Chronic estrogen depletion alters adenosine diphosphate-induced pial arteriolar dilation in female rats

Abstract

We examined pial arteriolar reactivity to a partially endothelial nitric oxide synthase (eNOS)-dependent vasodilator ADP as a function of chronic estrogen status. The eNOS-dependent portion of the ADP response was ascertained by comparing ADP-induced pial arteriolar dilations before and after suffusion of a NOS inhibitor, N(omega)-nitro-L-arginine (L-NNA; 1 mM) in intact, ovariectomized (Ovx), and 17beta-estradiol (E2)-treated Ovx females. We also examined whether ovariectomy altered the participation of other factors in the ADP response. Those factors were the following: 1) the prostanoid indomethacin (Indo); 2) the Ca2+-dependent K+ (K(Ca)) channel, iberiotoxin (IbTX); 3) the ATP-regulated K+ (K(ATP)) channel glibenclamide (Glib); 4) the K(Ca)-regulating epoxygenase pathway miconazole (Mic); and 5) the adenosine receptor 8-sulfophenyltheophylline (8-SPT). In intact females, the eNOS-dependent (L-NNA sensitive) portion of the ADP response represented approximately 50% of the total. The ADP response was retained in the Ovx rats but L-NNA sensitivity disappeared. On E2 replacement, the initial pattern was restored. ADP reactivity was unaffected by Indo, Glib, Mic, and 8-SPT. IbTX was associated with 50-80% reductions in the response to ADP in the intact group that was nonadditive with L-NNA, and 60-100% reductions in the Ovx group. The present findings suggest that estrogen influences the mechanisms responsible for ADP-induced vasodilation. The continued sensitivity to IbTX in Ovx rats, despite the loss of a NO contribution, is suggestive of a conversion to a hyperpolarizing factor dependency in the absence of E2.

Nascent EDHF-mediated cerebral vasodilation in ovariectomized rats is not induced by eNOS dysfunction

“…In confirmation of earlier results published from our laboratory (24,25), initial suffusions with ADP, at 10 and 100 M, elicited similar dosedependent vasodilations in intact (13.4 Ϯ 1.9% and 29.8 Ϯ 5.8%, respectively), Ovx (14.1 Ϯ 2.4% and 35.3 Ϯ 8.4%, respectively), and OVE (12.3 Ϯ 3.0% and 28.4 Ϯ 4.9%, respectively) females (Fig. 1).…”

“…In intact and OVE groups, topical applications of L-NNA for 60 min combined with 10 mg/kg iv Indo resulted in 70% and 50% reductions in the vasodilations produced by 10 and 100 M ADP, respectively. These changes can be ascribed entirely to L-NNA, because it was previously shown that Indo alone has no effect on ADP reactivity in the same female groups (25). Chronic L-NAME treatment affected ADP responses in a manner similar to that observed in vehicle control rats after acute topical application of a NOS inhibitor (L-NNA).…”

“…Furthermore, it has been proposed that this relates to NO acting to inhibit EDHF production or function (1,13). Because cerebrovascular eNOS expression and activity are diminished in Ovx females (16,25), it is tempting to ascribe the nascent EDHF dependency in the pial arteriolar response to ADP in these animals to the loss of a NO-associated inhibitory influence. However, in cerebral arteries, present and previously published results do not support such a mechanism, irrespective of whether the changes in NO are imposed chronically or acutely (17).…”

Essential Role of Gap Junctions in NO- and Prostanoid-Independent Relaxations Evoked by Acetylcholine in Rabbit Intracerebral Arteries

“…For example, estrogens, which are known to modulate gap junctional communication, have been reported to upregulate the EDHF phenomenon in peripheral vessels 39 but to depress EDHF-type relaxations in cerebral arteries. 6,40 Indeed, in pial arterioles 37,43 Gap27 attenuates the endothelium-dependent component of ADP-induced dilation in ovariectomized rats but not in control rats. 36 Finally, there may be significant regional variations in connexin expression in intracerebral arteries from the same species.…”

“…Although less well documented, agonists such as acetylcholine (ACh), ATP, and substance P also stimulate EDHF-type relaxations in isolated cerebral vessels, including human vessels, [1][2][3][4][5][6] and analogous responses have been observed in the pial microcirculation in vivo. 6 EDHF-type relaxations appear to play a more prominent role in small branch arteries and arterioles from peripheral beds and the intracerebral vasculature than in major supply vessels, whereas the importance of NO-mediated relaxations may diminish progressively along the vascular tree. 4,7 Such observations suggest that the EDHF phenomenon may be a significant determinant of microvascular resistance and cerebral perfusion under physiological conditions.…”