NO alters contractile and relaxant properties of the heart. However, it is not known whether changes in ventricular loading conditions affect cardiac NO synthesis. To understand this potential contractile-relaxant autoregulatory mechanism, production of cardiac NO in response to mechanical stimuli was measured in vivo using a porphyrinic sensor placed in the left ventricular myocardium. The beating rabbit heart exhibited cyclic changes in [NO], peaking at 2.7+/-0.1 micromol/L near the endocardium and 0.93+/-0.20 micromol/L in the midventricular myocardium (concentrations were 15+/-4% lower in the rat heart). In the present study, we demonstrate for the first time that increasing or decreasing ventricular preload in vivo is followed by parallel changes in [NO], which may represent a novel autoregulatory mechanism to adjust cardiac performance or perfusion on a beat-to-beat basis. To quantify the relationship between applied force and NO synthesis, intermittent compressive or distending forces applied to ex vivo nonbeating hearts were shown to cause bursts of NO synthesis, with peak [NO] linearly related to ventricular transmural pressure. Experiments in which denuding cardiac endothelial and endocardial cells abrogated the NO signal indicate that these cells transduce mechanical stimulation into NO production in the heart. Taken together, these studies may help explain load-dependent relaxation, cardiac memory for mechanical events of preceding beats, diseases associated with myocardial distension, autoregulation of myocardial perfusion, and protection from thrombosis in the turbulent flow environment within the beating heart.

Reestablishment of vascular homeostasis following ex vivo preservation is a critical determinant of successful organ transplantation. Because the nitric oxide (NO) pathway modulates pulmonary vascular tone and leukocyte/endothelial interactions, we hypothesized that reactive oxygen intermediates would lead to decreased NO (and hence cGMP) levels following pulmonary reperfusion, leading to increased pulmonary vascular resistance and leukostasis. Using an orthotopic rat model of lung transplantation, a porphyrinic microsensor was used to make direct in vivo measurements of pulmonary NO. NO levels measured at the surface of the transplanted lung plummeted immediately upon reperfusion, with levels moderately increased by topical application of superoxide dismutase. Because cGMP levels declined in preserved lungs after reperfusion, this led us to buttress the NO pathway by adding a membrane-permeant cGMP analog to the preservation solution. Compared with grafts stored in its absence, grafts stored with supplemental 8-Br-cGMP and evaluated 30 min after reperfusion demonstrated lower pulmonary vascular resistances with increased graft blood flow, improved arterial oxygenation, decreased neutrophil inffiltration, and improved recipient survival. These beneficial effects were dose dependent, mimicked by the type V phosphodiesterase inhibitor 2-o-propoxyphenyl-8-azapurin-6-one, and inhibited by a cGMP-dependent protein kinase antagonist, the R isomer of 8-(4-chlorophenylthio)guanosine 3',5'-cycic monophosphorothioate. Augmenting the NO pathway at the level of cGMP improves graft function and recipient survival following lung transplantation.One of the major impediments to the transplantation of vascular organs has been the short interval during which the organ can survive in transit from donor to recipient. This is especially problematic during clinical lung transplantation, where the inability to preserve lungs beyond 4-6 hr does not allow sufficient time for immunologic cross-matching and impedes efforts at multiple or distant organ procurement (1). Current lung preservation strategies have focused on preventing oxygen free radical damage to the pulmonary parenchyma as well as optimizing electrolyte and solute concentrations of the preservation solution, but lungs still fail after transplantation, with elevated pulmonary vascular resistance, neutrophil infiltration, and poor gas exchange as cardinal features (1).Nitric oxide (NO) released from endothelial cells maintains vascular homeostatic properties (2) by relaxing vascular smooth muscle (3), inhibiting neutrophil adhesivity (4) and platelet aggregation (5), and maintaining endothelial barrier properties (6). In the lungs, endogenously produced NO stimulates basal cGMP production and regulates pulmonary vascular tone (7). We hypothesized that diminished NO availability during the immediate reperfusion period might contribute to the elevated pulmonary vascular resistance and neutrophil recruitment that occurs after lung transplantation. These experiments were ...

A porphyrinic sensor was used to monitor nitric oxide release from vascular smooth muscle in response to exposure to ultraviolet light. Aortic rings exposed to UV light relaxed with a time course that parallels this observed NO release. With repeated UV light treatments, the magnitude of the relaxations diminished, suggesting that a store of NO was being exhausted. Photorelaxation in response to UV light was studied in aortic ring from two types of hypertensive rats, genetic (SHRSP) and nitroarginine-induced. These aortic rings showed greater photorelaxation and evidenced less tolerance than did aortic rings from control normotensive rats. Since NO synthase activity is depressed in both types of hypertension, it appears, paradoxically, that the UV light-releasable store of NO is augmented when NO synthase activity is depressed.

These observations indicate that the /Sdiketonate ligand and Lewis base ligands play a crucial role in determining the deposition selectivity. It is noteworthy that some degree of selectivity has recently been reported (under different conditions) for (hfac)Cu(l,5-COD) below 200 °C for Ta, Cu, Ag, Au, and Cr versus Si02 and Si3N4.33 On the basis of the trends observed for the (/3-diketonate)CuPMe3 series, it is tempting to speculate that the cleavage of the d-diketonate ligand is involved in the rate-determining step of the reaction. However, differences in the adsorption/desorption behavior of the reactants and products are likely to be important also and are currently under investigation.47,48 Acknowledgment. M.J.H.-S. and T.T.K. thank NSF (No. CHE-9107035) for partially funding this work. M. J.H.-S. thanks the NSF chemical instrumentation program for purchase of a low-field NMR spectrometer, and T.T.K. acknowledges support from the NSF Presidential Young Investigator program .Registry No. (hfac)Cu(PMe3), 135707-05-0; (tfac)Cu(PMe3),