Abstract-Large-conductance Ca 2ϩ -activated potassium (BK) channels modulate vascular smooth muscle tone. Tempol, a superoxide dismutase (SOD) mimetic, lowers blood pressure and inhibits sympathetic nerve activity in normotensive and hypertensive rats. In the present study, we tested the hypotheses depressor responses caused by tempol are partly mediated by vasodilation. It was found that tempol, but not tiron (a superoxide scavenger), dose-dependently relaxed mesenteric arteries (MA) in anesthetized sham and deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Tempol also reduced perfusion pressure in isolated, norepinephrine (NE) preconstricted MA from sham and DOCA-salt hypertensive rats. Maximal responses in DOCA-salt rats were twice as large as those in sham rats. The vasodilation caused by tempol was blocked by iberiotoxin (IBTX, BK channel antagonist, 0.1 mol/L) and tetraethylammonium chloride (TEA) (1 mmol/L). Tempol did not relax KCl preconstricted arteries in sham or DOCA-salt rats, and N -nitro-L-arginine methyl ester (L-NAME), apamin, or glibenclamide did not alter tempol-induced vasodilation. IBTX constricted MA and this response was larger in DOCA-salt compared with sham rats. Western blots and immunohistochemical analysis revealed increased expression of BK channel ␣ subunit protein in DOCA-salt arteries compared with sham arteries. Whole-cell patch clamp studies revealed that tempol enhanced BK channel currents in HEK-293 cells transiently transfected with mslo, the murine BK channel a subunit. These currents were blocked by IBTX. The data indicate that tempol activates BK channels and this effect contributes to depressor responses caused by tempol. Upregulation of the BK channel ␣ subunit contributes to the enhanced depressor response caused by tempol in DOCA-salt hypertension. Ϫ ) increases blood pressure in hypertensive animals and humans in part by reducing the vascular bioavailability of nitric oxide (NO). 1 4-Hydroxy 2,2,6,6,-tetramethyl piperidine 1-oxyl (tempol), a superoxide dismutase (SOD) mimetic, lowers blood pressure in normotensive and hypertensive rats by multiple mechanisms. [2][3][4][5] Acute tempol treatment of normotensive, DOCA-salt and spontaneously hypertensive rats (SHRs) inhibits sympathetic nerve activity and this effect is not prevented by nitric oxide synthase (NOS) inhibition. 2-6 Local application of tempol onto renal sympathetic nerves decreased nerve activity without changing blood pressure (BP) or heart rate (HR). 7 The results suggested that changes in K ϩ channel activity might contribute to sympatho-inhibition caused by tempol. Central administration of tempol in normotensive rats reduced sympathetic nerve discharge 8,9 and attenuated sympathetic excitation caused by central angiotensin II administration. 9 Therefore, it is possible that tempol-induced vasodilation in vivo is masked by its sympatho-inhibitory effects. 9 Chronic tempol treatment attenuates blood pressure increases in hypertensive animals, an effect attributed to improvement in endothelium f...

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Mesenteric veins are more sensitive than arteries to the constrictor effects of sympathetic nerve stimulation and α-adrenergic receptor agonists. In the present study, we tested the hypothesis that α 2 -adrenergic receptors (α 2 -ARs) contribute to in vitro agonist-induced constriction in veins but not arteries and that α 2 -AR function is down-regulated in mesenteric arteries and veins in deoxycorticosterone acetate-salt (DOCA-salt) hypertension. Norepinephrine (NE) concentrationresponse curves were similar in SHAM and DOCA-salt arteries and veins indicating that adrenergic reactivity of mesenteric blood vessels is not altered in murine DOCA-salt hypertension in vitro. Veins were 30-fold more sensitive to NE than arteries. The α 1 -AR antagonist, prazosin (. 003-0.3μM), produced concentration-dependent rightward shifts of the NE concentrationresponse curves in arteries but not veins. The α 2 -AR agonists, clonidine and UK-14,304, did not constrict arteries or veins in the absence or presence of indomethacin (10 μM) and nitro-Larginine (NLA; 100 μM). The α 2 -AR antagonists, yohimbine (.003-0.3 μM) and rauwolscine (0.1μM) did not affect NE responses in SHAM or DOCA-salt arteries but antagonized NE responses in veins. These data indicate that there are different α-AR contractile mechanisms in murine mesenteric arteries and veins. α 1 -ARs, but not α 2 -ARs, mediate direct contractile responses in arteries and veins while α 2 -ARs contribute indirectly to NE-induced constrictions in veins but not arteries in vitro. There may be direct protein-protein interactions between α 1 -and α 2 -ARs or between their signaling pathways in veins. This contribution of α 2 -ARs may account for the greater sensitivity of veins compared to arteries to the contractile effects of NE.

Mesenteric veins are more sensitive to adrenergic stimulation than arteries and this could be due to different Ca2+ handling mechanisms in arteries and veins. We studied Ca2+ handling in pressurized arteries (60 mmHg) and veins (8 mmHg). Veins were more sensitive to the constrictor effects of norepinephrine (NE) than arteries; EC50 values were 50 and 300 nM respectively. CdCl2 (100 μM), but not nifedipine (1 μM) or GdCl3 (10 μM), blocked NE responses in arteries and veins. Thapsigargin (1 μM) caused a strong contraction in veins that recovered slowly (~30 min). Thapsigargin did not contract arteries. NE responses in arteries and veins were blocked by thapsigargin. In the presence of ouabain (0.1 mM), thapsigargin produced a small arterial contraction. NE responses after in the presence of thapsigargin and ouabain were reduced in arteries but abolished in veins. We conclude that veins are more reactive to NE than arteries. Both vessels use extracellular Ca2+ to support NE‐induced contraction but capacitive Ca2+ entry and L‐type Ca2+ do not contribute to Ca2+ entry in arteries or veins. Facilitation of Ca2+ influx and inhibition of Ca2+ removal by ouabain after intracellular Ca2+ depletion is sufficient for NE to contract arteries, but not veins. Veins have larger Ca2+ stores and more efficient store refilling than arteries; this may account for increased reactivity of veins to NE.

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