الفهرس 
Chapter 1Only 14 pages are availabe for public view
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Abstract
In the present study, in-vitro experiments were undertaken in isolated
perfused kidneys preconstricted with phenylephrine to identify cellular mechanisms
involved in the vasodilatory action of the adenosine analogue NECA in the female
renal vasculature. This included the investigation of the adenosine receptor subtype
involved, the role of the NOS/HO/K+ channel pathway, and the hormonal (estrogen)
modulation of the NECA response. The study also reports on the interaction of
chronic nicotine with NECA vasodilations in female preparations with intact,
depleted, or repleted estrogen and the impact of K+ channel modulators on this
interaction. A summary of the main results and conclusions are outlined below:
1. A2BARs preferentially mediate the renal vasodilatory effect of NECA because
pharmacologic blockade of this receptor subtype by alloxazine, but not A2AARs
(CSC) or A3ARs (VUF5574), significantly reduced the NECA response.
2. The renal vasodilatory action of NECA was attenuated after the infusion of the
NOS inhibitor L-NAME, but remained unaltered after inhibition of HO activity
(ZnPP), suggesting a selective role for the NOS/NO signaling in the elicitation
of the A2BAR-mediated renal vasodilations. This conclusion is further supported
by the findings that alloxazine lost its ability to attenuate NECA vasodilations in
preparations supplemented with the NOS substrate L-arginine. The exaggerated
inhibition of NECA responses after concurrent administration of L-NAME and
alloxazine may reflect that their respective targets (A2BARs and NOS) constitute
two sequential events along the cellular cascade that leads to the renal
vasodilatory action of NECA in female rats.
3. Pharmacologic studies showed NECA vasodilations in kidneys of intact female
rats were attenuated after selective inhibition of Kir (BaCl2) and KATP
(glibenclamide), but not BKCa (TEA), channels. It is plausible, therefore, that
selective activation of Kir and KATP channels, perhaps following upregulated
NOS activity, is required for the elicitation of the A2BAR-dependent vasodilatory
effect of NECA.
4. The notion that functional K+ channel signaling is critically required for NOSdependent
NECA vasodilations is bolstered by the observation that Na+/K+-
ATPase inhibition by ouabain abrogated NECA renal vasodilations. Further,
renal vasodilations caused by minoxidil, a K+ channel opener, were similarly
attenuated in preparations with pharmacologically eliminated NOS, Na+/K+-
ATPase or K+ channel activity. Finally, vasodilations caused by NECA or
minoxidil were reduced in preparations with KCl-induced tone.