1 We have studied the e ect of endothelin-1 stimulation on protein tyrosine phosphorylation levels in intact small mesenteric arteries of the rat and investigated the e ects of tyrosine kinase inhibition on the contractile response to this agonist. 2 Endothelin-1 stimulated a rapid (20 s), sustained (up to 20 min) and concentration-dependent (1 ± 100 nM) increase in protein tyrosine phosphorylation levels which coincided temporally with the contractile response in intact and a-toxin permeabilized small artery preparations. Tyrosine phosphorylation was increased in four main clusters of proteins of apparent molecular mass 28 ± 33, 56 ± 61, 75 ± 85 and 105 ± 115 kDa. Endothelin-1-induced protein tyrosine phosphorylation was independent of extracellular calcium, antagonized by the tyrosine kinase inhibitor tyrphostin A23 but not by the inactive tyrphostin A1. 3 In intact small arteries tyrphostin A23 inhibited the force developed to endothelin-1 at all concentrations studied; at higher concentrations (10 and 100 nM) the pro®le of contraction was altered from a sustained to a transient response. Tyrphostin A1 inhibited the contractile response to endothelin-1 at all concentrations except 100 nM; the pro®le of the response was not altered. Neither tyrphostin a ected the transient phasic contraction induced by endothelin-1 (100 nM) in the absence of extracellular calcium. 4 In rat a-toxin permeabilized mesenteric arteries endothelin-1 caused a concentration-dependent increase in force in the presence of 10 mM GTP and low (pCa 6.7) constant calcium, demonstrating increased sensitivity of the contractile apparatus to calcium. Tyrphostin A23 inhibited this response by approximately 50%, tyrphostin A1 did not a ect endothelin-1-induced calcium sensitization of force. 5 We conclude that increased tyrosine phosphorylation is important in the contractile response induced by endothelin-1 in intact small mesenteric arteries. Furthermore our data implicate activation of this signalling pathway in the tonic phase of contraction possibly through modulation of the sensitivity of the contractile apparatus to calcium.

Background: Coronary artery obstruction is a rare, devastating complication of transcatheter aortic valve replacement. Transcatheter electrosurgical aortic leaflet laceration (Bioprosthetic or Native Aortic Scallop Intentional Laceration to Prevent Iatrogenic Coronary Artery Obstruction [BASILICA]) is a novel technique to prevent coronary artery obstruction. We report the 1-year outcomes of the BASILICA trial. Primary end points of 30-day success and safety have been reported previously. Methods: The BASILICA trial was a prospective, multicenter, single-arm safety and feasibility study. Subjects with severe native or bioprosthetic aortic valve disease at high or extreme risk for surgery, and high risk of coronary artery obstruction, were included. End points at 1 year included death, stroke, and myocardial infarction. Source data was independently verified and end points independently adjudicated. Results: Thirty subjects were enrolled between February 2018 and July 2018. At 30 days, BASILICA was successful in 28 subjects (93.3%), there were 3 strokes (10%), including 1 disabling stroke (3.3%), 1 death (3.3%), and 1 periprocedural myocardial infarction (3.3%). Between 30 days and 1 year, there were no additional strokes, no myocardial infarction, and 2 deaths (10% 1-year mortality). No subject needed repeat intervention for aortic valve or coronary disease. Two subjects had infective endocarditis (6.7%), but neither was isolated to the aortic valve. There were no hospital admissions for heart failure. Fourteen (46.7%) subjects required repeat hospital admission for other causes. Aortic valve gradients on echocardiography, New York Heart Association functional class, and Kansas City Cardiomyopathy Questionnaire scores improved from baseline to 30 days and were maintained at 1 year. Conclusions: In these subjects with multiple comorbidities and restrictive anatomy that underwent transcatheter aortic valve replacement, there was no late stroke, myocardial infarction, or death related to BASILICA. Mitigation of coronary obstruction remained intact at 1 year and was not related to recurrent readmission. These results are reassuring for patients and physicians who wish to avoid the long-term complications related to snorkel stenting. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03381989.

Vitamin C is a key antioxidant in human blood plasma and hence could influence the outcome of conditions such as acute pancreatitis in which oxidative stress apparently plays a pivotal role. The concentrations of vitamin C and its immediately bioavailable form, ascorbic acid, in fasting plasma samples from 30 healthy volunteers were compared with those in admission samples from 29 consecutive patients with acute pancreatitis and 27 patients with other acute abdominal crises. Median (range) levels of vitamin C and ascorbic acid, respectively, were 15 (6.3-19) and 12 (4.5-18) micrograms/ml in the control group, 2.8 (0.3-10) and < 0.5 (< 0.5-6.0) micrograms/ml in patients with acute pancreatitis, and 3.7 (0.6-15) and 2.3 (< 0.5-15) micrograms/ml in those with other acute abdominal problems. Admission plasma samples showed equally low vitamin C levels in both groups of patients (P < 0.001 versus controls), but those from patients with acute pancreatitis were further characterized by a disproportionate reduction in ascorbic acid, such that the concentration of ascorbic acid and its ratio to vitamin C were both significantly lower than in samples from patients with an acute abdomen (P < 0.005 and P < 0.001 respectively). It is concluded that the stress of an acute intra-abdominal crisis is accompanied by a non-specific decrease in the plasma level of vitamin C. In acute pancreatitis early and profound oxidative stress compounds this problem by denaturing the available vitamin. There may be a case for the judicious parenteral administration of ascorbic acid to patients with acute pancreatitis to boost plasma antioxidant defence.

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