Ikhlass N. Ibrahim

An analysis of responses to levosimendan in the pulmonary vascular bed of the cat.

Calcium-sensitizing drugs, such as levosimendan, are a novel class of drug therapy for heart failure. We investigated the hypothesis that levosimendan is a pulmonary vasodepressor mediated through inhibition of phosphodiesterase, adenosine triphosphate (ATP)-dependent potassium channels, or both. We investigated responses to the calcium sensitizer levosimendan in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure when lobar arterial pressure was increased to a high steady level with the thromboxane A2 analog U-46619. Under increased-tone conditions, levosimendan caused dose-related decreases in lobar arterial pressure without altering systemic arterial and left atrial pressure. Responses to levosimendan were significantly attenuated, although not completely, after the administration of U-37883A, a vascular selective nonsulfonylurea ATP-sensitive K+-channel-blocking drug. Responses to levosimendan were not significantly different after the administration of the nitric oxide synthase inhibitor l-N5-(1-iminoethyl)-ornithine or the cyclooxygenase inhibitor sodium meclofenamate or when lung ventilation was interrupted. These data show that levosimendan has significant vasodilator activity in the pulmonary vascular bed of the cat. They also suggest that pulmonary vasodilator responses to levosimendan are partially dependent on activation of ATP-sensitive K+ channels and independent of the synthesis of nitric oxide, activation of cyclooxygenase enzyme, or changes in bronchomotor tone in the pulmonary vascular bed of the cat.

An analysis of remifentanil in the pulmonary vascular bed of the cat

In this investigation we sought to identify the role of remifentanil in the feline pulmonary vascular bed. Using adult mongrel cats in separate experiments, the effects of glibenclamide (adenosine triphosphate-sensitive K+ channel blocker), diphenhydramine (histamine H1-receptor antagonist), L-N5-(1-Iminoethyl) ornithine hydrochloride (nitric oxide synthase inhibitor), and naloxone (opioid receptor antagonist) were investigated in pulmonary arterial responses to remifentanil (opioid agonist), pinacidil (adenosine triphosphate-sensitive K+ channel activator), and bradykinin (nitric oxide synthase inducer). Under increased tone conditions in the isolated left lower lobe vascular bed of the cat, remifentanil induced a dose-dependent vasodepressor response that was not significantly altered after administration of glibenclamide and L-N5-(1-Iminoethyl) ornithine hydrochloride. Responses to remifentanil were significantly attenuated after administration of diphenhydramine and naloxone. The results suggest that remifentanil has potent vasodepressor activity in the feline pulmonary vascular bed and that these responses are mediated by histamine and opioid receptor sensitive pathways.

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; Nω‐l‐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, Nω‐l‐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.

Analysis of the effects of fentanyl in the feline pulmonary vascular bed

The objective of this study was to test the hypothesis that fentanyl induces a depressor response in the pulmonary vascular bed of the cat and to identify the receptors involved in the mediation or modulation of these effects. The authors conducted a prospective vehicle-controlled study at a university research laboratory using intact chest preparation in adult mongrel cats. In separate experiments, the effects of diphenhydramine (histamine receptor blocker), glibenclamide (ATP-sensitive K+ channel blocker), l-N5-(1-Iminoethyl) ornithine hydrochloride (l-NIO) (nitric oxide synthase inhibitor), nimesulide (selective cyclooxygenase [COX]-2 inhibitor), and naloxone (opiate receptor antagonist) were investigated on pulmonary arterial responses to fentanyl and other agonists in the pulmonary vascular bed of the cat. The systemic pressure and lobar arterial perfusion pressure were continuously monitored, electronically averaged, and recorded. In the feline pulmonary vascular bed of the isolated left lower lobe, fentanyl induced a dose-dependent vasodepressor response that was not significantly altered after administration of glibenclamide, l-NIO, and nimesulide. However, the responses to fentanyl were significantly attenuated after administration of diphenhydramine and naloxone. The results of the present study suggest that fentanyl has potent vasodepressor activity in the pulmonary vascular bed of the cat and that this response may be mediated or modulated by both histaminergic and opiate receptor sensitive pathways.

Blockade of thromboxane/endoperoxide receptor-mediated responses in the pulmonary vascular bed of the cat by sulotroban

The effects of sulotroban (BM13.177; SK & F 95587), a thromboxane (TX) A2/endoperoxide (PGH2) receptor blocking agent on responses to the TXA2/PGH2 mimics, U46619 and U44069, were investigated in the pulmonary vascular bed of the intact-chest cat under constant flow conditions. Injections of U46619 and U44069 directly into the perfused lobar artery caused dose-related increases in lobar arterial pressure without altering left atrial pressure. Following administration of sulotroban in a dose of 5 mg/kg i.v., dose-response curves for U46619 and U44069 were shifted to the right in a parallel manner. The duration of the blocking effect of sulotroban was investigated, and responses to U46619 returned to approximately 50% of control in 120 min and were not significantly different from control 240 min after administration of the receptor antagonist. Sulotroban was without significant effect on responses to prostaglandin (PG) D2 or F2 alpha or serotonin, histamine, norepinephrine, angiotensin II or BAY K8644, an agent which enhances calcium entry. Sulotroban was without effect on responses to endothelin (ET)-1, sarafotoxin (S) 6a or S6c and platelet-activating factor (PAF). Sulotroban did not alter baseline vascular pressures in the cat and responses to the PG and TXA2/PGH2 precursor, arachidonic acid, were reduced. The present data show that sulotroban selectively blocks TXA2/PGH2 receptor-mediated responses in a competitive and reversible manner in the pulmonary vascular bed.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary Vascular Responses to Ma Huang Extract

OBJECTIVE To test the hypothesis that ma huang induces a pressor response in the pulmonary vascular bed of the cat by activating alpha(1)-adrenergic receptors DESIGN Prospective vehicle-controlled study. SETTING Research laboratory at Texas Tech University School of Medicine, Lubbock, TX. SUBJECTS Intact chest preparation; adult mongrel cats. INTERVENTIONS The effects of phentolamine, a nonselective alpha receptor blocker, and prazosin, an alpha(1) selective antagonist, were investigated on pulmonary arterial responses to ma huang, phenylepherine, norepinephrine, and U-46619, a thromboxane A(2) mimic. MEASUREMENTS AND MAIN RESULTS Lobar arterial perfusion pressure was continuously monitored, electronically averaged, and recorded with constant flow in the isolated left lower lobe vascular bed of the cat. Phentolamine and prazosin significantly reduced vasoconstrictor pulmonary perfusion pressure increases induced by ma huang. CONCLUSIONS Ma huang has significant vasopressor activity in the pulmonary vascular bed of the cat mediated predominantly by alpha(1)-adrenergic receptor activation.

Analysis of Responses to Valerian Root Extract in the Feline Pulmonary Vascular Bed

OBJECTIVES This study was undertaken to investigate pulmonary vascular response to valerian (Valeriana officinalis) in the feline pulmonary vasculature under constant flow conditions. DESIGN In separate experiments, the effects of NG-L-nitro-L-arginine methyl ester (L-NIO), a nitric oxide synthase inhibitor, glibenclamide, an adenosine triphosphate (ATP)-sensitive potassium (K+) channel blocker, meclofenamate, a nonselective cyclooxygenase (COX) inhibitor, bicuculline, a GABA(A) receptor antagonist, and saclofen, a GABA(B) antagonist, were investigated on pulmonary arterial responses to various agonists in the feline pulmonary vascular bed. These agonists included valerian, muscimol, a GABA(A) agonist, SKF-97541 a GABA(B) agonist, acetylcholine (ACh), and bradykinin, both inducers of nitric oxide synthase, arachidonic acid, a COX substrate, and pinacidil, an ATP-sensitive K+ channel activator, during increased tone conditions induced by the thromboxane A2 mimic, U46619. SETTINGS/LOCATION Laboratory investigation. SUBJECTS Mongrel cats of either gender. INTERVENTIONS Injections of the abovementioned agonists and antagonists were given. OUTCOME MEASURES Baseline pulmonary tone, responses to the agonists, and responses to the agonists after injections of antagonists were all measured via a pulmonary catheter transducer and recorded. RESULTS Valerian root extract is a potent smooth muscle dilator in the feline pulmonary vascular bed. The vasodilatory effects of valerian root extract were unchanged after the administration of L-NIO, glibenclamide, and meclofenamate. These effects were ablated, however, by both saclofen and bicuculline. The ability of saclofen and bicuculline to modulate the dilatory effects of valerian root extract was not statistically different. CONCLUSIONS The vasodilatory effects of valerian root extract are mediated by a nonselective GABA mechanism.

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.

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 thromboxane receptor-mediated responses in the feline pulmonary vascular bed.

OBJECTIVE Current evidence suggests that thromboxane plays a role in pathophysiologic processes in the lung. Efforts to find effective, specific therapy to modify these effects have led to the development of a new class of thromboxane receptor blockers. This present investigation examined the selectivity and duration of the inhibitory effects of one of these novel agents in the pulmonary vascular bed of anesthetized cats. DESIGN Prospective, randomized, controlled study with repeated measures. SETTING University research laboratory. SUBJECTS Twenty-nine adult cats obtained from the Tulane University School of Medicine vivarium. INTERVENTIONS The effects of GR32191, a thromboxane receptor antagonist, were investigated under constant-flow conditions in the intact-chest cat, using a triple-lumen, 6-Fr, balloon perfusion catheter that was placed by means of fluoroscopic guidance. Data were analyzed using a paired or unpaired t-test or analysis of variance. A p < .05 was considered statistically significant. MEASUREMENTS AND MAIN RESULTS Aortic, left atrial, and left lobar arterial pressures were measured. After administration of GR32191 (0.25 and 1.0 mg/kg iv), pulmonary vasoconstrictor responses to U46619, a thromboxane mimic, were significantly decreased. Blockade was overcome with higher doses of the thromboxane mimic. GR32191 was without significant effect on the responses to prostaglandin (PG) D2, PGF2 alpha, serotonin, the calcium-channel agonist BAY K8644, or norepinephrine. Additionally, GR32191 did not alter baseline vascular pressures. Responses to U46619 returned to 50% of control value 90 mins after administration of 0.25 mg/kg of U46619. Responses to GR32191 returned to 50% of control value 180 mins after administration of 1.0 mg/kg of GR32191. These data suggest that GR32191 selectively blocks thromboxane A2 receptor-mediated responses in a competitive and reversible manner in the pulmonary vascular bed of the cat. CONCLUSIONS These results are consistent with the hypothesis that discrete thromboxane A2 receptors, unrelated to receptors activated by PGF2 alpha or PGD2, are present in the feline pulmonary vascular bed. Specific thromboxane receptor antagonists, such as GR32191, could be useful therapeutic agents in the treatment of pulmonary hypertensive and thromboembolic disorders.