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The role of adenosine triphosphate-sensitive potassium ion (KATP) channels in receptor-dependent pulmonary vasorelaxation responses was investigated. Male Sprague-Dawley rats were used as experimental models to determine the effect of activating KATP channels on pulmonary vascular smooth muscle. Results showed that KATP channels linked with adenosine 3',5'-cyclic monophosphate (cAMP) production enhanced the receptor-dependent mechanisms of pulmonary vasorelaxation.

A study was conducted on lipopolysaccharide (LPS) induction of late cardiac functional protection against ischemia independent of cardiac and circulating tumor necrosis factor (TNF)-alpha. The findings indicate that LPS-induced cardiac functional protection against ischemia is a delayed and long-lasting protective response that may involve de novo protein synthesis. Moreover, LPS-induced increase in myocardial and circulating TNF-alpha may not be essential for the delayed protection.

The effects of hemorrhage and resuscitation in the induction of endogenous cardiac adaptive state were analyzed in sham operated, hemorrhaged and resuscitated rats. Analysis of myocardial adaptation in rats after hemorrhage and resuscitation (H-R) indicated the role of H-R in inducing acute, protective myocardial adaptation to subsequent goal warm ischemia-reperfusion injury. Furthermore, myocardial adaptation induced H-R was mediated by the adrenergic signaling pathway.

Preconditioning of the heart ventricle was investigated using isolated rat and human ventricular trabeculae. Experiments using organ bath, followed by hypoxia-reoxygenation, revealed preconditioning of the rat ventricle during simulated ischemia, and alpha1-adrenoceptor and adenosine receptor stimulation. This was shown by improved recovery of developed tension compared with control. In human trabeculae, ischemic preconditioning augmented recovery of developed tension. These results provide evidence of the protective effect of preconditioning in the ventricle.

The effect of neutrophil depletion on pulmonary vascular smooth muscle relaxation in endotoxin-induced acute lung injury was investigated in male Sprague-Dawley rats. Assays of lung tissue and histological studies revealed endotoxin-induced lung injury results in dysfunction of guanosine 3',5'-cyclic monophosphate (cGMP)-mediated pulmonary vasorelaxation. Neutrophil depletion resulted in significant impairment of vasorelaxation, suggesting that neutrophil depletion attenuates endotoxin-induced dysfunction of cGMP-mediated pulmonary vasorelaxation.

The role of protein kinase C (PKC) in cardiovascular response to ischemia-reperfusion (IR) injury was investigated in an isolated crystalloid-perfused rat heart model. IR experiments showed that PKC mediates cardioadaptation to IR injury through a mechanism which involves preischemia calcium loading from the sarcoplasmic reticulum.

Administration of exogenous nitric oxide stops lung neutrophil accumulation and pulmonary vascular endothelial dysfunction after mesenteric ischemia-reperfusion in rats. Nitric oxide stops the damage of endothelial-dependent guanosine 3',5'-cyclic monophosphate-mediated vascular smooth muscle relaxation in lungs after mesenteric ischemia-reperfusion. The endothelial-independent pulmonary vasorelaxation after mesenteric ischemia-reperfusion was unimpaired.

Differential inducible nitric oxide synthase expression in systemic and pulmonary vessels after endotoxin. Am J Physiol Regulatory Integrative Comp Physiol 278: R1232-R1239, 2000.--Inducible nitric oxide synthase (iNOS) is associated with vascular hypocontractility in systemic vessels after endotoxin lipopolysaccharide (LPS) administration. Although lung iNOS is increased after LPS, its role in the pulmonary circulation is unclear. We hypothesized that whereas iNOS upregulation is responsible for LPS-induced vascular dysfunction in systemic vessels, iNOS does not play a significant role in the pulmonary artery (PA). Using isolated aorta (AO) and PA rings, we examined the effect of nonselective NOS inhibition [[N.sup.G]-monomethyl-L-arginine (L-NMMA); 100 [micro] mol/l] and selective iNOS inhibition (aminoguanidine, AG; 100 [micro] mol/l) on [[Alpha].sub.1]-adrenergic-mediated vasoconstriction (phenylephrine; [10.sup.-9] to [10.sup.-3] M) after LPS (Salmonella typhimurium, 20 mg/kg ip). We also determined the presence of iNOS using Western blot and immunohistochemistry. LPS markedly impaired AO contractility (maximal control tension 1,076 [+ or -] 33 mg vs. LPS 412 [+ or -] 39 mg, P [is less than] 0.05), but PA contractility was unchanged (control 466 [+ or -] 29 mg vs. LPS 455 [+ or -] 27 mg, P [is greater than] 0.05). Selective iNOS inhibition restored the AO's response to vasoconstriction (LPS + AG 1,135 [+ or -] 54 mg, P [is greater than] 0.05 vs. control and P [is less than] 0.05 vs. LPS), but had no effect on the PA (LPS + AG 422 [+ or -] 38 mg, P [is greater than] 0.05 vs. control and LPS). Western blot and immunohistochemistry revealed increased iNOS expression in the AO after LPS, but iNOS was not detected in the PA. Our results suggest that differential iNOS expression after LPS in systemic and pulmonary vessels contributes to the phenomenon of sepsis/endotoxemia-induced systemic hypotension and pulmonary hypertension. aorta; pulmonary artery; aminoguanidine; [N.sup.G]-monomethyl-L-arginine; Salmonella tymphimurium

Sheridan, Brett C., Charles A. Dinarello, Daniel R. Meldrum, David A. Fullerton, Craig H. Selzman, and Robert C. Mclntyre, Jr. Interleukin-11 attenuates pulmonary inflammation and vasomotor dysfunction in endotoxin-induced lung injury. Am. J. Physiol. 277 (Lung Cell. Mol. Physiol. 21): L861-L867, 1999.--Interleukin (IL)-11, like other members of the gp130 receptor class, possesses anti-inflammatory properties. We hypothesized that IL-11 pretreatment would attenuate endotoxin [lipopolysaccharide (LPS)]-induced lung inflammation and diminish injury to endothelium-dependent and -independent mechanisms of pulmonary vasorelaxation that require cGMP in Sprague-Dawley rats. LPS (20 mg/kg ip) increased lung tumor necrosis factor (TNF)-[Alpha] compared with the saline control (0.7 [+ or -] 0.15 ng/g lung wet wt for control vs. 3.5 [+ or -] 0.09 ng/g lung wet wt for LPS; P [is less than] 0.05). IL-11 (200 mg/kg ip) injected 10 min before LPS administration attenuated the LPS-induced lung TNF-[Alpha] levels (1.6 [+ or -] 0.91 ng/g lung wet wt; P [is less than] 0.05 vs. LPS). IL-11 also diminished LPS-induced lung neutrophil sequestration as assessed by myeloperoxidase units (2.1 [+ or -] 0.25 U/g lung wet wt for saline and 15.6 [+ or -] 2.02 U/g lung wet wt for LPS vs. 7.07 [+ or -] 1.65 U/g lung wet wt for LPS plus IL-11; P [is less than] 0.05). Similarly, TNF-[Alpha] binding protein (175 mg/kg) attenuated LPS-induced myeloperoxidase activity (6.04 [+ or -] 0.14 U/g lung wet wt; P [is less than] 0.05). Both IL-11 and TNF-[Alpha] binding protein similarly attenuated LPS-induced endothelium-dependent vasomotor dysfunction with improved relaxation responses to [10.sup.-7] and [10.sup.-6] M acetylcholine and A-23187 in phenylephrine-preconstricted isolated pulmonary artery rings (P [is less than] 0.05 vs. LPS). Endothelium-independent relaxation responses to sodium nitroprusside were also improved after LPS at [10.sup.-6] M (P [is less than] 0.05 vs. LPS). Moreover, IL-11 decreased endotoxin-induced mortality in CF1 mice from 90 to 50% (P [is less than or equal to] 0.05 vs. LPS). Therefore, IL-11 prevents LPS-induced lung TNF-[Alpha] production, neutrophil sequestration, and pulmonary vasomotor dysfunction. We conclude that IL-11 possesses anti-inflammatory activity that protects against LPS-induced lung injury and lethality. tumor necrosis factor-[Alpha]; neutrophil; lung myeloperoxidase; guanosine 3t,5'-cyclic monophosphate; gp130