Abstract-This study tested the hypothesis that afferent arteriolar responses to purinoceptor activation are attenuated, and Ca 2ϩ signaling mechanisms are responsible for the blunted preglomerular vascular reactivity in angiotensin II (Ang II) hypertension. Experiments determined the effects of ATP, the P2X 1 agonist ␤,␥-methylene ATP or the P2Y agonist UTP on arteriolar diameter using the juxtamedullary nephron technique and on renal myocyte intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) using single cell fluorescence microscopy. Six or 13 days of Ang II infusion significantly attenuated the vasoconstrictor responses to ATP and ␤,␥-methylene ATP (PϽ0.05). During exposure to ATP (1, 10, and 100 mol/L), afferent diameter declined by 17Ϯ2%, 29Ϯ3%, and 30Ϯ2% in normal control rats and 8Ϯ3%, 7Ϯ3%, and 22Ϯ3% in kidneys of Ang II-infused rats (13 days). Renal myocyte intracellular calcium responses to ATP or ␤,␥-methylene ATP were also decreased in Ang II hypertensive rats. In myocytes of control rats, peak increases in [Ca 2ϩ ] i averaged 107Ϯ21, 170Ϯ38, and 478Ϯ79 nmol/L at ATP concentrations of 1, 10, and 100 mol/L, respectively. Ang II infusion for 13 days decreased the peak responses to ATP (1, 10, and 100 mol/L) to 65Ϯ13, 102Ϯ20, and 367Ϯ73 nmol/L, respectively. The peak increases in [Ca 2ϩ ] i in response to ␤,␥-methylene ATP were also reduced in Ang II hypertensive rats. However, angiotensin hypertension did not change the UTP-mediated vasoconstrictor responses or the myocyte calcium responses to UTP. These results indicate that the impaired autoregulatory response observed in Ang II-dependent hypertension can be attributed to impairment of P2X 1 receptor-mediated signal transduction. (Hypertension. 2005;46:562-568.)

The cytokines generated locally in response to infection play an important role in CD8 T cell trafficking, survival, and effector function, rendering these signals prime candidates for immune intervention. In this paper, we show that localized increases in the homeostatic cytokine IL-15 induced by influenza infection is responsible for the migration of CD8 effector T cells to the site of infection. Moreover, intranasal delivery of IL-15–IL-15Rα soluble complexes (IL-15c) specifically restores the frequency of effector T cells lost in the lung airways of IL-15–deficient animals after influenza infection. Exogenous IL-15c quantitatively augments the respiratory CD8 T cell response, and continued administration of IL-15c throughout the contraction phase of the anti-influenza CD8 T cell response magnifies the resultant CD8 T cell memory generated in situ. This treatment extends the ability of these cells to protect against heterologous infection, immunity that typically depreciates over time. Overall, our studies describe what to our knowledge is a new function for IL-15 in attracting effector CD8 T cells to the lung airways and suggest that adjuvanting IL-15 could be used to prolong anti-influenza CD8 T cell responses at mucosal surfaces to facilitate pathogen elimination.

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Effective vaccines against intracellular pathogens rely on the generation and maintenance of memory CD8 T cells (Tmem). Hitherto, evidence has indicated that CD8 Tmem use the common gamma chain cytokine IL-15 for their steady-state maintenance in the absence of antigen. This evidence, however, has been amassed predominantly from models of acute, systemic infections. Given that the route of infection can have significant impact on the quantity and quality of the resultant Tmem, reliance on limited models of infection may restrict our understanding of long-term CD8 Tmem survival. Here we show IL-15-independent generation, maintenance, and function of CD8 Tmem following respiratory infection with influenza virus. Importantly, we demonstrate that alternating between mucosal and systemic deliveries of the identical virus prompts this change in IL-15 dependence, necessitating a reevaluation of the current model of CD8 Tmem maintenance.

The epoxyeicosatrienoic acids (EETs) have been identified as endothelium-derived hyperpolarizing factors. Metabolism of the EETs to the dihydroxyeicosatrienoic acids is catalyzed by soluble epoxide hydrolase (sEH). Administration of urea-based sEH inhibitors provides protection from hypertension-induced renal injury at least in part by lowering blood pressure. Here, we investigated the hypothesis that a mechanism by which sEH inhibitors elicit their cardiovascular protective effects is via their action on the vasculature. Mesenteric resistance arteries were isolated from Sprague-Dawley rats, pressurized, and constricted with the thromboxane A2 agonist U46619 (9,11-dideoxy-11,9-epoxymethano-prostaglandin F2␣). Mesenteric arteries were then incubated with increasing concentrations of the sEH inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA). AUDA resulted in a concentration-dependent relaxation of mesenteric arteries, with 10 M resulting in a 48 Ϯ 7% relaxation. Chain-shortened analogs of AUDA had an attenuated vasodilatory response. Interestingly, at 10 M, the sEH inhibitors 1-cyclohexyl-3-dodecylurea, 12-(3-cyclohexylureido)dodecanoic acid, and 950 [adamantan-1-yl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pentyl}urea] were significantly less active, resulting in a 25 Ϯ 8%, 10 Ϯ 9%, and Ϫ8 Ϯ 3% relaxation, respectively. Treatment of mesenteric arteries with tetraethylammonium, iberiotoxin, ouabain, or glibenclamide did not alter AUDA-induced relaxation. The AUDA-induced relaxation was completely inhibited when constricted with KCl. In separate experiments, denuding mesenteric resistance vessels did not alter AUDA-induced relaxation. Taken together, these data demonstrate that adamantyl-urea inhibitors have unique dilator actions on vascular smooth muscle compared with other sEH inhibitors and that these dilator actions depend on the adamantyl group and carbon chain length.