Net hepatic glucose uptake (NHGU) is much greater during oral or intraportal glucose loading than during peripheral intravenous glucose delivery even when similar glucose loads and hormone levels reaching the liver are maintained. To determine whether this difference is influenced by the hepatic nerves, nine conscious 42-h-fasted dogs in which a surgical denervation of the liver (liver norepinephrine levels postdenervation averaged 2.4% of normal) had been performed were subjected to a 40-min control period and two randomized 90-min test periods during which somatostatin (0.8 microgram.kg-1.min-1), intraportal insulin (1.2 mU.kg-1.min-1), and intraportal glucagon (0.5 ng.kg-1.min-1) were infused. The glucose load to the liver was increased twofold by infusing glucose into a peripheral vein (Pe) or the portal vein (Po). Arterial insulin and glucagon concentrations were 39 +/- 2 and 39 +/- 3 microU/ml and 55 +/- 5 and 54 +/- 7 pg/ml during Pe and Po, respectively. The hepatic glucose loads were 50.3 +/- 4.4 and 51.4 +/- 5.8 mg.kg-1.min-1 while NHGU was 2.1 +/- 0.5 and 2.2 +/- 0.7 mg.kg-1.min-1 during Pe and Po, respectively. Similar hormone levels and glucose loads reaching the liver in dogs with intact hepatic nerve supplies were previously shown to be associated with NHGU of 1.4 +/- 0.7 and 3.5 +/- 0.8 mg.kg-1.min-1 in the presence of peripheral and portal glucose delivery, respectively. In conclusion, an intact nerve supply to the liver appears to be vital for the normal response of the liver to intraportal glucose delivery.

The disposition of a mixed meal administered intragastrically was examined in 13 24-h-fasted conscious dogs, using the arteriovenous (AV) difference technique (and isotopic methods in 6 dogs). Postprandial net gut output totaled (in g of glucose equivalents) 42 +/- 6 glucose, 3 +/- 0.3 lactate, 2 +/- 0.2 alanine, and 0.2 +/- 0.0 glycerol. The gut oxidized 2 +/- 1 g of glucose, and 0.2 +/- 0.1 g remained within the intestinal lumen. Of the administered glucose 68 +/- 6% were accounted for, and volatile fatty acid production by the gut (n = 1) accounted for at least an additional 4%. Of the labeled glucose in the meal 82 +/- 5% appeared in the systemic circulation, an apparent overestimate of absorption of glucose from the meal. Cumulative net hepatic uptakes (in g of glucose equivalents) were 4.1 +/- 3.1 glucose, 12.1 +/- 2.1 gluconeogenic amino acids, and 1.5 +/- 0.2 glycerol. Net hepatic glycogen synthesis and lactate and CO2 production accounted for 6.2 +/- 4.1, 9.3 +/- 2.8, and 1.6 +/- 0.8 g of glucose equivalents, respectively. In summary, the AV difference method could account for the gut disposition of about two-thirds of the meal glucose. Nonsplanchnic tissues disposed of threefold more glucose than the liver. Net hepatic uptake of glucose equivalents as gluconeogenic amino acids was threefold > glucose uptake, and net hepatic uptake of gluconeogenic amino acids was > net gut release of gluconeogenic amino acids. In conclusion, the net hepatic uptake of glucose and gluconeogenic substrates provided adequate carbon for net hepatic synthesis of glycogen and production of lactate and CO2. In a net sense, peripheral tissues must have been the source of some of the gluconeogenic carbon taken up by the liver after the meal.

We examined the disposition of a mixed meal by nine conscious dogs fasted for 24 hours with surgical hepatic denervation. The results were compared with those from identical studies carried out previously in 13 hepatic-innervated dogs. Net gut release of glucose and gluconeogenic precursors (assessed with the arteriovenous difference technique), the resulting blood glucose and plasma insulin concentrations, and the hepatic glucose load were remarkably similar in the two groups. Net hepatic glucose uptake was 4.8 +/- 3.6 g in hepatic-denervated and 7.7 +/- 3.3 g in hepatic-innervated dogs. Cumulative net hepatic lactate release in hepatic-denervated dogs was 4.3 +/- 1.4 g of glucose equivalents, half the value for hepatic-innervated dogs. Net hepatic carbon intake was similar in the two groups. Hepatic lipogenesis, oxidation, and net glycogen synthesis were qualitatively similar between groups. In conclusion, the disposition of a mixed meal by hepatic-innervated and hepatic-denervated dogs was very similar. Subtle alterations in net hepatic balance of substrates (tendencies toward decreases in net hepatic glucose uptake and lactate release) made net carbon retention in denervated livers virtually identical with that in innervated livers. When other compensatory mechanisms are intact, hepatic denervation does not significantly alter hepatic disposition of a mixed meal.

The hepatic nerves can modulate hepatic glycogenolysis and glycogenesis and thus might be expected to be involved in the response of the animal to the transition from the fed to the food-deprived state. Therefore the arterial concentrations and net hepatic balance of glucose and its metabolites, as well as the hepatic glycogen concentrations, were compared in hepatic-innervated and -denervated dogs 18, 24 and 42 h after their usual daily meal. Arterial concentrations of glucose, alanine, lactate and glycerol; net hepatic balances of glucose, alanine and glycerol; and glycogen concentrations were similar in hepatic-innervated and -denervated dogs at each time investigated. Net hepatic balances of lactate (with negative values indicating uptake) in hepatic-innervated and -denervated dogs, respectively, were: 18 h, 4.1 +/- 4.3 vs. -4.3 +/- 3.6 mumol.kg-1 x min-1; 24 h, 4.8 +/- 3.6 vs. -6.7 +/- 1.7 mumol.kg-1 x min-1 (P < 0.05); 42 h, -7.0 +/- 2.0 vs. -6.8 +/- 1.0 mumol.kg-1 x min-1. Based on changes in net hepatic lactate balance, the denervated liver responds more rapidly to food deprivation than the innervated liver, but the metabolic state of the liver appears similar by 42 h after a meal.

The development of new antihypertensive agents is becoming even more important. We need better blood pressure control and also agents that treat hypertension as a disease of the vascular endothelium. Recently, it has been shown that blocking the renin-angiotensin system with angiotensin converting enzyme (ACE) inhibitors reduces blood pressure and decreases the incidence of vascular disease. Another peptide system, the natriuretic peptide system, has also been shown to be important in blood pressure control and volume homeostasis. Because ACE and neutral endopeptidase, the enzyme responsible for the degradation of the natriuretic peptides, are both zinc metalloproteases, new pharmaceuticals that inhibit both enzymes have been developed. The first of these, omapatrilat, has been shown to be an effective antihypertensive agent and to have great potential for treating congestive heart failure.