1. It has been suggested that oestrogen-produced vasodilatation is due to induction of endothelial nitric oxide synthase (NOS), but there are many reports of direct effects on vascular smooth muscle. In the present study, these processes were investigated in rat aorta isolated from ovariectomized rats. 2. Short-term treatment (10 min) with 17beta-oestradiol (10 micromol/L) produced a small attenuation of the phenylephrine (PE)-induced constriction, which was unaffected by the nitric oxide synthase inhibitor L-N5(-1-iminoethyl)ornithine (NIO; 100 micromol/L). Long-term treatment (6 h) with 17beta-oestradiol (10 micromol/L) did not affect acetylcholine-mediated vasorelaxation in endothelium-intact aortic rings, but did attenuate PE-induced constriction. This attenuation was also observed in endothelium-denuded preparations after 17beta-oestradiol (10 micromol/L for 6 h) and was far greater than the acute effect of 17beta-oestradiol (10 micromol/L). 3. The attenuation produced by 17beta-oestradiol (10 micromol/L for 6 h) was significantly inhibited by concomitant treatment with cycloheximide (1 micromol/L), suggesting that protein synthesis was involved. NIO (100 micromol/L) also attenuated the effect, which suggests that the anti-constrictor effect of 17beta-oestradiol occurs through the increased production of nitric oxide (NO). 17Beta-oestradiol increased NO production, as assessed by the conversion of [3H]-arginine to [3H]-citrulline in rat aorta. These effects were prevented by cycloheximide and NIO. The anti-constrictor effect of oestrogen was blocked by the oestrogen receptor antagonist ICI 182 780 (100 nmol/L). 4. Western blotting using an antibody specific for inducible nitric oxide synthase (NOS) revealed that 17beta-oestradiol (10 micromol/L for 24 h) treatment induced the formation of inducible NOS protein in the aorta, an effect blocked by cycloheximide. The results indicate that 17beta-oestradiol can attenuate the vasoconstrictor effect of PE by a specific receptor-mediated process that involves induction of inducible NOS.

1. Protein kinase C (PKC) is an important second messenger-activated enzyme. In noradrenergic nerves it appears to be tonically activated by diacylglycerol (DAG) to facilitate transmitter release and the steps in this involve activation of phospholipase C, generation of DAG and activation of PKC. It is suggested that the subsequent facilitation of transmitter release is due to the phosphorylation of proteins involved in the release process distal to Ca2+ entry, presumably those involved in vesicle dynamics. 2. There are differences between central noradrenergic neurons and sympathetic nerves. In central neurons PKC appears to be tonically active and its inhibition results in a decrease in noradrenaline release under most, if not all, conditions. 3. In sympathetic nerves PKC inhibitors only decrease transmitter release during high-frequency stimulation and not during low-frequency stimulation. At high frequency there is a gradual increase in the effect of PKC inhibitors on transmitter release during the first 15 s of a stimulation train. It is suggested that this is due to a progressive rise in intracellular Ca2+ and a consequent activation of PKC. 4. Activation of PKC by phorbol esters produces a large enhancement in action potential-evoked noradrenaline release in both the central nervous system and in peripheral tissues. The structural requirements of the phorbol esters for maximal effect suggest that the phorbol esters must access the interior of the nerve terminal to activate PKC and the neural membrane acts as a barrier for highly lipophilic phorbol esters, thereby reducing their activity. Activation of PKC represents one of the most powerful ways to enhance transmitter release and may have therapeutic potential.

These recommendations of the Advisory Committee on Immunization Practices (ACIP) for poliomyelitis prevention replace those issued in 1997. As of January 1, 2000, ACIP recommends exclusive use of inactivated poliovirus vaccine (IPV) for routine childhood polio vaccination in the United States. All children should receive four doses of IPV at ages 2, 4, and 6-18 months and 4-6 years. Oral poliovirus vaccine (OPV) should be used only in certain circumstances, which are detailed in these recommendations. Since 1979, the only indigenous cases of polio reported in the United States have been associated with the use of the live OPV. Until recently, the benefits of OPV use (i.e., intestinal immunity, secondary spread) outweighed the risk for vaccineassociated paralytic poliomyelitis (VAPP) (i.e., one case among 2.4 million vaccine doses distributed). In 1997, to decrease the risk for VAPP but maintain the benefits of OPV, ACIP recommended replacing the all-OPV schedule with a sequential schedule of IPV followed by OPV. Since 1997, the global polio eradication initiative has progressed rapidly, and the likelihood of poliovirus importation into the United States has decreased substantially. In addition, the sequential schedule has been well accepted. No declines in childhood immunization coverage were observed, despite the need for additional injections. On the basis of these data, ACIP recommended on June 17, 1999, an all-IPV schedule for routine childhood polio vaccination in the United States to eliminate the risk for VAPP. ACIP reaffirms its support for the global polio eradication initiative and the use of OPV as the only vaccine recommended to eradicate polio from the remaining countries where polio is endemic.