1 Adrenomedullin (ADM), a recently discovered circulating hypotensive peptide, shares limited sequence homology with the sensory nerve-derived vasodilator, calcitonin gene-related peptide (CGRP). This study compared the vasodilator effect of sequence 13-52 of human adrenomedullin (ADM,352) with that of human a CGRP (CGRP), in the microvasculature of the hamster cheek pouch and rat skin in vivo.2 Single arterioles (20-40 lim diameter) in the hamster cheek pouch were visualised by intravital microscopy and video recording, and measured by image analysis. Both ADM1352 (1 pmol-0.4 nmol) and CGRP (0.1 pmol-1 nmol) evoked dose-related increases in the diameter of preconstricted arterioles (n = 6). ADM1352 (ED5o 14 pmol) was 20 fold less active than CGRP (ED50 0.71 pmol). The kinetics of onset and decline of vasodilator responses to both peptides were similar, with vasodilator responses to both peptides reaching a maximum at ca. 2 min, and reversing after 10-15 min (n = 5-7). The submaximal increase in blood flow evoked by ADM,3.52 was significantly inhibited (P<0.05; n = 6) by the CGRPI receptor antagonist, CGRP837, at a dose (300 nmol kg-', i.v.) that we have previously shown to inhibit significantly equivalent vasodilator responses to CGRP in this preparation.3 In experiments measuring changes in local blood flow in rat skin by a 133xenon clearance technique, intradermal injection of both ADM,352 (3-300 pmol) and CGRP (0.1-30 pmol) evoked dose-related increases in local blood flow. ADM13.52 (ED50 27 pmol) was 17 fold less potent than CGRP (ED50 1.6 pmol) (n = 6). The submaximal increase in blood flow evoked by both peptides was significantly inhibited (P<0.02; n = 5) by CGRP837 (100 nmol kg-', i.v.).4 We conclude that ADM1352 is a potent vasodilator in the microvasculature of the hamster and rat in vivo. It mediates its vasodilator effect by arteriolar dilatation and this effect is due, at least in part, to the stimulation of CGRPI receptors.
1 The involvement of the neuropeptides, substance P (SP) and calcitonin gene-related peptide (CGRP) in plasma extravasation following thermal injury of rat dorsal skin was investigated. 2 Heat applied to the dorsal skin of anaesthetized rats by a temperature-controlled skin heater (1 cm diameter) for 5 min induced temperature-dependent plasma protein extravasation at 46°C to 50°C measured over the 20 min following initiation of heat.3 The NKI-receptor antagonist, SR140333, at doses above 36 nmol kg-', significantly (P<0.05) inhibited plasma extravasation by up to 79 + 3% (120 nmol kg-') after heat application at 48°C and by up to 53 + 10% (120 nmol kg-') after heat application at 50°C.4 The CGRP1-receptor antagonist, CGRPS-37, at doses of 200 and 400 nmol kg-', significantly inhibited (P<0.01) plasma extravasation by 55+9 and 60+12%, respectively, after heat application at 48°C. At a dose of 200 nmol kg' CGRP837 inhibited plasma extravasation by 41+8% after heat application at 50°C. 5 SR140333, 120 nmol kg-', and CGRP8-37, 200 nmol kg-' together significantly (P<0.01) inhibited plasma extravasation by 84+15% after heating at 48°C for 5 min.6 In experiments where the response was measured for 0-5, 5-10, 10-15 or 15-20 min, SR140333, 120 nmol kg-', significantly (P<0.05) inhibited plasma extravasation which had accumulated during all the time periods measured. In comparison, CGRP837, 200 nmol kg-', was significantly (P<0.05) effective at time-points up to 15 min after initiation of injury. 7 In longer term experiments plasma protein extravasation continued for at least 95 min after initiation of thermal injury. SR140333, at a dose of 120 nmol kg-', significantly inhibited plasma extravasation for up to 65 min after initiation of injury. 8 In conclusion, the data from the present study demonstrate that both SP and CGRP are likely to have a role in the acute plasma extravasation after thermal injury. In addition, evidence suggests SP may have a role in plasma extravasation for up to 65 min.
The endocardial endothelium covering the mitral valves releases NO under basal conditions and following stimulation with several agonists. The NO synthase enzyme is calcium dependent. Different mechanisms may exist for the synthesis of basal and agonist dependent NO release in these cells.
It is well known that cardiopulmonary bypass (CPB) causes major hemodynamic and physiologic disturbances. These may be alleviated by replacing conventional nonpulsatile perfusion with pulsatile flow, which under normothermic conditions results in a lower peripheral vascular resistance, associated with lower plasma angiotensin II and vasopressin levels, t, 2 It is also known that release of the endogenous vasodilator nitric oxide (NO) is sensitive to flow pulsatility, 3' 4 a mechanism that may contribute to the improved peripheral hemodynamics associated with pulsatile perfusion. We therefore tested the hypothesis that higher NO activity is associated with pulsatile flow than with nonpulsatile flow during and immediately after normothermic CPB. We also investigated whether hypothermic CPB modulated any observed differences.Twenty-four patients without diabetes who were undergoing elective CPB (2.4 L-min -1. m -2) for coronary artery bypass grafting were randomly assigned to four groups: 37 ° C with pulsatile flow, 37 ° C with nonpulsatile flow, 28 ° C with pulsatile flow, and 28 ° C with nonpulsatile flow (n = 6 per group). There were no differences among the groups with respect to age (mean for 24 patients of 59.3 years), number of arteries grafted (median for all groups of 3), crossclamp time (mean for 24 patients of 33.9 minutes), or smoking habits. The same anesthetic regimen (methohexitone, fentanyl, midazolam, and enflurane) was employed for all subjects. Preoperative use of /3-blockers, calcium antagonists, oral nitrates, and aspirin did not differ among the groups; any nitrate medications were discontinued at least 12 hours before operation and were not recommenced until after our investigation. In each patient, arterial blood pressure, cardiac output (by thermal dilution), and gastric mucosal blood flow (by laser Doppler velocimetry) were measured, and peripheral vascular resistance was calculated. Sampling of peripheral venous blood for plasma nitrite plus nitrate (index of NO activity) was achieved at the following time points: 45 minutes after induction of anesthesia (time point A, baseline); 10 minutes (B) and 20 minutes (C) after commencement of CPB; 10 minutes after release of the aortic crossclamp (D); and 10 minutes (E) and 30 minutes (F) after CPB was discontinued. Plasma nitrite plus
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