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Activation of phospholipases leads to the release of arachidonic acid and lysophospholipids that play prominent roles in regulating vasomotor tone. To identify the role of calcium-independent phospholipase A2β (iPLA2β) in vasomotor function, we measured vascular responses to phenylephrine (PE) and ACh in mesenteric arterioles from wild-type (WT; iPLA2β+/+) mice and those lacking the β-isoform (iPLA2β−/−) both ex vivo and in vivo. Vessels isolated from iPLA2β−/−mice demonstrated increased constriction to PE, despite lower basal smooth muscle calcium levels, and decreased vasodilation to ACh compared with iPLA2β+/+mice. PE constriction resulted in initial intracellular calcium release with subsequent steady-state constriction that depended on extracellular calcium influx. Endothelial denudation had no effect on vessel tone or PE-induced constriction although the dilation to ACh was significantly reduced in iPLA2β+/+vessels. In contrast, vessels from iPLA2β−/−constricted by 54% after denudation, indicating smooth muscle hypercontractility. In vivo, blood pressure, resting vessel diameter, and constriction of mesenteric vessels to PE were not different in iPLA2β−/−vessels compared with WT mouse vessels. However, relaxation after ACh administration in situ was attenuated, indicating an endothelial inability to induce dilation in response to ACh. In cultured endothelial cells, inhibition of iPLA2β with ( S)-(E)-6-(bromomethylene)tetrahydro-3-(1-naphthalenyl)-2 H-pyran-2-one (BEL) decreased endothelial nitric oxide synthase phosphorylation and reduced endothelial agonist-induced intracellular calcium release as well as extracellular calcium influx. We conclude that iPLA2β is an important mediator of vascular relaxation and intracellular calcium homeostasis in both smooth muscle and endothelial cells and that ablation of iPLA2β causes agonist-induced smooth muscle hypercontractility and reduced agonist-induced endothelial dilation.

To determine whether alterations in the mechanical properties (i.e., stiffening) of the right and left ventricles contribute to the decrease in right and left ventricular end-diastolic volumes during continuous positive-pressure ventilation (CPPV), we studied six dogs anesthetized with chloralose urethane and ventilated with a volume ventilator. We varied ventricular volumes by withdrawing or infusing blood. Pressure-volume curves, constructed by plotting transmural ventricular end-diastolic pressures against ventricular end-diastolic volumes, did not change during CPPV (12 cmH2O positive end-expiratory pressure) compared to intermittent positive-pressure ventilation (IPPV, 0 cmH2O end-expiratory pressure). We conclude that decreased ventricular end-diastolic volumes during CPPV result primarily from a decrease in venous return. Alterations in the mechanical properties of the ventricles do not play a significant role in this response.

We examined whether submaximal treadmill exercise during acute isovolumic anemia altered the distribution of myocardial blood flow and thus caused subendocardial ischemia in unsedated dogs. Myocardial blood flow (determined by the microsphere method) and left ventricular function (indicated by pressures, volumes, and contractile indices) were measured in five dogs at rest and during exercise before and after equal volume exchange of blood and 6% dextran 70, which lowered hematocrit from 36 +/- 4 to 18 +/- 2% (SD). Total myocardial blood flow increased from 175 +/- 65 to 296 +/- 151 ml . min-1 . 100 g-1 (69%) during exercise before anemia and from 329 +/- 61 to 599 +/- 126 (82%) during exercise after anemia. The distribution of blood flow to the left and right ventricles and interventricular septum as well as the subendothelial-to-subepicardial blood flow ratio in these areas did not change during exercise either before or after anemia. Left ventricular function was not impaired during exercise after anemia. We conclude that subendocardial ischemia does not occur when dogs exercise during acute isovolumic anemia.