Background-A respiratory cycle for nitric oxide (NO) would involve the formation of vasoactive metabolites between NO and hemoglobin during pulmonary oxygenation. We investigated the role of these metabolites in hypoxic tissue in vitro and in vivo in healthy subjects and patients with congestive heart failure (CHF compared with relaxations induced at 95% (PϽ0.05), consistent with an allosteric mechanism of hypoxic vasodilation. We also measured transpulmonary gradients of NO metabolites in healthy control subjects and in patients with CHF. In CHF patients but not control subjects, levels of SNO-Hb increase from 0.00293Ϯ0.00089 to 0.00585Ϯ0.00137 mol NO/mol hemoglobin tetramer (Pϭ0.005), whereas HbFeNO decreases from 0.00361Ϯ0.00109 to 0.00081Ϯ0.00040 mol NO/mol hemoglobin tetramer (Pϭ0.03) as hemoglobin is oxygenated in the pulmonary circulation. These metabolite gradients correlated with the hemoglobin O 2 saturation gradient (PϽ0.05) and inversely with cardiac index (PϽ0.05) for both CHF patients and control subjects. Conclusions-We confirm that RBC-bound NO mediates hypoxic vasodilation in vitro. Transpulmonary gradients of hemoglobin-bound NO are evident in CHF patients and are inversely dependent on cardiac index. Hemoglobin may transport and release NO bioactivity to areas of tissue hypoxia or during increased peripheral oxygen extraction via an allosteric mechanism.
Low-dose NaNO₂ improves functional responses in ischemic myocardium but has no effect on normal regions. Low-dose NaNO₂ protects against vascular ischemia-reperfusion injury only when it is given before the onset of ischemia.
Cerebral vasomotor tone is difficult to assess in patients. Wave intensity analysis has been applied to resolve complex upstream and downstream events within the vascular system. We hypothesized that the backward-traveling wave measured in the common carotid artery was caused by reflection from the cerebrovascular "beach", and that the magnitude of this reflected wave would be altered by changes in cerebral vasomotor tone. We measured common carotid arterial diameter and velocity of flow to calculate wave intensity in ten healthy male volunteers (age mean 31 +/- 3 years). Applying a rebreathing technique, we were able to increase the inspired carbon dioxide concentration to a mean of 5.9% +/- 1.7% and to compare baseline wave intensity readings to those recorded during hypercapnia. The magnitude of the reflected wave decreased significantly after CO(2) rebreathing, from -43.0 +/- 27.1 to -25.0 +/- 16.9 mmHg m s(-2), P = 0.02. This reduction in negative wave reflections in mid-systole during hypercapnia remained significant when it was analyzed as the reflection coefficient (the magnitude of the reflected wave normalized for the magnitude of the initiating forward wave, which fell from -2.8 +/- 1.5 to -1.6 +/- 1.4 ms (P = 0.01). Carotid wave reflection was significantly decreased during cerebral vasodilatation induced by increased arterial pCO(2). Wave intensity may provide a simple noninvasive means of assessing changes in cerebral vasomotor tone in vivo.
Background-Left ventricular (LV) pacing improves hemodynamics in patients with heart failure. We hypothesized that at least part of this benefit occurs by minimization of external constraint to LV filling from ventricular interaction. Methods and Results-We present median values (interquartile ranges) for 13 heart failure patients with LV pacing systems implanted for New York Heart Association class III/IV limitation. We used the conductance catheter method to measure LV pressure and volume simultaneously. External constraint was measured from the end-diastolic pressure-volume relation recorded during inferior vena caval occlusion, during LV pacing, and while pacing was suspended. External constraint to LV filling was reduced by 3.0 (4.6 to 0.6) mm Hg from 4.8 (0.6 to 7.5) mm Hg (PϽ0.01) in response to LV pacing; effective filling pressure (LV end-diastolic pressure minus external constraint) increased by 4.0 (2.2 to 5.8) mm Hg from 17.7 (13.3 to 22.6; PϽ0.01). LV end-diastolic volume increased by 10 (3 to 11) mL from 238 (169 to 295) mL (Pϭ0.01), whereas LV end-systolic volume did not change significantly (Ϫ1 [Ϫ2 to 3] mL from 180 [124 to 236] mL, Pϭ0.97), which resulted in an increase in stroke volume of 11 (5 to 13) mL from 49 (38 to 59) mL (PϽ0.01). LV stroke work increased by 720 (550 to 1180) mL ⅐ mm Hg from 3400 (2110 to 4480) mL ⅐ mm Hg (Pϭ0.01), and maximum dP/dt increased by 120 (2 to 161) mm Hg/s from 635 (521 to 767) mm Hg/s (Pϭ0.03). Conclusions-This study suggests a potentially important mechanism by which LV pacing may produce hemodynamic benefit. LV pacing minimizes external constraint to LV filling, resulting in an increase in effective filling pressure; the consequent increase in LV end-diastolic volume increases stroke volume via the Starling mechanism. (Circulation.
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