Low adherence was the most common cause of poor blood pressure control in patients with apparent resistant hypertension, being twice as frequent as secondary causes of hypertension. Incomplete adherence was far more common than complete nonadherence; thus, assessment of adherence in patients on multiple drug regime is only reliable when all drugs are included in assessment. Assessing adherence by toxicological urine screening is a useful tool in detecting low adherence, especially in the setting of multidrug regimen as a cause of apparently resistant hypertension.

The rational construction and operation of an ideal helical spring has been investigated. The infinite helices, [Ag(Py 2 O)]X (Py 2 O ) 3,3′-oxybispyridine; X -) NO 3 -, BF 4 -, ClO 4 -, and PF 6 -), have been constructed in high yield via cooperative effects of the skewed conformer of Py 2 O and the potential linear geometry of the N-Ag(I)-N bond. Crystallographic characterization reveals that the polymer framework is an ideal cationic cylindrical helix and that its counteranions are pinched in two columns inside the helix. The four anions have been exchanged for each other in an aqueous solution without destruction of the helical skeleton. In particular, [Ag(Py 2 O)]NO 3 prepared by the counteranion exchange can be isolated as crystals suitable for X-ray crystallography in water. The helical pitch is reversibly stretched via the counteranion exchange from 7.430(2) to 9.621(2) Å, and is exactly proportional to the volume of the anion guests. This pitch-tuning is attributed to subtle change in the nonrigid dihedral angles between two pyridyl groups around O and Ag atoms that act as hinges within the helical subunit. Thermal analyses indicate that the helical compounds are stable up to 231-332 °C in the solid state.

Abstract-The bioavailability of nitric oxide (NO) within the vascular wall is limited by superoxide anions (O 2 ·Ϫ ). The relevance of extracellular superoxide dismutase (ecSOD) for the detoxification of vascular O 2 ·Ϫ is unknown. We determined the involvement of ecSOD in the control of blood pressure and endothelium-dependent responses in angiotensin II-induced hypertension and renovascular hypertension induced by the two-kidney, one-clip model in wild-type mice and mice lacking the ecSOD gene. Blood pressure was identical in sham-operated ecSOD ϩ/ϩ and ecSOD Ϫ/Ϫ mice. After 6 days of angiotensin II-treatment and 2 and 4 weeks after renal artery clipping, blood pressure was significantly higher in ecSOD Ϫ/Ϫ than ecSOD ϩ/ϩ mice. Recombinant ecSOD selectively decreased blood pressure in hypertensive ecSOD Ϫ/Ϫ mice, whereas ecSOD had no effect in normotensive and hypertensive ecSOD ϩ/ϩ mice. Compared with sham-operated ecSOD ϩ/ϩ mice, sham-operated ecSOD Ϫ/Ϫ mice exhibited attenuated acetylcholineinduced relaxations. These responses were further depressed in vessels from clipped animals. Vascular O 2 ·Ϫ , as measured by lucigenin chemiluminescence, was higher in ecSOD Ϫ/Ϫ compared with ecSOD ϩ/ϩ mice and was increased by clipping. The antioxidant tiron normalized relaxations in vessels from sham-operated and clipped ecSOD Ϫ/Ϫ , as well as from clipped ecSOD ϩ/ϩ mice. In contrast, in vivo application of ecSOD selectively enhanced endothelium-dependent relaxation in vessels from ecSOD Ϫ/Ϫ mice. These data reveal that endogenous ecSOD is a major antagonistic principle to vascular O 2 ·Ϫ , controlling blood pressure and vascular function in angiotensin II-dependent models of hypertension. ecSOD is expressed in such an abundance that even in situations of high oxidative stress no relative lack of enzyme activity occurs.

Background-Isoforms of the NADPH oxidase contribute to vascular superoxide anion ( · O 2 Ϫ ) formation and limit NO bioavailability. We hypothesized that the endothelial gp91phox-containing NADPH oxidase is predominant in generating the O 2 Ϫ to scavenge endothelial NO and thus is responsible for the development of endothelial dysfunction. Methods and Results-Endothelial dysfunction was studied in aortic rings from wild-type (WT) and gp91phox-knockout (gp91phox Ϫ/Ϫ ) mice with and without renovascular hypertension induced by renal artery clipping (2K1C). Hypertension induced by 2K1C was more severe in WT than in gp91phox Ϫ/Ϫ mice (158Ϯ2 versus 149Ϯ2 mm Hg; PϽ0.05). Endothelium-dependent relaxation to acetylcholine (ACh) was attenuated in rings from clipped WT but not from clipped gp91phox Ϫ/Ϫ mice. The reactive oxygen species (ROS) scavenger Tiron, PEG-superoxide dismutase, and the NADPH oxidase inhibitory peptide gp91ds-tat enhanced ACh-induced relaxation in aortae of clipped WT mice. Inhibition of protein kinase C, Rac, and the epidermal growth factor receptor kinase, elements involved in the activation of the NADPH oxidase, restored normal endothelium-dependent relaxation in vessels from clipped WT mice but had no effect on relaxations in those from gp91phox Ϫ/Ϫ mice. Relaxations to exogenous NO were attenuated in vessels from clipped WT but not clipped gp91phox Ϫ/Ϫ mice. After removal of the endothelium or treatment with PEG-superoxide dismutase, NO-induced relaxations were identical in vessels from clipped and sham-operated WT and gp91phox mice. Conclusions-These data indicate that the formation of O 2Ϫ by the endothelial gp91phox-containing NADPH oxidase accounts for the reduced NO bioavailability in the 2K1C model and contributes to the development of renovascular hypertension and endothelial dysfunction.

Abstract-The soluble epoxide hydrolase (sEH) metabolizes vasodilatory epoxyeicosatrienoic acids (EETs) to their di-hydroxy derivatives. We hypothesized that the metabolism of EETs by the sEH contributes to angiotensin II-induced hypertension and tested the effects of a water-soluble sEH inhibitor, 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) on blood pressure. AUDA (130 g/mL in drinking water) did not affect blood pressure in normotensive animals but markedly lowered it in mice with angiotensin II-induced hypertension (1 mg/kg per day). The effect of AUDA was accompanied by an increase in urinary salt and water excretion. Intravenous application of AUDA (8 mg/kg) acutely lowered blood pressure and heart rate in animals with angiotensin II-induced hypertension but failed to affect blood pressure in animals with phenylephrine-induced hypertension (29 mg/kg per day). AUDA (0.1 mol/L) selectively lowered vascular resistance in an isolated perfused kidney preparation from angiotensin II-pretreated mice but not from control mice. In the perfused hind limb and in isolated carotid arteries from angiotensin II-treated mice, AUDA was without effect. The -hydroxylase inhibitor N-methylsulfonyl-12,12-dibromododec-11-enamide, which attenuates formation of the potent vasoconstrictor 20-hydroxyeicosatetraenoic acid, decreased tone in carotid arteries from angiotensin II-treated but not from control mice. These data demonstrate that the decrease in blood pressure observed after sEH inhibition in angiotensin II-induced hypertension can be attributed to an initial reduction in heart rate followed by pressure diuresis resulting from increased perfusion of the kidney. Direct vasodilatation of resistance arteries in skeletal muscles does not appear to contribute to the antihypertensive effects of sEH inhibition in mice. Key Words: angiotensin Ⅲ lipids E poxyeicosatrienoic acids (EETs) are important signaling molecules derived from arachidonic acid by the action of cytochrome P450 (CYP) epoxygenases. 1 Endotheliumderived EETs are potent vasodilators involved in the action of the endothelium-derived hyperpolarizing factor (EDHF), 2 lower blood pressure, and increase renal sodium excretion. 1,3 Consequently, it may be possible to attenuate or prevent the development of hypertension by maintaining high intravascular EET concentrations. The arachidonic acid epoxides are metabolized to their di-hydroxyl derivatives (DHETS) by the soluble epoxide hydrolase (sEH), 4 and this hydrophilic modification facilitates their diffusion out of the cells and renal clearance. 5,6 The activity of the sEH is therefore thought to be a major determinant of EET bioavailability. 4 The expression of the sEH is high in a number of organs, including the kidney and the liver, 7 and several publications have suggested that the sEH plays a role in regulation of blood pressure. For example, male sEH Ϫ/Ϫ mice have a lower blood pressure than their control litter mates, 8 and inhibition of sEH using N,NЈ-dicyclohexylurea lowers blood pressure in spontaneously ...

Low-density lipoprotein increases the AT1-receptor gene expression in vascular smooth muscle cells. To elucidate whether elevated cholesterol serum levels upregulate the AT1 receptor and its functional response to angiotensin II in vivo, we compared 1) the vasoconstrictive effect of angiotensin II and 2) the level of expression of the vascular AT1 receptor in aortas of normocholesterolemic and hypercholesterolemic rabbits. Contraction experiments on isolated aortic rings showed that the angiotensin II-induced vasoconstriction was increased in hypercholesterolemic New Zealand White rabbits compared with normocholesterolemic New Zealand White rabbits. This difference in the angiotensin II-induced vasoconstriction was caused by a twofold increase in the density of cell surface AT1 receptors in hypercholesterolemic rabbits, as assessed by radioligand binding assays. The enhanced expression of AT1 receptors on the surface of these vascular cells was caused by elevated steady-state levels of the AT1-receptor mRNA to 220 +/- 35% in aortas excised from hypercholesterolemic rabbits compared with levels in aortas from normocholesterolemic rabbits, as measured by Northern blot analysis. These data indicate that hypercholesterolemia is associated with upregulation of expression and function of vascular AT1 receptors in vivo. This suggests a novel mechanism by which hypercholesterolemia could be involved in the onset and progression of chronic vascular diseases such as hypertension and arteriosclerosis if the phenomenon is confirmed in humans.

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