforded by pre-conditioning. Vagotomy abolished the preconditioning effect on the tissue cyclic GMP, but it did not attenuate the decrease in tissue cyclic AMP. The results suggest that muscarinic stimulation exerts preconditioning-mimetic protective effects in ischemic/reperfused hearts, but that a contribution of reflective vagal activity to the mechanism for preconditioning is unlikely.

Aims Enteropeptidase is a serine protease localized on the duodenal brush border that catalyzes the conversion of inactive trypsinogen into active trypsin, thereby regulating protein breakdown in the gut. We evaluated the effects of SCO‐792, a novel enteropeptidase inhibitor, in mice. Materials and methods In vivo inhibition of enteropeptidase was evaluated via an oral protein challenge. Pharmacological effects were evaluated in normal mice, in diet‐induced obese (DIO) mice and in obese and diabetic ob/ob mice. Results A single oral administration of SCO‐792 inhibited plasma branched‐chain amino acids (BCAAs) in an oral protein challenge test in mice, indicating in vivo inhibition of enteropeptidase. Repeated treatment with SCO‐792 induced reduction in food intake and decrease in body weight in DIO and ob/ob mice. Plasma FGF21 levels were increased in SCO‐792‐treated DIO mice, an observation that was probably independent of reduction in food intake. Hyperglycaemia was markedly improved in SCO‐792‐treated ob/ob mice. A hyperinsulinaemic‐euglycaemic clamp study revealed improved muscle insulin sensitivity in SCO‐792‐treated ob/ob mice. SCO‐792 also improved plasma and liver lipid profiles and decreased plasma alanine transaminase, suggesting a potential treatment for liver diseases. Dietary supplementation with essential amino acids attenuated the effect of SCO‐792 on reduction in food intake and decrease in body weight in normal mice, suggesting a pivotal role for enteropeptidase in these biological phenomena. Conclusions SCO‐792 inhibited enteropeptidase in vivo, reduced food intake, decreased body weight, increased insulin sensitivity, improved glucose and lipid control, and ameliorated liver parameters in mouse models with obesity and/or diabetes. SCO‐792 may exhibit similar effects in patients.

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1 The eects of long-term treatment with trandolapril, an angiotensin I-converting enzyme inhibitor, on exercise capacity of rats with chronic heart failure (CHF) following coronary artery ligation were examined. CHF was developed by 8 weeks after the coronary artery ligation. 2 The running time of rats with CHF in the treadmill test was shortened to approximately 65% of that of sham-operated rats (16.3+1.2 vs 25.1+1.6 min, n=7; P50.05). ATP, creatine phosphate (CP), and lactate contents of the gracilis muscle of rats with CHF were similar to those of shamoperated rats before running. After running, ATP and CP were decreased and lactate was increased in both rats with CHF and sham-operated rats. There were no signi®cant dierences in the levels of energy metabolites between rats with CHF and sham-operated rats. The rates of decrease in ATP and CP and rate of increase in lactate in the gracilis muscle of rats with CHF during exercise were greater than those of sham operated rats (2.5, 2.0 and 1.5 fold high, respectively), suggesting wastage of energy during exercise in the animals with CHF. , n=7; P50.05) and composition ratio of MHC isoforms in the gracilis muscle. 5 The results suggest that long-term trandolapril treatment of rats with CHF may restore their ability to utilize energy without wastage and thus improve exercise capacity.

The results suggest that chronic treatment with NEP inhibitor improves depressed cardiac function in rats with CHF. ONO-9902 may offer a new and possible therapeutic approach in patients with CHF.

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