Use of ambulatory blood pressure monitoring to compare antihypertensive efficacy and safety of two angiotensin II receptor antagonists, losartan and valsartan. Losartan Trial Investigators.

The efficacy and safety of losartan and valsartan were evaluated in a multicenter, double-blind, randomized trial in patients with mild to moderate essential hypertension. Blood pressure responses to once-daily treatment with either losartan 50 mg (n = 93) or valsartan 80 mg (n = 94) for 6 weeks were assessed through measurements taken in the clinic and by 24-hour ambulatory blood pressure monitoring (ABPM). Both drugs significantly reduced clinic sitting systolic (SiSBP) and diastolic blood pressure (SiDBP) at 2, 4, and 6 weeks. Maximum reductions from baseline in SiSBP and SiDBP on 24-hour ABPM were also significant with the two treatments. The reduction in blood pressure was more consistent across patients in the losartan group, as indicated by a numerically smaller variability in change from baseline on all ABPM measures, which achieved significance at peak (P = .017) and during the day (P = .002). In addition, the numerically larger smoothness index with losartan suggested a more homogeneous antihypertensive effect throughout the 24-hour dosing interval. The antihypertensive response rate was 54% with losartan and 46% with valsartan. Three days after discontinuation of therapy, SiDBP remained below baseline in 73% of losartan and 63% of valsartan patients. Both agents were generally well tolerated. Losartan, but not valsartan, significantly decreased serum uric acid an average 0.4 mg/dL at week 6. In conclusion, once-daily losartan 50 mg and valsartan 80 mg had similar antihypertensive effects in patients with mild to moderate essential hypertension. Losartan produced a more consistent blood pressure-lowering response and significantly lowered uric acid, suggesting potentially meaningful differences between these two A II receptor antagonists.

Ontogeny of temperature-regulated heat shock protein 70 synthesis in preimplantation bovine embryos.

Development of the preimplantation embryo is very susceptible to disruption by heat shock. As embryos proceed through development, they acquire resistance to heat shock, perhaps because they become transcriptionally active and can respond to environmental changes by undergoing transcriptionally-regulated cellular adaptation. Objectives were to determine the ontogeny of heat shock protein 70 (HSP70) synthesis in preimplantation bovine embryos and to ascertain whether heat-induced increases in HSP70 in embryos are caused by environmental alterations in gene expression. Exposure of bovine embryos to heat shock induced synthesis of a 68 kDa form of HSP70 called HSP68 as early as the two-cell stage of development. Induction of HSP68 was alpha-amanitin independent at the two-cell stage but was blocked by alpha-amanitin as early as the early four-cell stage. Therefore, heat-induced synthesis of HSP68 is regulated at the level of transcription at a time before the major round of embryonic genome activation is considered to occur. Two other constitutive HSP70 molecules were identified called heat shock cognates (HSC) 71 and 70; both proteins were synthesized during all stages of development from the two-cell to hatched blastocyst stages. However, heat-induced synthesis of HSC71 and HSC70 was not evident until the expanded blastocyst stage. In conclusion, environmental signals can activate gene expression before the major round of embryonic genome activation occurs in bovine embryos. Moreover, differences in thermal sensitivity of early embryos to heat shock is not caused by an inability to synthesize HSP70, suggesting that other mechanisms are involved in developmental acquisition of thermotolerance.

Effect of heat shock on function of frozen/thawed bull spermatozoa.

Deposition of spermatozoa in the reproductive tract of hyperthermic cows could conceivably result in sperm damage. Accordingly, a series of experiments tested the effects of heat shock on functional characteristics and free radical production of bull spermatozoa. Viability was reduced slightly by short-term (1 to 3 h) culture at 42 and 43 degrees C as compared with culture at 39 degrees C. There was no effect of culture at 42 degrees C on the ability of spermatozoa to undergo swim-up or of 42 degrees C on the percentage of motile spermatozoa. However, exposure to 41 degrees C for 3 h reduced percentage of motile sperm, 41 and 42 degrees C reduced sperm velocity and 43 degrees C decreased the proportion of spermatozoa undergoing swim-up. In other experiments, there was no effect of heat shock (41 or 42 degrees C for 1 to 3 h) on DNA integrity, presence of intact acrosomes, or fertilizing ability of the spermatozoa. Superoxide production by spermatozoa was higher at 42 degrees C than at 39 or 41 degrees C, but there was no detectable hydrogen peroxide production at any temperature. The antioxidant, glutathione, tended to improve the ability of spermatozoa to undergo swim-up at 39 degrees C but not at 43 degrees C. Taken together, these results suggest that heat shock of a magnitude similar to that seen in vivo (41 to 42 degrees C) has little effect on sperm functions that affect fertilizing capability.

Developmental changes in sensitivity of bovine embryos to heat shock and use of antioxidants as thermoprotectants.

Experiments were conducted with in vitro-produced bovine embryos to determine whether 1) increased culture temperatures (i.e., heat shock) adversely affected embryonic development, 2) embryos become more resistant to heat shock as they advance in development, and 3) selective antioxidant molecules alleviate heat shock effects on embryonic development. Development of 2-cell embryos to > or = 16-cell stage on d 5 after in vitro fertilization was not affected by a heat shock of 40 degrees C for 3 h, but 41 or 42 degrees C for 3 h decreased (P = .004) development. In a separate experiment, development of 2-cell embryos was decreased (P = .01) by exposure to 41 degrees C for 3 h but not for 1 h. In contrast, development of morulae to blastocysts was not affected by heat shock of 41 degrees C for 1 or 3 h. Medium supplementation with 50 nM glutathione or 50 mM taurine before heat shock did not reduce the effects of heat shock (41 degrees C for 3 h) on 2-cell embryos. Likewise, addition of glutathione ester, a more membrane-permeable analog of glutathione, did not protect 2-cell embryos from heat shock. In conclusion, early bovine embryos are susceptible to disruption in development caused by heat shock. As embryos progress in development, they acquire resistance to heat shock. Glutathione, taurine, and glutathione ester were not effective in alleviating the effects of heat shock on development of 2-cell embryos. Consequently, molecules have yet to be identified that can protect early-stage bovine embryos from the adverse effects of heat shock.

Effects of interferon-tau and interferon-alpha on proliferation of bovine endometrial cells.

The ruminant conceptus secretes a unique interferon, interferon-tau, that regulates endometrial prostaglandin secretion during early pregnancy. Because one of the pleiotropic effects of interferons is to inhibit cellular proliferation, a series of experiments was conducted to determine whether or not the bovine endometrium is sensitive to the antiproliferative effect of interferon-tau and the related interferon, interferon-alpha. Endometrial epithelial and stromal cells were prepared from the endometrium of cows from Days 11-17 after estrus and incubated with recombinant bovine interferon-tau (rbIFN tau; 1-1000 ng/ml), recombinant bovine interferon-alpha 1 (rbIFN alpha; 1-1000 ng/ml), recombinant human interferon-alpha 2b (rhIFN alpha; 100 ng/ml), or ovine interferon-tau (oIFN tau; 100 ng/ml). Proliferation was determined by monitoring uptake of [3H]thymidine into DNA. Generally, interferons did not inhibit proliferation of endometrial epithelial cells. Exceptions were for 1000 ng/ml rbIFN tau, which inhibited proliferation by 23%; 100 ng/ml rbIFN alpha, which inhibited proliferation by 28% in one of two experiments only; and 100 ng/ml oIFN tau, which inhibited proliferation by 17%. Proliferation of endometrial stromal cells was not inhibited by any concentration of any interferon in two separate experiments. Therefore, unlike other bovine cells tested previously (lymphocytes and oviductal cells), bovine endometrial cells were not consistently inhibited by IFN tau or IFN alpha. Such reduced responsiveness of endometrial cells to the antiproliferative effects of type I interferons could allow for growth of the endometrium during the period of pregnancy when the conceptus produces IFN tau.

Regulation of bovine and ovine lymphocyte proliferation by progesterone: modulation by steroid receptor antagonists and physiological status.

Lectin-stimulated sheep and cow lymphocytes were used to test whether inhibitors of classical steroid receptors block suppressive effects of progesterone and whether effects of progesterone vary with physiological status. Neither RU 38486 nor RU 43044 blocked the inhibitory effects of progesterone on lymphocyte proliferation. Rather, these antagonists were themselves inhibitory. Effects of progesterone and antagonists were additive: the percentage inhibition caused by progesterone was similar whether antagonists were present or not. The degree of lymphocyte proliferation and the inhibitory effects of progesterone were of the same magnitude for pregnant/lactating cows, pregnant/non-lactating cows, postpartum/lactating cows and cyclic/non-lactating cows. In conclusion, progesterone does not appear to inhibit lymphocyte proliferation through actions that involve classical steroid receptors. There was no evidence that lymphocyte proliferation in the cow is suppressed during pregnancy or that the inhibitory effects of progesterone increase during pregnancy.