A redox switch in angiotensinogen modulates angiotensin release.

Blood pressure is critically controlled by angiotensins, which are vasopressor peptides specifically released by the enzyme renin from the tail of angiotensinogen-a non-inhibitory member of the serpin family of protease inhibitors. Although angiotensinogen has long been regarded as a passive substrate, the crystal structures solved here to 2.1 Å resolution show that the angiotensin cleavage site is inaccessibly buried in its amino-terminal tail. The conformational rearrangement that makes this site accessible for proteolysis is revealed in our 4.4 Å structure of the complex of human angiotensinogen with renin. The co-ordinated changes involved are seen to be critically linked by a conserved but labile disulphide bridge. Here we show that the reduced unbridged form of angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized sulphydryl-bridged form, which preferentially interacts with receptor-bound renin. We propose that this redox-responsive transition of angiotensinogen to a form that will more effectively release angiotensin at a cellular level contributes to the modulation of blood pressure. Specifically, we demonstrate the oxidative switch of angiotensinogen to its more active sulphydryl-bridged form in the maternal circulation in pre-eclampsia-the hypertensive crisis of pregnancy that threatens the health and survival of both mother and child

Cocaine and the British Empire : the drug and the diplomats at the Hague Opium Conference, 1911–12

This article will consider the reasons for the inclusion of cocaine in the Hague Opium Convention of 1912. This was the first time that the emerging international drugs regulatory system considered substances other than opiates and it was British delegates who took the initiative to include cocaine in discussions and in the final version of the agreement. Historians have tended to keep brief their accounts of this episode, seeing the British agenda on cocaine as driven primarily by their wider interests in opium, or alluding briefly to colonial anxieties about manufactured drugs. This article returns to the events of 1911–12 and argues that Britain's position on cocaine deserves greater attention. It shows that British administrations in Asia had tried to control a growing market there for the drug since the turn of the century, and that their efforts had failed. In exploring the history of these efforts, and their impacts in the early days of the international narcotics-control regime, the article suggests that imperial policies are more complex than many historians have previously acknowledged, and that it may be time for fresh thinking on the relationship between empires and drugs in modern Asia