Sphingosine-1-phospate (S1P) and S1P receptor agonists elicit mechanism-based effects on cardiovascular function in vivo. Indeed, FTY720 (non-selective S1PX receptor agonist) produces modest hypertension in patients (2–3 mmHg in 1-yr trial) as well as acute bradycardia independent of changes in blood pressure. However, the precise receptor subtypes responsible is controversial, likely dependent upon the cardiovascular response in question (e.g. bradycardia, hypertension), and perhaps even species-dependent since functional differences in rodent, rabbit, and human have been suggested. Thus, we characterized the S1P receptor subtype specificity for each compound in vitro and, in vivo, the cardiovascular effects of FTY720 and the more selective S1P1,5 agonist, BAF312, were tested during acute i.v. infusion in anesthetized rats and after oral administration for 10 days in telemetry-instrumented conscious rats. Acute i.v. infusion of FTY720 (0.1, 0.3, 1.0 mg/kg/20 min) or BAF312 (0.5, 1.5, 5.0 mg/kg/20 min) elicited acute bradycardia in anesthetized rats demonstrating an S1P1 mediated mechanism-of-action. However, while FTY720 (0.5, 1.5, 5.0 mg/kg/d) elicited dose-dependent hypertension after multiple days of oral administration in rat at clinically relevant plasma concentrations (24-hr mean blood pressure = 8.4, 12.8, 16.2 mmHg above baseline vs. 3 mmHg in vehicle controls), BAF312 (0.3, 3.0, 30.0 mg/kg/d) had no significant effect on blood pressure at any dose tested suggesting that hypertension produced by FTY720 is mediated S1P3 receptors. In summary, in vitro selectivity results in combination with studies performed in anesthetized and conscious rats administered two clinically tested S1P agonists, FTY720 or BAF312, suggest that S1P1 receptors mediate bradycardia while hypertension is mediated by S1P3 receptor activation.

Therapies that restore renal cGMP levels are hypothesized to slow the progression of diabetic nephropathy. We investigated the effect of BI 703704, a soluble guanylate cyclase (sGC) activator, on disease progression in obese ZSF1 rats. BI 703704 was administered at doses of 0.3, 1, 3, and 10 mg/kg/d to male ZSF1 rats for 15 weeks, during which mean arterial pressure (MAP), heart rate (HR), and urinary protein excretion (UPE) were determined. Histologic assessment of glomerular and interstitial lesions was also performed. Renal cGMP levels were quantified as an indicator of target modulation. BI 703704 resulted in sGC activation, as evidenced by dose-dependent increases in renal cGMP levels.After 15 weeks of treatment, sGC activation resulted in dosedependent decreases in UPE (from 463 6 58 mg/d in vehicle controls to 328 6 55, 348 6 23, 283 6 45, and 108 6 23 mg/d in BI 703704-treated rats at 0.3, 1, 3, and 10 mg/kg, respectively). These effects were accompanied by a significant reduction in the incidence of glomerulosclerosis and interstitial lesions. Decreases in MAP and increases in HR were only observed at the high dose of BI 703704. These results are the first demonstration of renal protection with sGC activation in a nephropathy model induced by type 2 diabetes. Importantly, beneficial effects were observed at doses that did not significantly alter MAP and HR.

A split-plot experiment was conducted in thermally controlled chambers using Columbian Plymouth Rock chickens to determine the effect of water-cooled roosts on performance in hot ambient conditions. The birds were subjected to 25 +/- 1, 35 +/- 1, and 25 +/- 1 C ambient temperature treatments for 2, 3, and 2 wk, respectively. Roost temperature treatments were either cool (20 +/- 1 C) or air-equilibrated (25 +/- 1 or 35 +/- 1 C). The performance parameters evaluated were percentage hen-day egg production, egg weight, feed intake, feed conversion, fertility, and hatchability. Birds subjected to the water-cooled roost treatment had consistently higher performance than birds using the air-equilibrated roost under all three ambient temperatures. Both ambient and roost temperature treatments significantly influenced percentage hen-day egg production, average daily feed intake, and percentage hatchability (P less than or equal to .05). However, the biggest differences in performance were observed during the heat-stress period. Decreases in performance during the heat-stress period from the thermoneutral control values were: 5.95 and 13.1 percentage points for hen-day egg production, 22.2 and 34.8 percentage points for average daily feed intake, and 5.17 and 15.38 percentage points for hatchability in water-cooled and air-equilibrated roost treatments, respectively. The ambient and roost temperature treatments did not significantly affect egg weight, feed conversion, or percentage fertility. The improved performance with water-cooled over air-equilibrated roost treatments, especially during heat-stress periods, indicates that the water-cooled roosts minimized the deleterious effects of heat stress through conductive heat loss from the birds to the roost.

Forty-eight crossbred ewes were subjected to heat stress of short or long duration during the last third of gestation in a completely randomized design to determine the effects of maternal heat stress on lamb birth weight, lamb conformation and subsequent preweaning growth rate. Ewe treatments were spring range pasture, confinement on slotted floors in a heated room maintained between 28 to 38 C or in a slotted floor barn with feed intake equal to the feed intake of the 38 C housed ewes. Treatment exposure averaged 25 and 53 days for short and long duration, respectively. Lamb birth weights of heated, range and restricted fed ewes were 3.18, 4.57 and 4.16 kg, respectively. After adjustment for sex and multiple birth effects, birth weight of lambs from hot environment ewes were smaller (P<.01) for both durations of treatment. Lamb birth weights from heated ewes were smaller than those of lambs from restricted fed ewes (P<.05). Relative kidney and liver weights were greater in lambs from heated ewes (P<.05). Relative muscle weights and relative linear equivalent bone lengths were not different among ewe treatments. Lambs from heated ewes had 30 and 56-day weights similar to those of lambs from range and restricted fed ewe groups. Small Iambs resulting from maternal heat stress of 25 or 53 days duration are proportional dwarfs and occur independently of ewe level of nutrition. Department of Animal Science. 2Studies were conducted at the Dixon Springs Agricultural Center, Simpson, IL. The cooperation of Drs. M. E. Mansfield and D. Drori is gratefully appreciated.

Twenty Hubbard cockerels each weighing 2.4 kg were surgically fitted with plastic cannulae in the carotid artery and crop. A solution of either tap water (TW), carbonated water (CW), 2% sodium bicarbonate (HCO3-), or 3.5% calcium chloride (CaCl2) with pH of 7.8, 5.2, 8.0, and 7.4, respectively, was infused into the crop at .41 ml X min-1 X kg body weight (BW)-1. Blood pH, carbon dioxide partial pressure (PCO2), and respiratory rate (RR) were measured at 15-min intervals during a 90-min thermoneutral period (25 C) followed by a 90-min heat stress (37 C). Polypnea occurred in all treatments in the 37 C environment. Infusion of HCO3- increased blood pH throughout the thermoneutral and heat stress periods, and CaCl2 infusion decreased blood pH throughout the experimental periods. At thermoneutral temperature, TW and CW infusions did not affect blood pH or PCO2. During heat stress, blood pH increased in TW and CW treatments; change and final pH were significantly lower (P less than .05) for CW- compared with TW-infused birds. Although blood PCO2 decreased in all treatments with the imposition of heat stress, blood PCO2 was significantly greater (P less than .05) in birds infused with HCO3- at the end of the heat-stress period. The results demonstrate that CW treatment produced a more favorable acid-base balance during acute heat stress than TW by reducing blood pH change during thermal polypnea. Also, high levels of NaHCO3 and CaCl2 intake can produce abnormal acid-base equilibrium conditions during the heat stress-induced respiratory alkalosis.