Structure—Activity Relations of the Fibrinolytic Response to Vasopressins in Man

Abstract

1. The systemic plasminogen activator response has been examined after intravenous infusion of the following peptides related to neurohypophyseal hormones in approximately equimolar dosages into informed, consenting human volunteer subjects: (a) the natural nonapeptides: lysine-and argininevasopressin, oxytocin and arginine-vasotocin, (b) the N-and C-terminal tripeptide fragments of vasopressin and (c) four vasopressin analogues without pressor activity, altered at the jV-terminus, the disulphide bridge and/or sequence position 8 in the C-terminal tripeptide. In addition, angiotensin II and adrenaline were infused.2. It was' observed that some of the cyclic nonapeptides resulted in high and prolonged increases in amounts of plasminogen activator in venous blood, in the following order, both for amplitude and duration: l-desamino-6-monocarba-[8-D-arginine]-vasopressin > l-desamino-[8-D-arginine]-vasopressin i> arginine-vasopressin = lysinevasopressin > JV a -glycyl-glycyl-glycyl-lysine-vasopressin.3. No plasminogen activator responses followed infusions of vasopressin tripeptide fragments, oxy tocin, angiotension II, l-desamino-[8-iV-MeArg]-vasopressin or 9-desglycineamide-lysinevasopressin octapeptide.4. Mole for mole, the four most active substances were approximately two orders of ten * Deceased 29 April, 1977. Correspondence: Dr J. D. Cash, Regional Blood Transfusion Centre, Royal Infirmary, Edinburgh EH3 9HB, Scotland, U.K. more potent than adrenaline by amplitude com parison alone.5. Intra-arterial adrenaline, in one-tenth the systemic dose, stimulated a release of plasminogen activator from the infused local vascular bed only, This did not occur with equivalent doses of arginine-vasopressin and l-desamino-[8-Dargininel-vasopressin.6. It is concluded that plasminogen activator release arising from catecholamine-responding and vasopressin-responding receptors are both molecule-specific and different in anatomical location. The molecular structural requirements for triggering the latter hypothetical receptor type and potential clinical applications are discussed.

Availability of endothelial von Willebrand factor and platelet function in diabetic patients infused with a vasopressin analogue

“…The drug has minimal vasoactive properties, yet it has been reported to be more effective than adrenaline and lysine-or arginine-vasopressin in mobilising endothelial molecules [24]. Small, though significant, changes of blood pressure and heart rate, together with marked flushing, were observed in all subjects in this study, suggesting that DDAVP is active at some vascular sites (i. e. the skin of the face, neck and chest) and that the endothelium may be differentially affected by the action of the analogue.…”

“…The plasma levels of von Willebrand factor (vWF), a glycoprotein synthesized and stored in the endothelial cells [1], are increased in patients with diabetic microangiopathy [24]. This abnormality is associated with hyperperrneability of the retinal capillaries to fluorescein [5] and could result from widespread endothelial damage in diabetes.…”

Endothelial Stimulation by DDAVP in von Willebrand’s Disease and Haemophilia

“…The mechanism for the action of DDAVP on PGI2 production is not en tirely clear. Previous in vitro studies have shown DDAVP to have a direct stimulatory effect on PGI2 production from arterial tissue [7], while there is mounting evidence that the effect of DDAVP on FVIIR:Ag release is mediated via a secondary messenger [20,21]. In the absence of any change in TxB2 levels following DDAVP, the stimulatory effect on PGI2 production may be mediated through an endothelial cell receptor rather than a gen eral activation of the arachidonic acid cas cade.…”

Fibrinolytic Responses to 1-Desamino-8-<i>D</i>-Arginine-Vasopressin in Patients with Congenital Nephrogenic Diabetes insipidus

“…On the other hand, it has been suggested that these receptors may be located in the central nervous system. Cash et al [27] hypothesized that vasopressin-like molecules may be hu moral messengers acting on a cephalic center, which may in turn release a second messenger that stimulates the endothelial cells indirectly. However, this putative sec ond messenger has not been identified in bovine pituitary and hypothalamic extracts [28].…”