Goat meat does not cause increased blood pressure.

While there are persistent rumors that the consumption of goat meat dishes increases blood pressure, there is no scientific evidence to support this. Two experiments were conducted to clarify whether or not blood pressure increases in conjunction with the consumption of goat meat dishes. In experiment 1, 24 Dahl/Iwai rats (15 weeks old, body weight 309.3±11.1 g) were evenly separated into 4 groups. The control group (CP) was fed a diet containing 20% chicken and 0.3% salt on a dry matter basis. The goat meat group (GM) was fed a diet containing 20% goat meat and 0.3% salt. The goat meat/salt group (GS) was fed a diet containing 20% goat meant and 3% to 4% salt. The Okinawan mugwort (Artemisia Princeps Pampan)/salt group (GY) was fed a diet containing 20% goat meat, 3% to 4% salt and 5% of freeze-dried mugwort powder. The experiment 1 ran for a period of 14 weeks during which time the blood pressure of the animals was recorded. The GS, and GY groups consumed significantly more water (p<0.01) than the CP and GM groups despite the fact that their diet consumption levels were similar. The body weight of animals in the CP, GM, and GS groups was similar while the animals in the GY group were significantly smaller (p<0.01). The blood pressure in the GM group was virtually the same as the CP group throughout the course of the experiment. In contrast, while the blood pressure of the animals in the GS and GY group from 15 to 19 weeks old was the same as the CP group, their blood pressures were significantly higher (p<0.01) after 20 weeks of age. The GY group tended to have lower blood pressure than the GS group. In experiment 2, in order to clarify whether or not the increase in blood pressure in the GS group and the GY group in experiment 1 was caused by an excessive intake of salt, the effects on blood pressure of a reduction of salt in diet were investigated. When amount of salt in the diet of the GS and GY group was reduced from 4% to 0.3%, the animal's blood pressure returned to normotensive. These results indicate that, as in the case of chicken consumption, prolonged consumption of goat meat does not cause increased blood pressure, rather the large amount of salt used in the preparation of goat meat dishes is responsible for the increase in blood pressure.

Phosphodiesterase inhibitors. Part 5: hybrid PDE3/4 inhibitors as dual bronchorelaxant/anti-inflammatory agents for inhaled administration.

(-)-6-(7-Methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (KCA-1490) exhibits moderate dual PDE3/4-inhibitory activity and promises as a combined bronchodilatory/anti-inflammatory agent. N-alkylation of the pyridazinone ring markedly enhances potency against PDE4 but suppresses PDE3 inhibition. Addition of a 6-aryl-4,5-dihydropyridazin-3(2H)-one extension to the N-alkyl group facilitates both enhancement of PDE4-inhibitory activity and restoration of potent PDE3 inhibition. Both dihydropyridazinone rings, in the core and extension, can be replaced by achiral 4,4-dimethylpyrazolone subunits and the core pyrazolopyridine by isosteric bicyclic heteroaromatics. In combination, these modifications afford potent dual PDE3/4 inhibitors that suppress histamine-induced bronchoconstriction in vivo and exhibit promising anti-inflammatory activity via intratracheal administration.

Phosphodiesterase inhibitors. Part 6: design, synthesis, and structure-activity relationships of PDE4-inhibitory pyrazolo[1,5-a]pyridines with anti-inflammatory activity.

We previously identified KCA-1490 [(-)-6-(7-methoxy-2-trifluoromethyl-pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone], a dual PDE3/4 inhibitor. In the present study, we found highly potent selective PDE4 inhibitors derived from the structure of KCA-1490. Among them, N-(3,5-dichloropyridin-4-yl)-7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-4-carboxamide (2a) had good anti-inflammatory effects in an animal model.

Phosphodiesterase inhibitors. Part 4: design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-4,4-dimethylpyrazolones.

(-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. Here we show that a 4,4-dimethylpyrazolone subunit serves as an effective surrogate for the 5-methyl-4,5-dihydropyridazin-3(2H)-one ring of KCA-1490 whilst lacking a stereogenic centre. The 2- and 7-substituents in the pyrazolo[1,5-a]pyridine subunit markedly influence the PDE-inhibitory profile and can be adjusted to afford either potent PDE4-selective inhibitors or dual PDE3/4 inhibitors. A survey of bicyclic heteroaromatic replacements for the pyrazolo[1,5-a]pyridine allowed further refinement of the inhibitory profile and identified 3-(8-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridin-5-yl)-4,4-dimethyl-1H-pyrazol-5(4H)-one as an orally active, achiral KCA-1490 analog with well-balanced dual PDE3/4-inhibitory activity.

Phosphodiesterase inhibitors. Part 3: Design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicyclic heteroaromatic-dihydropyridazinones with anti-inflammatory and bronchodilatory activity.

(-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. A survey of potential bicyclic heteroaromatic replacement subunits for the pyrazolo[1,5-a]pyridine core of KCA-1490 has identified the 4-methoxy-2-(trifluoromethyl)benzo[d]thiazol-7-yl and 8-methoxy-2-(trifluoromethyl)quinolin-5-yl analogues as dual PDE3/4-inhibitory compounds that potently suppress histamine-induced bronchoconstriction and exhibit anti-inflammatory activity in vivo.

Use of Awamori-pressed Lees and Tofu Lees as Feed Ingredients for Growing Female Goats.

Okinawan Awamori is produced by fermenting steamed indica rice with black mold, yeast, and water. Awamori-pressed lees is a by-product of the Awamori production process. Tofu lees is a by-product of the Tofu production process. This research consisted of two experiments conducted to elucidate whether or not dried Awamori-pressed lees and Tofu lees can be used as a mixed feed ingredient for raising female goats. In experiment 1, digestion trials were conducted to ascertain the nutritive values of dried Awamori-pressed lees and dried Tofu lees for goats. The digestible crude protein (DCP) and total digestible nutrients (TDN) contents of dried Awamori-pressed lees and Tofu lees were 22.5%, 22.5% (DCP), and 87.2%, 94.4% (TDN) respectively. In experiment 2, 18 female goats (Japanese Saanen×Nubian, three months old, body weight 15.4±0.53 kg) were divided into three groups of six animals (control feed group (CFG), Awamori-pressed lees mixed feed group (AMFG), Tofu lees mixed feed group (TMFG)). The CFG control used feed containing 20% soybean meal as the main protein source, while the AMFG and TMFG treatments used feed mixed with 20% dried Awamori-pressed lees or dried Tofu lees. The groups were fed mixed feed (volume to provide 100 g/d increase in body weight) twice a day (10:00, 16:00). The klein grass hay and water was given ad libitum. The hay intake was measured at 08:00 and 16:00. Body weight and size measurements were taken once a month. At the end of the experiment, a blood sample was drawn from the jugular vein of each animal. The DCP and TDN intakes in AMFG and TMFG showed no significant difference to the CFG. Cumulative measurements of growth in body weight, withers height, chest depth, chest girth, and hip width over the 10 mo period in the AMFG and TMFG were similar to the CFG. By contrast, cumulative growth in body length and hip height in the AMFG and TMFG tended to be larger than the CFG. Cumulative growth in chest width in the AMFG was significantly larger (p<0.05) than the CFG. Blood parameter values were similar to those in normal goats reported by other scientists. The coats of the AMFG and TMFG animals looked shinier than the animals in the CFG. The results demonstrate that dried Awamori-pressed lees and Tofu lees can be used as a feed ingredient for the raising female goats.

The Main Suppressing Factors of Dry Forage Intake in Large-type Goats.

In large-type goats that were fed on dry forage twice daily, dry forage intake was markedly suppressed after 40 min of feeding had elapsed. The objective of this study was to determine whether or not marked decreases in dry forage intake after 40 min of feeding are mainly caused by the two factors, that is, ruminal distension and increased plasma osmolality induced thirst produced by dry forage feeding. Six large-type male esophageal- and ruminal-fistulated goats (crossbred Japanese Saanen/Nubian, aged 2 to 6 years, weighing 85.1±4.89 kg) were used in two experiments. The animals were fed ad libitum a diet of roughly crushed alfalfa hay cubes for 2 h from 10:00 to 12:00 am during two experiments. Water was withheld during feeding in both experiments but was available for a period of 30 min after completion of the 2 h feeding period. In experiment 1, saliva lost via the esophageal fistula was replenished by an intraruminal infusion of artificial parotid saliva (RIAPS) in sham feeding conditions (SFC) control, and the treatment was maintained under normal feeding conditions (NFC). In experiment 2, a RIAPS and non-insertion of a balloon (RIAPS-NB) control was conducted in the same manner as the SFC control of experiment 1. The intraruminal infusion of hypertonic solution and insertion of a balloon (RIHS-IB) treatment was carried out simultaneously to reproduce the effects of changing salt content and ruminal distension due to feed entering the rumen. The results of experiment 1 showed that due to the effects of multiple dry forage suppressing factors when feed boluses entered the rumen, eating rates in the NFC treatment decreased (p<0.05) after 40 min of feeding and cumulative dry forage intake for the 2 h feeding period reduced to 43.8% of the SFC control (p<0.01). The results of experiment 2 indicated that due to the two suppressing factors of ruminal distension and increased plasma osmolality induced thirst, eating rates in the RIHS-IB treatment were, as observed under NFC, reduced (p<0.05) and cumulative dry forage intake for the 2 h feeding period decreased to 34.0% of the RIAPS-NB control (p<0.01). The combined effects of ruminal distension and increased plasma osmolality accounted for 77.5% of the suppression of dry forage intake 40 min after the start of dry forage feeding. The results indicate that ruminal distension and increased plasma osmolality induced thirst are the main factors in the suppression of dry forage intake in large-type goats.

A Physiological Stimulating Factor of Water Intake during and after Dry Forage Feeding in Large-type Goats.

When ruminants consume dry forage, they also drink large volumes of water. The objective of this study was to clarify which factor produced when feed boluses enter the rumen is mainly responsible for the marked increase in water intake in the second hour of the 2 h feeding period in large-type goats fed on dry forage for 2 h twice daily. Six large-type male esophageal- and ruminal-fistulated goats (crossbred Japanese Saanen/Nubian, aged 2 to 6 years, weighing 85.1±4.89 kg) were used in two experiments. In experiment 1, the water deprivation (WD) control and the water availability (WA) treatment were conducted to compare changes in water intake during and after dry forage feeding. In experiment 2, a normal feeding conditions (NFC) control and a feed bolus removal (FBR) treatment were carried out to investigate whether decrease in circulating plasma volume or increase in plasma osmolality is mainly responsible for the marked increase in water intake in the second hour of the 2 h feeding period. The results of experiment 1 showed that in the WA treatment, small amounts of water were consumed during the first hour of feeding while the majority of water intake was observed during the second hour of the 2 h feeding period. Therefore, the amounts of water consumed in the second hour of the 2 h feeding period accounted for 82.8% of the total water intake. The results of experiment 2 indicated that in comparison with the NFC control, decrease in plasma volume in the FBR treatment, which was indicated by increase in hematocrit and plasma total protein concentrations, was higher (p<0.05) in the second hour of the 2 h feeding period. However, plasma osmolality in the FBR treatment was lower (p<0.05) than compared to the NFC control from 30 min after the start of feeding. Therefore, thirst level in the FBR treatment was 82.7% less (p<0.01) compared with that in the NFC control upon conclusion of the 30 min drinking period. The results of the study indicate that the increased plasma osmolality in the second hour of the 2 h feeding period is the main physiological stimulating factor of water intake during and after dry forage feeding in large-type goats.

Phosphodiesterase inhibitors. Part 2: design, synthesis, and structure-activity relationships of dual PDE3/4-inhibitory pyrazolo[1,5-a]pyridines with anti-inflammatory and bronchodilatory activity.

A structural survey of pyrazolopyridine-pyridazinone phosphodiesterase (PDE) inhibitors was made with a view to optimization of their dual PDE3/4-inhibitory activity for respiratory disease applications. These studies identified (-)-6-(7-methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridine-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490, compound 2ac) as a compound with potent combined bronchodilatory and anti-inflammatory activity and an improved therapeutic window over roflumilast.

KRP-203, a novel synthetic immunosuppressant, prolongs graft survival and attenuates chronic rejection in rat skin and heart allografts.

BACKGROUND: A novel immunomodulator, KRP-203, the molecular structure of which has some similarity to FTY720, has been developed for use in organ transplantation. The present study was designed to investigate the potency and safety of KRP-203 on allograft survival against both acute and chronic rejection in rat skin and heart transplantation. METHODS AND RESULTS: KRP-203 significantly prolonged skin or heart allograft survival of a minor histocompatibility complex (mHC)-disparate (LEW to F344) rat combination. Histopathological and immunohistochemical analysis at 100 days after mHC-disparate rat heart transplantation revealed that KRP-203 treatment significantly inhibited infiltration of inflammatory cells, including macrophages and T cells; expression of endothelin-1 and transforming growth factor-beta1; and IgG deposition and eventually attenuated neointimal formation and myocardial fibrosis. KRP-203 also prolonged heart allograft survival in a major histocompatibility complex (MHC)-incompatible (DA to LEW) rat combination, but the efficacy was not as significant. However, KRP-203 combined with a subtherapeutic dose of cyclosporin A synergistically prolonged the heart allograft survival. Flow cytometric analysis demonstrated that KRP-203 reduced the number of peripheral blood mononuclear cells (lymphocytes and monocytes) but not granulocytes and enhanced lymphocyte homing into peripheral lymph nodes. The influence of KRP-203 on heart rate changes in Hartley guinea pigs was examined. KRP-203 had less of a tendency to cause bradycardia than FTY720. CONCLUSIONS: These findings demonstrated that KRP-203 prolonged skin and heart allograft survival and significantly attenuated chronic rejection and bradycardia as an adverse effect. Therefore, KRP-203 offers considerable potential as a novel therapeutic immunosuppressant in patients with organ transplantation.

The datA locus predominantly contributes to the initiator titration mechanism in the control of replication initiation in Escherichia coli.

Replication of the Escherichia coli chromosome is initiated synchronously from all origins (oriC) present in a cell at a fixed time in the cell cycle under given steady state culture conditions. A mechanism to ensure the cyclic initiation events operates through the chromosomal site, datA, which titrates exceptionally large amounts of the bacterial initiator protein, DnaA, to prevent overinitiation. Deletion of the datA locus results in extra initiations and altered temporal control of replication. There are many other sites on the E. coli chromosome that can bind DnaA protein, but the contribution of these sites to the control of replication initiation has not been investigated. In the present study, seven major DnaA binding sites other than datA have been examined for their influence on the timing of replication initiation. Disruption of these seven major binding sites, either individually or together, had no effect on the timing of initiation of replication. Thus, datA seems to be a unique site that adjusts the balance between free and bound DnaA to ensure that there is only a single initiation event in each bacterial cell cycle. Mutation either in the second or the third DnaA box (a 9 basepair DnaA-binding sequence) in datA was enough to induce asynchronous and extra initiations of replication to a similar extent as that observed with the datA-deleted strain. These DnaA boxes may act as cores for the cooperative binding of DnaA to the entire datA region.