Peroxynitrite does not impair pulmonary and systemic vascular responses.

The effects of peroxynitrite (ONOO-) on vascular responses were investigated in the systemic and hindquarters vascular bed and in the isolated perfused rat lung. Intravenous injections of ONOO- decreased systemic arterial pressure, and injections of ONOO- into the hindquarters decreased perfusion pressure in a dose-related manner. Injections of ONOO- into the lung perfusion circuit increased pulmonary arterial perfusion pressure. Responses to ONOO- were rapid in onset, short in duration, and repeatable without exhibiting tachyphylaxis. Repeated injections of ONOO- did not alter systemic, hindquarters, or pulmonary responses to endothelium-dependent vasodilators or other vasoactive agonists and did not alter the hypoxic pulmonary vasoconstrictor response. Injections of sodium nitrate or nitrite or decomposed ONOO- had little effect on vascular pressures. Pulmonary and hindquarters responses to ONOO- were not altered by a cyclooxygenase inhibitor in a dose that attenuated responses to arachidonic acid. These results demonstrate that ONOO- has significant pulmonary vasoconstrictor, systemic vasodepressor, and vasodilator activity; that short-term repeated exposure does impair vascular responsiveness; and that responses to ONOO- are not dependent on cyclooxygenase product release.

Effects of PKC isozyme inhibitors on constrictor responses in the feline pulmonary vascular bed.

The effects of Gö-6976, a Ca(2+)-dependent protein kinase C (PKC) isozyme inhibitor, and rottlerin, a PKC-delta isozyme/calmodulin (CaM)-dependent kinase III inhibitor, on responses to vasopressor agents were investigated in the feline pulmonary vascular bed. Injections of angiotensin II, norepinephrine (NE), serotonin, BAY K 8644, and U-46619 into the lobar arterial constant blood flow perfusion circuit caused increases in pressure. Gö-6976 reduced responses to angiotensin II; however, it did not alter responses to serotonin, NE, or U-46619, whereas Gö-6976 enhanced BAY K 8644 responses. Rottlerin reduced responses to angiotensin II and NE, did not alter responses to serotonin or U-46619, and enhanced responses to BAY K 8644. Immunohistochemistry of feline pulmonary arterial smooth muscle cells demonstrated localization of PKC-alpha and -delta isozymes in response to phorbol 12-myristate 13-acetate and angiotensin II. Localization of PKC-alpha and -delta isozymes decreased with administration of Gö-6976 and rottlerin, respectively. These data suggest that activation of Ca(2+)-dependent PKC isozymes and Ca(2+)-independent PKC-delta isozyme/CaM-dependent kinase III mediate angiotensin II responses. These data further suggest that Ca(2+)-independent PKC-delta isozyme/CaM-dependent kinase III mediate responses to NE. A rottlerin- or Gö-6976-sensitive mechanism is not involved in mediating responses to serotonin and U-46619, but these PKC isozyme inhibitors enhanced BAY K 8644 responses in the feline pulmonary vascular bed.

Analysis of responses of garlic derivatives in the pulmonary vascular bed of the rat.

Allicin, an extract from garlic, has been shown to be a systemic and pulmonary arterial vasodilator that acts by an unknown mechanism. In the present experiments, pulmonary vascular responses to allicin (10-100 microg), allyl mercaptan (0.3-1 mg), and diallyl disulfide (0.3-1 mg) were studied in the isolated lung of the rat under constant-flow conditions. When baseline tone in the pulmonary vascular bed of the rat was raised to a high-steady level with the thromboxane A(2) mimic U-46619, dose-related decreases in pulmonary arterial pressure were observed. In terms of the mechanism of action of allicin vasodilator activity in the rat, responses to allicin were not significantly different after administration of the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester, the K(ATP)(+) channel antagonist U-37883A, or the cyclooxygenase inhibitor sodium meclofenamate, or when lung ventilation was interrupted. These data show that allicin has significant vasodilator activity in the pulmonary vascular bed of the rat, whereas allyl mercaptan and diallyl disulfide produced no significant changes in pulmonary arterial perfusion pressure. The present data suggest that pulmonary vasodilator responses to allicin are independent of the synthesis of nitric oxide, ATP-sensitive K(+) channels, activation of cyclooxygenase enzyme, or changes in bronchomotor tone in the pulmonary vascular bed of the rat.

Analysis of ketamine responses in the pulmonary vascular bed of the cat.

OBJECTIVE: To test the hypothesis that pulmonary vasodilator responses of ketamine are dependent on activation of L-type calcium channels, independent of synthesis of nitric oxide from L-arginine, activation of adenosine triphosphate-sensitive potassium channels, and the release of cyclooxygenase products. DESIGN: Prospective study. SETTING: Research laboratory. SUBJECTS: Isolated lobar lung preparation, mongrel cats. INTERVENTIONS: In separate experiments, the effects of nicardipine; N omega-I-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase; glibenclamide, an adenosine triphosphate-sensitive potassium channel antagonist; and meclofenamate, a cyclooxygenase blocker, were investigated in the pulmonary vascular bed of the cat. The effects of these agents were evaluated on the pulmonary arterial responses of ketamine, acetylcholine, and isoproterenol during elevated tone conditions induced by the thromboxane A2 mimic, U46619 (Upjohn, Kalamazoo, MI). MEASUREMENTS: Lobar arterial perfusion pressure, systemic pressure, and left atrial pressure were continuously monitored, electronically averaged, and permanently recorded. MAIN RESULTS: Under elevated tone conditions in the isolated left lower lobe vascular bed of the cat, N omega-I-nitro-L-arginine methyl ester, glibenclamide, and meclofenamate had no significant effect on the vasodilator responses to ketamine. Nicardipine, in a dose that reduced significantly vasopressor effects to BAY K 8644, a calcium-channel opener, attenuated significantly vasodilator responses to ketamine, whereas the L-type calcium-channel blocker had no significant effects on responses to acetylcholine and to isoproterenol. CONCLUSIONS: These data show that ketamine has significant vasodilator activity in the pulmonary vascular bed of the cat. The present data also suggest that responses to ketamine during elevated tone conditions may in part be mediated by the activation of L-type calcium channels.

Changes in compliance predict pulmonary morbidity in patients undergoing abdominal plication.

The incidence and severity of the effects of pulmonary compliance changes were investigated in patients undergoing abdominal plication surgery. A total of 20 healthy adults scheduled for abdominal plication surgery who had no significant history of pulmonary disease and 20 adults scheduled for nonabdominal, nonthoracic surgery (control group) underwent general endotracheal anesthesia; neuromuscular blockade was confirmed with electrical twitch monitoring. Before abdominal plication, the mean airway compliance was measured under total neuromuscular blockade at 33.4 +/- 2.1 ml/cm water, which was not significant when compared with control patient values. After abdominal plication was performed, the mean airway compliance was remeasured under total neuromuscular blockade; it was significantly decreased at 24.0 +/- 1.8 ml/cm water when compared with values for control patients (32.6 +/- 1.6 ml/cm) and with preplication values. Patients with airway compliance changes of less than 4 ml/cm water (when compared with preplication pulmonary mechanics) had far less incidence of atelectasis, requirements for supplemental oxygen at 24 hours or longer, or hypoxia when compared with patients with compliance changes of greater than 4 ml/cm water. Patients with compliance changes greater than 9 ml/cm water had the highest incidence of pulmonary morbidity. These data suggest that significant changes in pulmonary compliance occur after abdominal plication and that these airway compliance changes are associated with a clinically increased incidence of pulmonary morbidity in the postoperative period.

Responses to propofol in the pulmonary vascular bed of the rat.

BACKGROUND: Although a great deal is known about responses to propofol, controversy remains about its mechanism of action. The present study was undertaken to investigate the direct effects of 2,6-diisopropyl phenol, disodium edetate, and its intralipid emulsion in the rat pulmonary vascular bed and to better understand the mechanisms involved in propofol-mediated responses. METHODS: The effects of N omega-l-nitro-l-arginine benzyl ester (L-NABE), an inhibitor of nitric oxide synthase, of the cyclooxygenase blocker, meclofenamate, and the K + ATP channel antagonist, U-37883A, an ATP-sensitive potassium channel antagonist, on responses to propofol, acetylcholine, nitroglycerin, and isoproterenol were investigated in the isolated blood-perfused rat lung under low tone and high steady-state tone. RESULTS: Propofol produced a dose-dependent decrease in pulmonary arterial perfusion pressure. L-NABE significantly reduced vasodilator responses to acetylcholine, whereas the nitric oxide synthase inhibitor had no significant effect on responses to propofol. Meclofenamate significantly reduced vasodilator responses to arachidonic acid without effecting responses to propofol. Responses to propofol were not significantly changed in the presence of U-37883A, whereas U-37883A reduced vasodilator responses to levcromakalim. Additionally, 2,6-diisopropylphenol in a pure preparation as well as an intralipid preparation similar to propofol emulsion had no significant effect while disodium edetate had a dose-dependent depressor effect under high steady-state tone. CONCLUSION: Propofol has significant vasodilator activity in the pulmonary vascular bed of the rat but responses to propofol are not mediated or modulated by the release of nitric oxide, opening of K + ATP channels, or the release of vasodilator cyclooxygenase products.

Pulmonary vasodilation by ketamine is mediated in part by L-type calcium channels.

UNLABELLED: We studied the effects of ketamine in the isolated rat lung under conditions of increased pulmonary arterial pressure using the thromboxane A2 mimic, U46619, and in response to ventilatory hypoxia. Ketamine caused dose-dependent vasodilation, and possible mechanisms were evaluated using verapamil, meclofenamate, N(omega)-L-nitro-L-arginine benzyl ester (an inhibitor of nitric oxide synthase), and U-38883A (an ATP-sensitive potassium channel antagonist) in the isolated blood-perfused rat lung. Under increased tone conditions, N(omega)-L-nitro-L-arginine benzyl ester, meclofenamate, and U-38883A had no significant effect in attenuating ketamine-induced vasodilator responses. In a final series of experiments, verapamil significantly attenuated ketamine-induced vasodilator responses. These data suggest that ketamine has significant vasodilator activity in the pulmonary vascular bed of the rat, which seems to be mediated by an L-type calcium channel-sensitive pathway. These responses are not mediated or modulated by the release of nitric oxide, the activation of K+ ATP channels, or the release of vasodilator cyclooxygenase products. IMPLICATIONS: In this study, we examined the mechanism of the vasodilator effects of ketamine in the blood-perfused rat lung. The results of the present study suggest that ketamine-induced vasodilator responses are mediated by an L-type calcium channel-sensitive pathway.

Analysis of responses to angiotensin I (3-10) and Leu3 angiotensin (3-8) in the pulmonary vascular bed of the cat.

Pulmonary vascular responses to angiotensin (3-8) (Ang IV), leu3 angiotensin (3-8) (LeuAng IV), an Ang IV analog and angiotensin I (3-10) [Ang I (3-10)], the precursor for Ang IV, were investigated in the intact-chest cat under conditions of controlled blood flow. Intralobar injections of Ang IV, LeuAng IV, and Ang I (3-10) caused dosage-related increases in lobar arterial pressure. When responses were compared, Ang IV, LeuAng IV, and Ang I (3-10) were equipotent and were approximately 100- to 300-fold less potent than Ang II when dosages are expressed on a nanomolar basis. DuP 753, an angiotensin II type 1 (AT1 ) receptor antagonist, attenuated pulmonary vasoconstrictor responses to LeuAng IV, Ang IV, and its precursor, Ang I (3-10), but did not significantly change pressor responses to serotonin, norepinephrine, or U46619. PD 123319, an angiotensin II type 2 (AT2 ) receptor antagonist, and WSU 3033, a putative angiotensin II type 4 (AT4 ) receptor antagonist, did not significantly change pressor responses to LeuAng IV, Ang IV, and its precursor, Ang I (3-10). Captopril, an angiotensin-converting enzyme (ACE) inhibitor, decreased pulmonary vasoconstrictor responses to Ang I (3-10) but did not significantly change responses to serotonin, norepinephrine, U46619, LeuAng IV, or Ang IV. These data show that LeuAng IV, Ang IV, and its precursor, Ang I (3-10), increase pulmonary vascular resistance by activating AT1 receptors, and that Ang I (3-10) is rapidly and efficiently converted by an ACE-dependent pathway into an active peptide. The present data suggest that Ang IV and LeuAng IV increase pulmonary vascular resistance by activating AT1 receptors and that activation of AT2 or AT4 are not involved in mediating or modulating responses to these peptides. These data provide support for the hypothesis that Ang I (3-10) is converted into an active peptide by ACE at or near the site of action within the pulmonary vascular bed.

Effects of phospholipase A2, 12-lipoxygenase, and cyclooxygenase inhibitors in the feline pulmonary bed.

The effects of phosphonofluoridic acid, methyl-5,8,11,14-eicosatetraenyl ester (MAFP), a phospholipase A2 inhibitor, on pressor responses to angiotensin II (ANG II), norepinephrine (NE), serotonin (5-HT), the calcium channel opener BAY K 8644, and the thromboxane A2 mimic U-46619 were studied in the pulmonary vascular bed of the intact-chest cat. Under conditions of constant lobar blood flow, injections of ANG II, NE, 5-HT, U-46619, and BAY K 8644 into the lobar arterial perfusion circuit caused dose-related increases in lobar arterial pressure that were reproducible with respect to time. Infusion of MAFP into the perfused lobar artery at doses of 100 to 300 microg/kg for 10 min significantly reduced vasoconstrictor responses to ANG II; however, the phospholipase A2 inhibitor did not alter vasoconstrictor responses to BAY K 8644, 5-HT, NE, or U-46619. The combination of the higher dose of the phospholipase A2 inhibitor MAFP with the phospholipase C inhibitor U-73122 significantly affected vasoconstrictor responses to ANG II, NE, and 5-HT but not to BAY K 8644. In a separate series of animals, the effects of a lipoxygenase inhibitor, baicalein, were investigated. Infusion of baicalein into the perfused lobar artery at doses of 100 microg/kg for 10 min significantly reduced vasoconstrictor responses to ANG II but not the vasoconstrictor responses to BAY K 8644, 5-HT, NE, or U-46619. In a final series of experiments, the effects of a cyclooxygenase inhibitor, meclofenamate, were investigated, and intravenous injection of the meclofenamate at a dose of 2.5 mg/kg did not significantly affect vasoconstrictor responses to ANG II, 5-HT, BAY K 8644, NE, or U-46619. These data provide support for the hypothesis that pulmonary vasopressor responses to ANG II are mediated, in part, by the activation of phospholipase A2, phospholipase C, and the lipoxygenase pathway in the pulmonary vascular bed of the cat.

Effects of charybdotoxin on responses to nitrosovasodilators and hypoxia in the rat lung.

This study investigated the effects of the Ca2+-sensitive K+ channel antagonist charybdotoxin on responses to the nitrosovasodilators nitroglycerin and sodium nitroprusside and on pulmonary pressor responses to ventilatory hypoxia in the isolated blood-perfused rat lung. Injections of nitroglycerin and sodium nitroprusside induced dose-related decreases in pulmonary arterial perfusion pressure when tone was increased with U-46619, whereas ventilatory hypoxia (3% O2-5% CO2-balance N2) increased pulmonary arterial perfusion pressure in a reproducible manner. After administration of charybdotoxin, the pressor response to ventilatory hypoxia was significantly increased, whereas charybdotoxin significantly decreased vasodilator responses to nitroglycerin and sodium nitroprusside but had no effect on the vasodilator responses to albuterol or to isoproterenol when tone was increased with U-46619. The results of the present study show that charybdotoxin enhances the pressor response to ventilatory hypoxia and significantly decreases responses to nitric oxide-donating vasodilator agonists in a selective manner. These data suggest that the response to ventilatory hypoxia is modulated by alterations in Ca2+-sensitive K+ channel activity and suggest that vasodilator responses to the nitric oxide donors nitroglycerin and sodium nitroprusside are dependent on the opening of large-conductance Ca2+-sensitive K+ channels in the pulmonary vascular bed of the rat.

Analysis of responses to bradykinin in the rat hindquarters vascular bed.

The mechanism by which bradykinin (BK) decreases vascular resistance was investigated in the hindquarters vascular bed of the rat. Under conditions of controlled blood flow, BK produced dose-related decreases in hindquarters perfusion pressure when injected into the perfusion circuit in doses of 0.1-1.0 pg. Responses to BK were reproducible with respect to time, and HOE-140 (D-Arg, [Hyp3,Thi5,D-Tic7,Oic8] -BK), a kinin B2 receptor antagonist, decreased hindquarters vasodilator responses to the peptide. HOE-140 had no significant effect on responses to vasodilator agents, which act by a variety of pharmacologically distinct mechanisms. Nitric oxide synthase inhibitors N(omega)-nitro-L-arginine methyl ester or N(omega)-nitro-L-arginine benzyl ester did not decrease responses to BK in doses that decreased hindquarters vasodilator responses to acetylcholine. The cyclooxygenase inhibitors meclofenamate and indomethacin had no effect on responses to BK in doses that attenuated vasodilator responses to the prostaglandin precursor, arachidonic acid. Clotrimazole or 5,8,11,14-eicosatetraynoic acid (ETYA), cytochrome P-450 arachidonic acid metabolism inhibitors, in doses that attenuated vasodilator responses to arachidonic acid, had no effect on responses to BK. Glybenclamide or U-37883A (4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl), K+-ATP channel antagonists, in doses that attenuated responses to lemakalim, had no significant effect on responses to BK. Finally, des-Arg9-BK, a reported kinin B1 receptor agonist, decreased hindquarters perfusion pressure when injected in doses of 3-30 microg, and responses to the B1 agonist were attenuated by HOE-140. The observation that des-Arg9-BK, in high doses, induces modest HOE-140-sensitive responses suggests that kinin B1 receptors are not normally expressed in the hindquarters vascular bed of the rat. The present results indicate that BK dilates the hindquarters vascular bed by a kinin B2 receptor mechanism that is independent of the release of nitric oxide, cyclooxygenase, or P-450 metabolites of arachidonic acid or the activation of K+-ATP channels.

Effects of captopril on responses to bradykinin in the hindquarters vascular bed of the rat.

The effects of captopril, and angiotensin converting enzyme (ACE) inhibitor, on responses to bradykinin (BK), to angiotensin (Ang) I and II, and to other agonists were investigated in the hindquarters vascular bed of the rat. Under conditions of controlled flow, intra-arterial (i.a.) injections of BK in doses of 0.1-1.0 microgram, produced dose related decreases in hindquarters perfusion pressure and evoked decreases in systemic arterial pressure. Intra-arterial injections of Ang I and II produced dose-related increases in hindquarters perfusion pressure. Following administration of captopril in a dose of 2 mg/kg i.v., vasodilator responses to i.a. injections of BK were only slightly enhanced in the hindquarters vascular bed, whereas the evoked systemic vasodepressor responses to i.a. injections of BK were markedly enhanced by the ACE inhibitor. Captopril significantly reduced vasoconstrictor responses to i.a. injections of Ang I, whereas vasoconstrictor responses to i.a. injections of Ang II were significantly enhanced. The ACE inhibitor did not significantly alter vasodilator responses to i.a. injections of acetylcholine, nitroglycerin, nitric oxide, albuterol, or pinacidil. The present data show that BK has potent vasodilator activity in the hindquarters vascular bed of the rat and suggest that the site of action is most likely upstream from the site of inactivation, whereas the site of action of Ang I is at or near the site of conversion to Ang II in the hindquarters vascular bed. The observation that the evoked systemic vasodepressor responses to i.a. injections of BK were greatly enhanced, suggest that the lung is the major site of inactivation of BK.

Differential effects of glibenclamide on responses to thromboxane A2 mimic, U46619, in the pulmonary and hindquarters vascular beds of the cat.

The inhibitory effects of the oral sulfonylurea, glibenclamide, on vasoconstrictor responses to the thromboxane A2 mimic, U46619, were investigated in the pulmonary and hindquarters vascular beds of the cat under constant flow conditions. When lobar arterial tone was at resting conditions (14 +/- 2 mm Hg), intralobar injections of U46619, prostaglandin F2alpha, prostaglandin D2, angiotensin II, norepinephrine, and BAY K 8644 caused dose-related increases in lobar arterial pressure without altering left atrial pressure. Following an intralobar infusion of glibenclamide (5 mg/kg), vasoconstrictor responses to U46619, prostaglandin F2alpha and prostaglandin D2 were significantly reduced, whereas vasoconstrictor responses to norepinephrine and angiotensin II were not altered and responses to BAY K 8644 were significantly enhanced. When tone in the pulmonary vascular bed was raised to a high steady level (36 +/- 3 mm Hg), glibenclamide in a dose of 5 mg/kg i.a. markedly attenuated responses to injections of U46619 and reduced the vasodilator responses to the K+-ATP channel opener, levcromakalim, whereas responses to acetylcholine and S-nitroso-N-acetylpenicillamine (SNAP), a nitric oxide donor, were not changed. In the hindquarters vascular bed of the cat, administration of glibenclamide in a dose of 5 mg/kg i.a. had no significant effect on vasoconstrictor responses to U46619, norepinephrine or angiotensin II. Hindquarters vasodilator responses to levcromakalim, but not to nitric oxide, were decreased significantly following administration of glibenclamide. These data suggest that glibenclamide, in addition to inhibiting K+-ATP channels, has thromboxane A2 receptor blocking activity in the pulmonary vascular bed of the cat. These data also suggest that vasoconstrictor responses to U46619 may be mediated by different thromboxane A2 receptors with different binding affinities in the pulmonary and in the hindquarters vascular beds of the cat.

Analysis of vancomycin in the hindlimb vascular bed of the rat.

Previously, studies have demonstrated that the effects of both a laboratory-produced vancomycin and a clinically available vancomycin were mediated, in part, by activation of both H(1) and H(2) receptors; however, other mechanisms may play a role in the vascular changes associated with vancomycin, since neither H(1) and H(2) receptor blockade has completely abolished the vasodilator responses to vancomycin in any model system. To study the mechanisms of vancomycin interactions in the hindlimb vascular bed of the rat, responses of two types of vancomycin preparations were studied. Vancomycin prepared for either clinical or laboratory use produced an initial short-lived period of vasoconstriction followed by a prolonged period of vasodilation in the hindlimb vascular bed. Responses to both the vancomycins and histamine on systemic arterial vasodilation were significantly decreased after administration of both the H(1)-receptor antagonist diphenhydramine and the H(2)-receptor antagonist famotidine. Verapamil, an L-type calcium channel blocker, significantly reduced the vasopressor responses to clinical vancomycin but not the vasopressor responses to laboratory vancomycin. Enalaprilat, and angiotensin-converting enzyme blocker, significantly reduced the vasodilator responses but not the vasoconstrictor responses of clinical vancomycin and significantly reduced the vasoconstrictor responses but not the vasodilator responses to laboratory vancomycin. Meclofenamate, a cyclo-oxygenase inhibitor, and N(omega)-L-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthetase inhibitor, had no significant effect on the biphasic responses with either vancomycin preparations. Atropine, an anticholinergic-antimuscarinic receptor antagonist, and propranolol, a beta adrenergic blocker, had no significant effect on vancomycin responses. Finally, ondansetron, a serotonin receptor blocker, and HOE 140, a bradykinin receptor blocker, also had no significant effect on vancomycin responses. These data suggest that both vancomycin preparations (clinically available and laboratory prepared) caused biphasic responses that differed from the dose-dependent vasodilation elicited by histamine. Both vancomycin preparations' vasodilator responses appear to be modulated, in part, by a histamine receptor--sensitive mechanism, while vancomycin-induced vasoconstrictor responses appear to be modulated, in part, by angiotensin-converting enzyme and L-type calcium channel--sensitive mechanisms in the rat hindlimb vascular bed. These data also suggest that the vascular responses of vancomycin are preparation dependent.

Pulmonary vasodilator responses to adrenomedullin are reduced by NOS inhibitors in rats but not in cats.

Responses to and the mechanism of action of adrenomedullin (ADM), the carboxy-terminal fragments of ADM, and calcitonin gene-related peptide (CGRP), a structurally related peptide, were investigated in the pulmonary vascular bed of the rat. Under conditions of elevated tone and controlled pulmonary blood flow in the isolated blood-perfused rat lung, injections of ADM, the 15-52 amino acid carboxy-terminal ADM analogue (ADM15-52), and CGRP caused dose-related decreases in pulmonary arterial perfusion pressure. In contrast, the carboxy-terminal 22-52 and 40-52 amino acid fragments had no consistent vasodilator activity. After administration of the nitric oxide synthase inhibitors, N omega-nitro-L-arginine benzyl ester or N omega-nitro-L-arginine methyl ester (L-NAME), pulmonary vasodilator responses to ADM, to ADM15-52, to CGRP, to acetylcholine, and to bradykinin were significantly decreased in the rat, whereas vasodilator responses to isoproterenol and nitroglycerin were not changed. However, in the pulmonary vascular bed of the cat, L-NAME had no significant effect on vasodilator responses to ADM in doses that attenuated vasodilator responses to acetylcholine and bradykinin. L-NAME had no effect on responses to isoproterenol or nitric oxide. When the relative vasodilator activity of the active peptides was compared, ADM15-52 was approximately three-fold less potent than ADM, and ADM was threefold less potent than CGRP in decreasing pulmonary vascular resistance in the rat lung. When vasodilator responses were compared in the rat and cat, ADM was threefold more potent in decreasing pulmonary vascular vascular resistance in the cat than in the rat, and vasodilator responses to ADM were independent of the intervention used to raise tone in the rat. The present data demonstrate that ADM and ADM15-52 have significant vasodilator activity in the pulmonary vascular bed of the rat, and that responses to ADM, ADM15-52, and CGRP are dependent on the release of nitric oxide in the rat. The present results indicate that pulmonary vasodilator responses to ADM are not dependent on the release of nitric oxide in the cat and suggest that responses to the peptide are mediated by different mechanisms in the pulmonary vascular bed of the rat and cat.

Analysis of responses to pentoxifylline in the pulmonary vascular bed of the cat.

OBJECTIVE: To test the hypothesis that pulmonary vasodilator responses to pentoxifylline are dependent on the synthesis of nitric oxide from L-arginine and are independent of the release of cyclooxygenase products. DESIGN: Prospective study. SETTING: Research laboratory. SUBJECTS: Isolated lobar lung preparation, using mongrel cats. INTERVENTIONS: In separate experiments, the effects of NG-L-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, and the effects of a cyclooxygenase blocker, meclofenamate, were investigated on pulmonary arterial responses to pentoxifylline, acetylcholine, and isoproterenol during increased tone conditions induced by the thromboxane A2 mimic, U46619, in the pulmonary vascular bed of the cat. MEASUREMENTS AND MAIN RESULTS: Lobar arterial perfusion pressure, systemic pressure, and left atrial pressure were continuously monitored, electronically averaged, and permanently recorded. Under increased tone conditions in the isolated left lower lobe vascular bed of the cat, NG-L-nitro-L-arginine methyl ester significantly reduced the vasodilator responses to pentoxifylline and to acetylcholine, whereas NG-L-nitro-L-arginine methyl ester had no significant effect on the vasodilator responses to isoproterenol. Vasodilator responses to pentoxifylline and acetylcholine were not significantly changed in the presence of meclofenamate, whereas meclofenamate markedly reduced the vasopressor effects of arachidonic acid. CONCLUSIONS: These data show that pentoxifylline has significant vasodilator activity in the pulmonary vascular bed of the cat. The present data also suggest that responses to pentoxifylline during increased tone conditions may, in part, be mediated by the release of nitric oxide and are independent of the release of cyclooxygenase products.

Vasodilator responses to desmopressin and its diluent, chlorobutanol, in the hindquarters vascular bed of the cat.

Desmopressin is a synthetic analog of vasopressin used to promote hemostasis and reduce postoperative blood loss. Recent studies have shown that desmopressin decreases arterial blood pressure in the anesthetized rat and relaxes isolated segments of aorta and pulmonary artery. Responses to a clinical preparation of desmopressin were investigated in the hindquarters vascular bed of the cat under constant flow conditions so that changes in perfusion pressure directly reflect changes in vascular resistance. Responses to desmopressin and its vehicle, and the effect of receptor antagonists, inhibitors of prostaglandin, and nitric oxide synthesis inhibitors, were investigated.

Responses to L-163,491, a nonpeptide angiotensin II mimic, in the pulmonary vascular bed of the cat.

Pulmonary vascular responses to 5,7-dimethyl-2-ethyl-3-[[2'-[butyloxycarbonyl)amino-sulfonyl]-5'-(3-meth oxybenzyl)-[1,1'-biphenyl]-4-yl]methyl]-3H-imidazo[4,5-b]pyridine (L-163,491), a novel nonpeptide angiotensin agonist, and angiotensin IV, the 3-8 amino acid fragment of angiotensin, were compared with responses to angiotensin II. Responses were investigated in the intact-chest cat under conditions of controlled blood flow and intralobar injections of angiotensin II, L-163,491, and angiotensin IV caused dose-related increases in lobar arterial pressure. When comparable in lobar arterial pressure of the three agents were examined, L-163,491 was approximately 3-fold less potent than angiotensin IV and approximately 100-fold less potent than angiotensin II when doses are expressed on a nmol basis. DuP 532, 2-propyl-4-pentafluoroethyl-1-([2'-(1H-tetrazol-5-yl)bipheny l-4]-methyl)imidazole-5-carboxylic acid, an angiotensin II AT1 receptor antagonist, reduced pulmonary vasoconstrictor responses to angiotensin II, angiotensin IV and L-163,491, but did not significantly change pressor responses to serotonin, norepinephrine, or the thromboxane A2 mimic, U46619. PD 123319, an angiotensin II subtype 2 receptor antagonist, did not significantly change pressor responses to L-163,491, angiotensin II, or angiotensin IV. Captopril, the angiotensin-converting enzyme inhibitor, decreased pulmonary vasoconstrictor responses to angiotensin I and enhanced vasodilator responses to bradykinin, but did not significantly change pressor responses to L-163,491. These data show that L-163,491 significant angiotensin AT1 receptor-mediated vasoconstrictor activity in the pulmonary vascular bed of the cat. These data also show the nonpeptide agonist has 3-fold less activity compared to angiotensin IV and is approximately 100-fold less potent than angiotensin II in the feline pulmonary vascular bed.

Influence of PLC and MLCK inhibitors and the role of L-calcium channels in the cat pulmonary vascular bed.

The effects of U-73122, a phospholipase C (PLC) inhibitor, on pressor responses to angiotensin II (ANG II), norepinephrine (NE), serotonin (5-HT), BAY K 8644, and the thromboxane A2 (TxA2) mimic, U-46619, were studied in the pulmonary vascular bed of the intact-chest cat. Under conditions of constant lobar blood flow, injections of ANG II, NE, 5-HT, U-46619, and the calcium channel opener, BAY K 8644, into the lobar arterial perfusion circuit caused dose-related increases in lobar arterial pressure, which were reproducible with respect to time. Infusion of U-73122, a PLC inhibitor, into the perfused lobar artery at 10-100 micrograms/kg for 10 min significantly reduced responses to ANG II, serotonin, and NE; however, U-73122 did not alter responses to BAY K 8644 or to U-46619. In a separate series of animals, the effects of the myosin light chain kinase inhibitor, KT-5926, were investigated, and after infusion of KT-5926 into the perfused lobar artery at 1-2 micrograms/kg for 10 min, responses to ANG II, NE, 5-HT, BAY K 8644, and U-46619 were reduced significantly. In a final series of experiments, the effects of the L-type calcium channel blocker, nicardipine, were investigated, and infusion of the L-type calcium channel blocker into the perfused lobar artery at 0.5-1 microgram/kg for 10 min reduced responses to ANG II, BAY K 8644, and NE. However, nicardipine did not alter pressor responses to 5-HT or the TxA2 mimic, U-46619.(ABSTRACT TRUNCATED AT 250 WORDS)

Local anesthesia infiltration as a cause of intraoperative tension pneumothorax in a young healthy woman undergoing breast augmentation with general anesthesia.

Pneumothorax may be a medical emergency. Iatrogenic pneumothorax is more common than all other forms of spontaneous pneumothorax, and surgical procedures involving the breast are a frequent setting for this. A 32-year-old, 60 kg, woman without any significant medical history underwent a bilateral breast augmentation and rhinoplasty. She underwent a routine general endotracheal anesthetic. Prior to surgical incision, the surgeon infiltrated the breast with lidocaine with epinephrine. Six hours into the surgical procedure, the patient developed hemodynamic compromise and was diagnosed with tension pneumothorax, which was treated emergently with a 14-gauge angiocatheter placed intrapleurally. The patient immediately returned to hemodynamic stability. This case report discusses iatrogenic pneumothoraces as well their most likely causes; which in this specific case was the injection of local anesthetic. Suggestions for prevention and treatment of the unusual complication are discussed.