Sirolimus causes relaxation of human vascular smooth muscle: a novel action of sirolimus mediated via ATP-sensitive potassium channels.

Little is known about the vasomotor effects of sirolimus, and preliminary studies using animal models have provided conflicting results. The present study was designed to determine the effects of sirolimus on vasomotor tone in human blood vessels. Human radial artery segments were cut into rings, denuded of endothelium, and placed into organ chambers for isometric tension recording. Sirolimus (10(-10) to 10(-6) M) caused concentration-dependent relaxation of human arteries contracted with U46619 (9,11-dideoxy-11alpha,9alpha-epoxymethano-prostaglandin F(2alpha); 10(-8) M) [-log (M) EC(50) (pD(2)) = 7.28 +/- 0.1; E(max) = 57 +/- 6%] or phenylephrine (10(-6) M) (pD(2) = 7.16 +/- 0.4; E(max) = 45 +/- 9%). Sirolimus-induced relaxation was unaffected by treatment with indomethacin (10(-5) M) but was nearly abolished in tissues contracted by depolarization with elevated K(+) (60 mM). In U46619-contracted rings, the response to sirolimus was markedly inhibited in the presence of the specific ATP-sensitive potassium (K(ATP)) channel blocker, glyburide (10(-6) M), but was unaffected by treatment with blockers of large conductance, calcium-activated potassium channel (iberiotoxin, 10(-7) M), small conductance, calcium-activated potassium channel (apamin, 10(-6) M), or voltage-gated potassium channel (4-aminopyridine, 10(-3) M). The K(ATP) channel opener, aprikalim (10(-7) to 10(-5) M), caused concentration-dependent relaxations that were inhibited by glyburide (10(-6) M) and abolished in tissues contracted with elevated K(+) (60 mM), thus confirming that K(ATP) channel opening causes relaxation of these arteries. These data suggest that sirolimus, at concentrations attained in vivo, causes relaxation of human arteries, and this effect is mediated by opening of K(ATP) channels in vascular smooth muscle. Reduced vasomotor tone is a heretofore unrecognized action of sirolimus that could potentially contribute to its efficacy in drug-eluting stents.

Hypertension and risk of brain metastasis from small cell lung cancer: a retrospective follow-up study.

BACKGROUND: Although metastatic brain cancer is one of the most common forms of cancer, little is known about the factors associated with its development. We examined the hypothesis that hypertension may increase the risk for brain metastasis (BM) in patients with primary small cell lung cancer (SCLC). MATERIALS AND METHODS: A retrospective review of medical charts of patients diagnosed with SCLC between June, 1986 and June, 2003 at MeritCare in Fargo, ND, USA, was done to determine which of these patients subsequently developed brain metastases. The effects of hypertension, age, gender, body mass index and the site of SCLC on the risk of developing BM were examined using both univariate and multivariable Cox proportional-hazards regression models. Two-way interactions between hypertension and other covariates were also included in the analyses. RESULTS: Two hundred and thirty-two patients were identified with SCLC and 185 patients were eligible for this study. Eighty-five (45.9%) patients developed BM. Over 54% of SCLC occurred in the right lobe and more than 70% of the patients with BM had them in multiple locations. The risk of BM is significantly higher in younger patients (p-value < 0.03). Univariate analysis showed a hazard ratio (HR) for hypertension of 1.01 (95% Confidence Interval (CI) 0.6-1.6) for BM from SCLC. The multivariable Cox model showed an adjusted HR for hypertension of 1.06 (95%CI 0.7-1.6) for BM from SCLC CONCLUSION: As has been consistently observed for other lung cancers, SCLC is more common in the right lung. The higher incidence of BM in younger patients suggests that more aggressive therapy is needed in these patients. Hypertension does not appear to increase the risk of BM from SCLC.