Inhaled amyl nitrite effectively reverses acute catastrophic thromboxane-mediated pulmonary hypertension in pigs.

Acute catastrophic pulmonary vasoconstriction frequently leads to cardiovascular collapse. Rapid and selective pulmonary vasodilation is desired in order to restore haemodynamic stability. This pilot study examined the effectiveness of inhaled amyl nitrite as a selective pulmonary vasodilator. Nine adult swine were anaesthetized. Acute pulmonary hypertension with haemodynamic collapse was induced with a bolus administration of a thromboxane analogue, U46619. Six animals then received a capsule of amyl nitrite. The administration of inhaled amyl nitrite decreased mean pulmonary artery pressure from 42 +/- 3 to 22 +/ 3 mmHg at five minutes (p < 0.05), with a concomitant increase in cardiac output and mean arterial pressure. Pulmonary vascular resistance decreased from 4889 +/- 1338 to 380 +/- 195 dyne. sec. cm(-5) (by 92% from the maximal pulmonary hypertension change), with significant improvement in systemic haemodynamics. During acute thromboxane-mediated pulmonary hypertension with cardiovascular collapse, prompt administration of inhaled amyl nitrite was effective in restoring pulmonary and systemic haemodynamics within five minutes.

The Effects of Methylene Blue on Hemodynamic Parameters and Cytokine Levels in Refractory Septic Shock

BACKGROUND: Endogenous nitric oxide (NO) induces the peripheral vasodilation via the activation of guanylate cyclase in patients with septic shock. The purpose of this study was to assess the acute effects of methylene blue (MB), which is an inhibitor of guanylate cyclase, on the hemodynamics and on the production of pro-inflammatory cytokines and nitric oxide (NO) in patients with refractory septic shock. METHODS: Twenty consecutive patients with refractory septic shock, which was defined as shock refractory to a dopamine infusion of more than 20 microgram/kg/min with the appropriate use of antibiotics and adequate volume replacement, received MB infusion of 1 mg/kg intravenously. The hemodynamic and respiratory variables were measured at baseline, 30, 60 and 120 min after an infusion of MB (1 mg/kg). The blood levels of NO, IL-1, IL-10 and TNF-alpha were measured at baseline, 30 and 120 min after MB infusion. RESULTS: The administration of MB induced an increase in the systemic vascular resistance (SVR) that resulted in an increase of the mean arterial pressure (MAP) in patients with refractory septic shock, and this was without a decrease in cardiac output. The administered MB induced an increase in pulmonary vascular resistance (PVR) that resulted in an increase of pulmonary arterial pressure (PAP), without any deterioration of gas exchange. However, the increases in SVR and PVR were not associated with the alteration of endogenous production of NO, IL-1, IL-10 and TNF-alpha. CONCLUSION: MB transiently elevated the MAP by increasing the SVR without altering the endogenous productions of NO, IL-1, IL-10 and TNF-alpha during the study period in patients with refractory septic shock.

Effects of mercury on the arterial blood pressure of anesthetized rats

The available data suggests that hypotension caused by Hg2+ administration may be produced by a reduction of cardiac contractility or by cholinergic mechanisms. The hemodynamic effects of an intravenous injection of HgCl2 (5 mg/kg) were studied in anesthetized rats (N = 12) by monitoring left and right ventricular (LV and RV) systolic and diastolic pressures for 120 min. After HgCl2 administration the LV systolic pressure decreased only after 40 min (99 +or - 3.3 to 85 + or - 8.8 mmHg at 80 min). However, RV systolic pressure increased, initially slowly but faster after 30 min (25 + or - 1.8 to 42 + or - 1.6 mmHg at 80 min). Both right and left diastolic pressures increased after HgCl2 treatment, suggesting the development of diastolic ventricular dysfunction. Since HgCl2 could be increasing pulmonary vascular resistance, isolated lungs (N = 10) were perfused for 80 min with Krebs solution (continuous flow of 10 ml/min) containing or not 5 µM HgCl2. A continuous increase in pulmonary vascular resistance was observed, suggesting the direct effect of Hg2+ on the pulmonary vessels (12 + or - 0.4 to 29 + or - 3.2 mmHg at 30 min). To examine the interactions of Hg2+ and changes in cholinergic activity we analyzed the effects of acetylcholine (Ach) on mean arterial blood pressure (ABP) in anesthetized rats (N = 9) before and after Hg2+ treatment (5 mg/kg). Using the same amount and route used to study the hemodynamic effects we also examined the effects of Hg2+ administration on heart and plasma cholinesterase activity (N = 10). The in vivo hypotensive response to Ach (0.035 to 10.5 µg) was reduced after Hg2+ treatment. Cholinesterase activity (µM h-1 mg protein-1) increased in heart and plasma (32 and 65 percent, respectively) after Hg2+ treatment. In conclusion, the reduction in ABP produced by Hg2+ is not dependent on a putative increase in cholinergic activity. HgCl2 mainly affects cardiac function. The increased pulmonary vascular resistance and cardiac failure due to diastolic dysfunction of both ventricles are factors that might contribute to the reduction of cardiac output and the fall in arterial pressure

Effects of hypoxia on pulmonary vascular contractility

Although hypoxic pulmonary vasoconstriction (HPV) has been recognized by many researchers, the precise mechanism remains unknown. As isolated pulmonary arteries will constrict in vitro in the response to hypoxia, the oxygen sensor/transduction mechanism must reside in the pulmonary arterial smooth muscle or in the endothelium, or in both. Unfortunately, much of the current evidence is conflicting, especially as to the dependency of HPV on the endothelium and the role of a K+ channel. Therefore, this experiment was attempted to clarify the dependency of HPV on the endothelium and the role of a K+ channel on HPV in rat pulmonary artery. The effects of hypoxia were investigated in isolated main pulmonary arteries precontracted with norepinephrine. Vascular rings were suspended for isometric tension recording in an organ chamber filled with a Krebs-Henseleit solution. Hypoxia was induced by gassing the chamber with 95% N2 + 5% CO2 and this was maintained for 20 min. Hypoxia elicited a vasoconstriction in arteries with endothelium. Mechanical disruption of the endothelium abolished HPV. There was no difference between the amplitude of the HPV induced by two consecutive hypoxic challenges and the effect of normoxic and hyperoxic control Krebs-Henseleit solution on a subsequent response to hypoxia. Inhibition of NO synthesis by treatment with N(omega)-nitro-L-arginine reduced HPV, but inhibition of a cyclooxygenase pathway by treatment with indomethacin had no effect on HPV. Blockades of a tetraetylammonium chloride-sensitive K+ channel abolished HPV. Verapamil, a Ca2+ entry blocker reduced HPV. In conclusion, these results suggest that HPV was dependent on the endothelium and that HPV can be considered to be induced by inhibition of the mechanisms of NO-dependent vasodilation such as the opening of a K+ channels.

H2O2-induced lipid peroxidation in mitochondria of pulmonary vascular smooth muscle tissue and its modification by DFO, DMTU and DIDS.

Treatment of bovine pulmonary artery smooth muscle tissue mitochondria with H2O2 stimulated iron release, hydroxyl radical (OH) production and lipid peroxidation. Pretreatment of mitochondria with deferoxamine (DFO) and dimethyl thiourea (DMTU) prevented OH production and markedly reduced lipid peroxidation without appreciably altering iron release caused by H2O2. Simultaneous treatment of either DFO or DMTU with H2O2 significantly reduced lipid peroxidation and also prevented OH production without causing marked decrease in iron release. In contrast, addition of DFO or DMTU even 2 min after treatment of the mitochondria with H2O2 did not significantly altered iron release, OH production and lipid peroxidation. Pretreatment of the mitochondria with 4,4'-dithiocyano-2,2'-disulfonic acid stilbene (DIDS) markedly reduced lipid peroxidation without appreciably altering the increase in OH production and iron release caused by H2O2.

Acute hemodynamic response to vasodilators in primary pulmonary hypertension.

Acute hemodynamic effects of high flow oxygen (O2) inhalation, sublingual isosorbide dinitrate (ISDN), intravenous aminophylline (AMN) and sublingual nifedipine (NIF) were studied in 32 patients with primary pulmonary hypertension (PPH). In 30 out of 32 patients the basal ratio of pulmonary to systemic vascular resistance (Rp/Rs) was > 0.5 (mean = 0.77 +/- 0.20). Oxygen caused significant decrease in the mean resistance ratio to 0.68 +/- 0.20 (p = 0.005). ISDN, AMN and NIF caused increase in the resistance ratio to 0.79 +/- 0.26; 0.78 +/- 0.26; and 0.80 +/- 0.23 respectively. O2, ISDN, AMN and NIF caused a fall of Rp/Rs in 21 (65.6%), 10 (31.2%), 10(31.2%) and 9(28.1%) patients respectively. Thus, of the four drugs tested high flow O2 inhalation resulted in fall of Rp/Rs in two thirds of patients whereas ISDN, AMN and NIF caused a mean rise in Rp/Rs. One third of patients did respond acutely to the latter three drugs. Acute hemodynamic studies are useful before prescribing vasodilators in patients with PPH since more of the commonly used drugs like ISDN, AMN, NIF could have detrimental hemodynamic responses in some patients. However, great caution should be exercised before performing hemodynamic study as the procedure has definite mortality and morbidity.

Acute effects of dobutamine and dopamine on renal and respiratory functions in patients on prolonged mechanical ventilation

Its is known that positive pressure mechanical ventilation (PPMV) decreases diuresis and increases extravascular water, thereby impairing pulmonary gas exhange. Sympathomimetic amines are commonly used to relieve these effects. To compare the effects of dobutamine (DT) and dopamine (DP) on renal and pulmonary function, we studied 30 patients submitted to continuous PPMV for a least 72 h. All were in stable hemodynamic conditions.patients had pulmonary insufficiency of different etiology. The drugs were randomly administered by continuous intravenous infusion at the dose of 4 to 6 *g kg-1 min-1 for 3 h. An interval of 60 min was allowed to elapse between treatments. A significant increases in arterial pressure and heart rate occurred with both drugs (P,0.05). DP increased urinary flow by 93.7% (1.6ñ0.1 to 3.1 ñ0.4 ml/min; P,0.05) and Na excretion fraction (NaEF) by 35.5% (P,0.05).In contrast, DT reduced NaEF by 58.9%(P,0.05) and had effect on urinary flow. Neither drug altered cretinine clearance.The alveolo-arterial O2 difference (a-aO2D), which was 370ñ20 mmHg during the control period, increased to 394 ñ 20 mmHg after DP and decreased to 355 ñ 22 mmHg after DT, the difference being statistically significant (P,0.05). Pulmonary shunt (%) and the venous pO2 (mmHg) did not change during the infusion of DP or DT.In conclusion, an acute increase in salt and water excretion does not necessarily lead to an immediate reduction in pulmonary "shunt". DT deserves further investigation since it may increase paO2 in the absence of ventricular failure

Pulmonary vasospasm in rabbits infused with stroma free haemoglobin solution.

Effect of infusion of stroma free haemoglobin solution into mice and rabbits was studied. Though no abnormalities were noted in mice, pulmonary vasospasm and hepatocytic necrosis were seen in all rabbits. In addition to reports that low adenosine deaminase levels in the solution could be a cause of vasoconstriction, it is proposed on the basis of present results that either denaturation of haemoglobin molecule itself or release of super oxide anion during oxygenation of haemoglobin, could cause cellular damage leading to toxicity.