Aspirin is not associated with a risk of ICH compared with no therapy. Chronic low-dose aspirin treatment may have a protective effect on the risk of SAH. Warfarin users in this study cohort were at a much higher risk of ICH than those receiving no therapy, with a marked association with international normalized ratio >3.

Whether leukocytes exert an influence on vascular function in vivo is not known. Here, genetic and pharmacologic approaches show that the absence of neutrophils leads to acute blood pressure dysregulation. Following neutrophil depletion, systolic blood pressure falls significantly over 3 days (88.0 ± 3.5 vs 104.0 ± 2.8 mm Hg, day 3 vs day 0, mean ± SEM, P < .001), and aortic rings from neutropenic mice do not constrict properly. The constriction defect is corrected using l-nitroarginine-methyl ester (L-NAME) or the specific inducible nitric oxide synthase (iNOS) inhibitor 1400W, while acetylcholine relaxation is normal. iNOS- or IFNγ-deficient mice are protected from neutropenia-induced hypotension, indicating that iNOS-derived nitric oxide (NO) is responsible and that its induction involves IFNγ. Oral enrofloxacin partially inhibited hypotension, implicating bacterial products. Roles for cyclooxygenase, complement C5, or endotoxin were excluded, although urinary prostacyclin metabolites were elevated. Neutrophil depletion required complement opsinization, with no evidence for intravascular degranulation. In summary, circulating neutrophils contribute to maintaining physiological tone in the vasculature, at least in part through suppressing early proinflammatory effects of infection. The speed with which hypotension developed provides insight into early changes that occur in the absence of neutrophils and illustrates the importance of constant surveillance of mucosal sites by granulocytes in healthy mice.

The cardiovascular safety of COX-2 selective and nonselective nonsteroidal antiinflammatory drugs (NSAIDs) has recently been called into question. The factors that predispose to adverse events by NSAIDs are unknown. Because patients with arthritis have decreased nitric oxide (NO) bioavailability, the in vivo effects of NSAIDs on murine vascular tone and platelet activity in the presence or absence of NO were examined. Here, we show that acute hypertensive and prothrombotic activities of the COX-2-selective inhibitor celecoxib are revealed only after in vivo inhibition of NO generation. The nonselective NSAID indomethacin was hypertensive but antithrombotic when NO was absent. In vitro myography of aortic rings confirmed that vasoconstriction required inhibition of both NOS and COX-2 and was abolished by supplementation with exogenous NO. These data indicate that NO suppresses vascular side effects of NSAIDs, suggesting that risk will be greatest in patients with impaired vascular function associated with decreased NO bioavailability. IntroductionRecently, concerns were raised over elevated cardiovascular risks following administration of selective COX-2 inhibitors and nonselective NSAIDs. [1][2][3][4][5][6][7][8][9] However, factors that interact with COX and modulate risk of adverse events are currently unknown. Prostacyclin (PGI) synthesis is elevated in patients with cardiovascular disease and arthritis. [10][11][12][13] Also, decreased large-vessel NO bioactivity is observed. 11,[14][15][16][17][18] Indeed, because of the lack of NO, it is possible PGI may play an even more important role in maintaining vascular homeostasis and preventing adverse events in these groups than in healthy subjects. This led us to hypothesize that the ability of NSAIDs to mediate undesirable vascular events would be revealed or magnified in the absence of NO. In support, previous studies have found multiple complex interactions between NO and COX, including studies showing that NO inhibition can alter PGI signaling, consistent with this hypothesis. [19][20][21][22][23] In this study, we examined acute effects of NSAID administration in healthy mice in vivo, with or without simultaneous NO blockade, specifically to examine whether NO influenced the ability of NSAIDs to mediate vascular side effects. The results suggest that NO bioactivity may be a determinant of susceptibility to adverse events of NSAIDs in patients with inflammatory diseases. Materials and methods Animal studiesAll animal experiments were performed in accordance with the United Kingdom Home Office Animals (Scientific Procedures) Act of 1986. Disruption of the Ptgs2 gene was originally carried out in AB2.1 (129) embryonic stem cells by homologous recombination as previously described. 24,25 Isometric tension functional studies Male mice (10-12 weeks old) were killed by cervical dislocation. The thoracic aorta was dissected, cut into rings (2-3 mm), and suspended in an isometric tension myograph (DMT, Aarhuis, Denmark) containing Krebs buffer at 37°C and gassed wi...

Summary Complement is a major pro‐inflammatory innate immune system whose serum activity correlates with systolic blood pressure in humans. To date, no studies using in vivo models have directly examined the role of individual complement components in regulating vessel function, hypertension and cardiac hypertrophy. Herein, in vivo responses to angiotensin (ang) II were characterized in mice deficient in CD59a or C3. CD59a–/– mice had slightly but significantly elevated systolic blood pressure (107·2 ± 1·7 mmHg versus 113·8 ± 1·31 mmHg, P < 0·01, for wild‐type and CD59a–/–, respectively). Aortic rings from CD59a–/– mice showed significantly less platelet endothelial cell adhesion molecule‐1 (PECAM‐1) expression, with elevated deposition of membrane attack complex. However, acetylcholine‐ and sodium nitroprusside‐dependent dilatation, plasma nitrate/nitrite and aortic cyclic guanosine monophosphate levels were unchanged from wild‐type. Also, in vivo infusion with either ang II or noradrenaline caused similar hypertension and vascular hypertrophy to wild‐type. Mice deficient in C3 had similar basal blood pressure to wild type and showed no differences in hypertension or hypertrophy responses to in vivo infusion with ang II. These data indicate that CD59a deficiency is associated with some vascular alterations that may represent early damage occurring as a result of increased complement attack. However, a direct role for CD59a or C3 in modulating development of ang II‐dependent hypertension or hypertrophy in vivo is excluded and we suggest caution in development of complement intervention strategies for hypertension and heart failure.