No abstract

No abstract

Ryanodine interferes with sarcoplasmic reticulum function in various types of muscle; in vascular smooth muscle, it can inhibit contractions that depend on sarcoplasmic reticulum calcium release, probably by depleting the sarcoplasmic reticulum calcium store. We tested ryanodine and calcium channel blockers (verapamil, diltiazem, and nitrendipine) on small rings of rat thoracic aorta (RA) and bovine tail artery (BTA) to determine the relative contributions of sarcoplasmic reticulum calcium release and gated calcium entry to contractions induced by norepinephrine, caffeine, and 100 mM K depolarization. Ryanodine blocked caffeine contractions in both tissues and attenuated norepinephrine responses (by 52% in RA, 14% in BTA) but minimally altered potassium contractions. Calcium channel blockers almost completely abolished potassium contractions and reduced norepinephrine contractions (by 45% in RA, 82% in BTA) but hardly affected caffeine responses. The blocking effects of ryanodine and calcium channel antagonists on the norepinephrine responses were additive. Ryanodine had no effect on baseline tension in the standard media; however, when calcium extrusion via Na-Ca exchange was inhibited by low external sodium (0-calcium, low-sodium solution), tension increased progressively after introduction of ryanodine. This indicates that the sarcoplasmic reticulum calcium released by ryanodine then accumulated in the cytosol and activated contraction; restoration of external sodium caused prompt relaxation. The smaller effects of caffeine and ryanodine in BTA indicate that sarcoplasmic reticulum plays a less important role in calcium control in this tissue, with gated calcium entry dominating. These functional findings are correlated with electron-microscopic evidence that BTA has about 60% less sarcoplasmic reticulum than does RA. Ryanodine appears to be a useful tool for determining the functional relevance of sarcoplasmic reticulum for contraction in different arterial smooth muscles.

Background Cancer patients with acute venous thromboembolism (VTE) receiving anticoagulant treatment have an increased bleeding risk. Objectives We performed a prespecified secondary analysis of the randomized, open-label, Phase III CATCH trial (NCT01130025) to assess the rate and sites of and the risk factors for clinically relevant bleeding (CRB). Patients/Methods Patients with active cancer and acute, symptomatic VTE received either tinzaparin 175 IU kg once daily or warfarin (target International Normalized Ratio [INR] of 2.0-3.0) for 6 months. Fisher's exact test was used to screen prespecified clinical risk factors; those identified as being significantly associated with an increased risk of CRB then underwent competing risk regression analysis of time to first CRB. Results Among 900 randomized patients, 138 (15.3%) had 180 CRB events. CRB occurred in 60 patients (81 events) in the tinzaparin group and in 78 patients (99 events) in the warfarin group (hazard ratio [HR] 0.64; 95% confidence interval [CI] 0.45-0.89). Common bleeding sites were gastrointestinal (36.7%; n = 66), genitourinary (22.8%; n = 41), and nasal (10.0%; n = 18). In multivariate analysis, the risk of CRB increased with age > 75 years (HR 1.83, 95% CI 1.14-2.94) and intracranial malignancy (HR 1.97, 95% CI 1.07-3.62). In the warfarin group, 40.4% of CRB events occurred in patients with with an INR of < 3.0. A lower time in therapeutic range was associated with a higher risk of CRB. Conclusions CRB is a frequent complication in cancer patients with VTE during anticoagulant treatment, and is associated with age > 75 years and intracranial malignancy.

A Na/Ca exchange system has been demonstrated in systemic vascular smooth muscle and has been suggested as a mechanism for the entry and extrusion of Ca2+. Using isolated rings of bovine intrapulmonary arteries, we sought to determine whether a Na/Ca exchange mechanism is present in pulmonary vascular smooth muscle, and if so, whether it contributes to the modulation of vascular tone during hypoxia. Under both normoxic (PO2 greater than or equal to 120 mm Hg) and hypoxic (PO2 less than or equal to 40 mm Hg) conditions, the amplitude of the 40 mM K+ contraction was significantly (p less than 0.005) enhanced when most of the external Na+ was replaced with N-methylglucamine (NMG) (Na+ = 1.2 mM). The rate of contraction was also increased by replacing Na+ with NMG during normoxia (1.02 +/- 0.24 to 2.52 +/- 0.57 mg/mg weight/s, p less than 0.005) and hypoxia (1.72 +/- 0.74 to 4.08 +/- 1.63 mg/mg weight/s, p less than 0.05). Although the relaxation rate was slowed in the low Na+ media during normoxia (3.48 +/- 1.07 with Na+ versus 2.58 +/- 0.81 mg/mg weight/s with NMG, p less than 0.02), it was unaltered during hypoxia (3.15 +/- 0.90 with Na+ versus 2.95 +/- 0.83 mg/mg weight/s with NMG, p = 0.3). The ratio of relaxation rates in the normal and low Na+ media correlated with the perfusate PO2 (r = 0.76, p less than 0.001). During normoxia and hypoxia, inhibition of the Na+,K+ pump by strophanthidin, which increases intracellular [Na+], reversibly enhanced the amplitude of the K+ contraction, even when the voltage-gated channels were blocked with verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)