BACKGROUND Within this thesis we have examined the effects on vascular tone of two
peptide hormones, urotensin II and vasopressin. Human urotensin II is a novel
vasoactive peptide hormone with receptors located on human arterial tissue and
ventricular myocytes. It is the most potent arterial vasoconstrictor yet discovered and
has a sustained effect on blood vessels from a variety of species with potency 28 to 50
fold greater than endothelin-1. Vasopressin has however, been known to have arterial
vasoconstrictor properties in man in vivo for many years. However, peptide antagonists
for the VI receptor, mediating vasoconstriction, and the V2 receptor, mediating
vasodilatation, have often been of poor selectivity and subject to inter-species variation,
thus clouding the true arterial pharmacodynamic effects of vasopressin. Two novel
peptidic arginine vasopressin antagonists have recently been produced and offer
potentially more receptor selectivityOBJECTIVES The aims of this thesis were: first to assess the effects of urotensin II on
human resistance vessels and venous tone in vivo; second, to study the effects of
systemic intravenous urotensin II on human haemodynamics such as blood pressure,
pulse, vascular resistance and arterial stiffness; third, to explore the human in vivo
pharmacodynamics of vasopressin in human resistance vessels in the skin
microcirculation and forearm as preparation for VI and V2 receptor antagonist studies;
forth, to demonstrate that vasopressin induced vasodilatation is mediated by nitric oxide;
and finally, fifth, to combine novel VI and V2 receptor antagonists with vasopressin in
the human skin and forearm to assess the efficacy of novel vasopressin peptide
antagonistsMETHODS Using the established method ofbilateral venous occlusion plethysmography
to measure forearm blood flow, combined with intra-arterial infusion of drugs into the
brachial artery, we sought to determine the effects of urotensin II on human forearm
blood flow. Other methods such as the Aellig venous displacement technique, to assess
venous tone, and pulse wave analysis, to quantify arterial stiffness were also used during
local and systemic urotensin II intravenous infusions respectively. Doppler flowmetry
was used to assess skin microcirculation combined with intra-dermal peptide injection
we assessed skin blood flow in response to vasopressin alone and in combination with a
novel selective VI antagonist. Venous occlusion plethysmography was again used to
determine forearm blood flow responses to vasopressin alone and in combination with
VI and V2 antagonists.RESULTS During intra-arterial infusion ofurotensin II we did not observe any significant
changes in forearm blood flow, even in the presence of endothelial inhibitors such as
aspirin and a 'nitric oxide clamp' nor was change observed in venous tone. Moreover,
no alteration in systemic haemodynamics or arterial stiffness was seen during systemic
intravenous infusion. We observed a significant fall in skin blood flow with intra¬
dermal injection of vasopressin, however, the VI receptor antagonist did not alter skin
vasoconstriction. Intra-arterial infusion of vasopressin caused a reproducible biphasic
change in forearm blood flow, low doses causing vasoconstriction and high doses, nitric
x
oxide mediated vasodilatation. Vasodilatation was subject to tachyphylaxis during
prolonged infusion ofhigh dose vasopressin. Neither intra-arterial VI or V2 antagonist,
when co-infused with vasopressin, altered this biphasic vasoconstriction and
vasodilatationCONCLUSION The majority of our findings for urotensin II were in contrast to our
hypothesis. Until a selective urotensin II antagonist is developed the physiological role
of urotensin II in human cardiovascular physiology will remain difficult to ascertain. Its
role may alternatively lie in longer term regulation of vascular tone or in sodium and
metabolic homeostasis. We defined the pharmacodynamics of vasopressin in humans in
vivo to a greater depth than previous studies and confirmed, using a 'nitric oxide clamp',
the dependence of vasopressin induced vasodilatation on locally derived nitric oxide.
Both vasopressin antagonists have yet again been subject to considerable inter-species
variation, as demonstrated by the efficacy of the VI receptor antagonist in our rat
biopressor assay. To date there are no truly selective peptidic vasopressin receptor
antagonists available for human in vivo studies
