Effects of sildenafil analogue UK 343-664 on a porcine model of acute pulmonary hypertension.

BACKGROUND: Sildenafil (Pfizer Pharmaceuticals, Sandwich, Kent, UK) has been associated with pulmonary vasorelaxation. A more potent Sildenafil analogue (UK 343-664 [Pfizer Pharmaceuticals]) has been developed, but its effects in vivo have not been studied. This study evaluated the effects of UK 343-664 (Pfizer) during acute pulmonary hypertension. METHODS: Fourteen adult swine were anesthetized with 1 minimum alveolar concentration isoflurane and were mechanically ventilated with an FIO(2) of 50%. End tidal CO(2) was maintained between 32 and 36 mm Hg. Micromanometer tipped catheters were placed in the ascending aorta, pulmonary artery, and right ventricle. Pulmonary flow was measured with a perivascular probe using transit time ultrasound. RESULTS: Pulmonary hypertension was induced with a continuous infusion of the thromboxane analogue U46619. Animals were randomized into two groups. Group 1 (n = 9) received 500 microg of UK 343-664 (Pfizer) intravenously for more than 2 minutes. Group 2 (n = 5) served as the control group. Data were recorded continuously for 60 minutes. Statistical analyses were performed with the analysis of variance and t tests. A p less than 0.05 was considered significant.Pulmonary hypertension was achieved in all animals. The administration of UK 343-664 (Pfizer) was associated with a significant decrease in pulmonary artery pressure (30.3%; p < 0.05) and pulmonary vascular resistance (42%; p < 0.05) with mild systemic vasodilatation. These effects were partially maintained at 30 minutes (a 17.3% and 39% decrease, respectively; p < 0.05). CONCLUSIONS: The administration of UK 343-664 (Pfizer) was associated with predominant pulmonary vasodilatation without systemic hypotension. This may represent a significant advance in the treatment of acute pulmonary hypertension. Potential clinical implications for this new phosphodiesterase enzyme type V (PDEV) inhibitor merit further study.

Treating myocardial stunning randomly, with either propofol or isoflurane following transient coronary occlusion and reperfusion in pigs.

Propofol and isoflurane may be used during fast track anesthesia for off-pump bypass, where transient ischemia is common. The purpose of this study was to compare the effects of propofol vs isoflurane in a porcine model of acute coronary occlusion. Twenty five pigs were randomized to receive general anesthesia with either isoflurane, 1 MAC (n = 13), or propofol, 3 mg/kg bolus followed by 200 microg/ kg/min infusion (n = 12). Pressure-tipped catheters were placed in the left ventricle (LV) and carotid artery; cardiac output was measured by ultrasound; two pairs of ultrasonic dimension catheters were placed in the subendocardium of LV. The slope of LV end-systolic pressure-volume relationship (Emax) was calculated. Reversible ischemia for 15 mins was accomplished with an occluder around the left anterior descending artery followed by reperfusion period. Measurements were done at baseline, end ischemia, early (5 min) and late (30 min) reperfusion. The data collected included systemic hemodynamics, LV end-diastolic pressure (LVEDP), dP/dt, Emax, and the presence of ventricular arrhythmias. The number of animals studied to completion was 19 (n = 11 in the isoflurane group; n = 8 in propofol group). There was a significant difference in Emax between isoflurane and propofol during early and late reperfusion [3.4 (0.5) and 4.0 (0.3) vs 2.6 (0.4) and 3.2 (0.5) mmHg/sec, respectively; P < 0.05]. Postreperfusion ventricular fibrillation occurred in 54% animals in the propofol group vs none in the isoflurane group ( P 0.05). Isoflurane administration was found to be cardioprotective against ventricular depression and arrhythmias compared to propofol.

Temporary biventricular pacing postcardiopulmonary bypass in patients with reduced ejection fraction.

BACKGROUND AND AIM: Patients with low ejection fraction (EF) undergoing myocardial revascularization frequently require ventricular pacing following cardiopulmonary bypass (CPB). While the benefits of chronic biventricular (BiV) pacing in patients with low EF are well established, there are little data on acute effects during heart surgery. This study analyzed the response of BiV versus single ventricle lead pacing on hemodynamics and left ventricular (LV) function immediately following CPB. METHODS: Ten patients with decreased LV EF (mean = 35 +/- 6%) underwent open-heart surgery with CPB. Temporary pacing electrodes were placed on the right atrium, apex of the right ventricle, and lateral wall of the LV after separation from CPB. The hemodynamic effects of three atrio-ventricular (right, left, and BiV) pacing modes were studied for four minutes each. The pacing sequence was randomly allocated with a resting period of three minutes between each mode. Hemodynamic and echocardiographic data of LV function were collected. Statistical analysis was performed with analysis of variance. RESULTS: BiV pacing increased cardiac output by 4%, 13%, and 44% over right ventricular pacing, LV pacing, and pre-bypass values, respectively. The fractional area of change increased significantly with BiV pacing compared to right ventricular and LV pacing (36%, 35% to 44%, p < 0.01). An increased propagation velocity of 49 cm/s compared to 38 cm/s and 40 cm/s for right ventricular and LV pacing, respectively, suggested an improvement in diastolic function. CONCLUSION: In patients with low EF, BiV pacing immediately after CPB significantly improves LV systolic function and cardiac output, and suggests significantly improved diastolic function.

Treatment of ethanol-induced acute pulmonary hypertension and right ventricular dysfunction in pigs, by sildenafil analogue (UK343-664) or nitroglycerin.

In patients at risk for sudden ethanol (ETOH) intravascular absorption, prompt treatment of pulmonary hypertension (PHTN) will minimise the risk of cardiovascular decompensation. We investigated the haemodynamic effects of intravenous ETOH and the pulmonary vasodilatory effects of a sildenafil analogue (UK343-664) and nitroglycerin (NTG) during ETOH-induced PHTN in pigs. We studied pulmonary and systemic haemodynamics, and right ventricular rate or time derivate of pressure rise during ventricular contraction ( =dP/dT), as an index of contractility, in 23 pigs. ETOH was infused at a rate of 50 mg/kg/min, titrated to achieve a twofold increase in mean pulmonary arterial pressure (MPAP), and then discontinued. The animals were randomised to receive an infusion of 2 ml/kg ( n = 7) normal saline, a 500-microg/kg bolus of UK343-664 ( n = 8), or NTG 1 microg/kg ( n = 8); each was given over 60 seconds. Following ETOH infusion, dP/dT decreased central venous pressure (CVP), and MPAP increased significantly, resulting in significantly increased pulmonary vascular resistance (PVR). Within 2 minutes after treatment with either drug, CVP, heart rate (HR), and the systemic vascular resistance-to-pulmonary vascular resistance (SVR/PVR) ratio returned to baseline. However, at that time, only in the UK343-664 group, MPAP and dP/dT partially recovered and were different from the respective values at PHTN stage. NTG and UK343-664 decreased PVR within 2 minutes, from 1241+/-579 and 1224+/-494 dyne . cm/sec 5 , which were threefold-to-fourfold increased baseline values, to 672+/-308 and 538+/-203 dyne . cm/sec 5 respectively. However, only in the UK343-664 group, changes from baseline PVR values after treatment were significant compared to the maximal change during target PHTN. Neither drug caused a significant change in SVR. In this model of ETOH-induced PHTN, both UK343-664 and NTG were effective pulmonary vasodilators with a high degree of selectivity. However, the changes from baseline values of PVR, and the partial recovery of systemic pressure and RV contractility compared to the maximal change during target PHTN, were significant only in the sildenafil analogue group.

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.

Treating ischemic left ventricular dysfunction with hypertonic saline administered after coronary occlusion in pigs.

OBJECTIVE(S): The effects of hypertonic saline on ventricular function are controversial, whether it is increasing contractility or preload. There are no data, however, on the influence of hypertonic saline in a stunned myocardium. DESIGN: This study was prospective and randomized in order to analyze the effects of hypertonic saline solution (7.5%) on myocardial function and systemic hemodynamics in a porcine model of ischemia and reperfusion. SETTING: A university teaching hospital, animal research laboratory. PARTICIPANTS: Twelve adult domestic swine. INTERVENTIONS: Myocardial stunning was produced by the complete occlusion of the proximal left anterior descending artery for 15 minutes followed by reperfusion. Five minutes after reperfusion, the animals were assigned to receive 4 mL/kg of hypertonic saline (n = 7) or normal saline (n = 5) over 10 minutes. Pressure-tipped catheters were placed in the left ventricular cavity and aorta. The dimensions of the left ventricle were measured with ultrasonic microcrystals. Cardiac output was measured with transit time ultrasound. Data were recorded continuously and compared before the occlusion, 5 minutes after reperfusion, and at the end of the infusion. MEASUREMENTS AND MAIN RESULTS: Compared with baseline, ventricular function was significantly depressed after left anterior descending artery occlusion. Left ventricular dP/dT and its end-systolic pressure-volume slope decreased (38% and 52%, respectively; p < 0.05), with a concomitant increase in systemic vascular resistance. The administration of hypertonic saline significantly improved left ventricular function (Emax 1,422 +/- 198 mmHg/mL, and dP/dT 3.2 +/- 0.4 mmHg/s v normal saline group values of 1,156 +/- 172 and 2.5 +/- 0.5, respectively; p < 0.05), cardiac output (2.5 +/- 0.5 v 1.84 +/- 0.4 L/min, p < 0.05), and lowered systemic vascular resistance (from 28.8 +/- 2.3 to 23.5 +/- 1.4, p < 0.05), with no significant changes with normal saline administration. CONCLUSIONS: After transient myocardial ischemia, hypertonic saline administered over a short period of time acts as an inodilator by increasing contractility while simultaneously lowering systemic vascular resistance.

Treating metabolic impairment and myocardial stunning with phosphodiesterase inhibitor type III, milrinone, administered prior to coronary artery occlusion in the presence of calcium channel blockade in pigs.

This study examined milrinone effects on ischaemic myocardial metabolism and function with calcium blockade. We studied 15 pigs in 3 groups: group C received no drugs; group D received diltiazem 5 mg bolus followed by infusion; group D+M received diltiazem and milrinone (50microg/Kg). The left anterior descending (LAD) artery was then occluded for 15 minutes. Left ventricular (LV) function data obtained included rate, pressures, output, Emax, and dP/dT. Blood lactate was obtained from the LAD and circumflex vessels at baseline, end of occlusion, early (15 min) and late (1 hour) reperfusion. In group D+M, less depression of LV function occurred during ischaemia and early reperfusion. Lactate extraction in the LAD region was less negative in D+M group than in the group without milrinone during ischaemia and late reperfusion. We conclude the preemptive administration of milrinone prior to ischaemia added to calcium blockade improved myocardialfunction and ischaemic metabolic effects.

Effect of sildenafil on pulmonary artery pressure, systemic pressure, and nitric oxide utilization in patients with left ventricular assist devices.

BACKGROUND: Pulmonary artery hypertension can complicate the early postoperative care of patients with left ventricular assist devices (LVADs). Inhaled nitric oxide (INO) is frequently used to manipulate pulmonary resistance after LVADs have been placed. We evaluated the effect of oral sildenafil therapy on pulmonary artery pressure, systemic pressure, and nitric oxide utilization. METHODS: After Institutional Review Board approval, the records of 10 consecutive adult patients with LVADs and pulmonary hypertension who received sildenafil were reviewed. Demographics, surgical history, INO use, inotrope requirements, and hemodynamic response to oral sildenafil at multiple intervals were collected. Hemodynamic data were analyzed with a two-way analysis of variance of repeated measures with correction for multiple comparisons. RESULTS: There were 8 men and 2 women with 6 Heartmate XVE LVADs and 4 Thoratec LVADs (both, Thoratec, Pleasanton, California). When weaning was attempted, 8 patients who received INO demonstrated rebound pulmonary hypertension or increased right heart dysfunction. All patients were on inotropic therapy with dobutamine and milrinone. Sildenafil produced a significant reduction in pulmonary artery systolic pressure within 90 minutes of oral administration (p = 0.042). Significant changes in systolic blood pressure, mean arterial pressure, systemic vascular resistance, and heart rate were not observed. All 8 patients receiving INO were weaned within 12 hours without recurrent pulmonary hypertension. All 10 patients were weaned from inotropic support within 72 hours. No patient suffered right-side heart failure requiring intervention. CONCLUSIONS: Oral sildenafil represents a useful adjunctive therapy for patients with LVADs. In our series, it provided additional reduction of pulmonary artery pressure, and facilitated weaning from INO and inotropes without deleterious hemodynamic consequences.

Effects of milrinone versus epinephrine on left ventricular relaxation after cardiopulmonary bypass following myocardial revascularization: assessment by color m-mode and tissue Doppler.

OBJECTIVE: The purpose of this study was to evaluate the left ventricular lusitropic effects of epinephrine versus milrinone after cardiopulmonary bypass. DESIGN: Prospective randomized study. SETTING: Single institution, university teaching hospital. PARTICIPANTS: Adult patients undergoing coronary artery bypass grafting under cardiopulmonary bypass. INTERVENTIONS: After separation from cardiopulmonary bypass, patients were randomized to receive intravenous epinephrine by continuous infusion (0.03 microg/kg/min) or milrinone (50 microg/kg followed by 0.5 microg/kg/min). Transesophageal echocardiographic evaluation of left ventricular diastolic function, with emphasis on relaxation, was performed before and after bypass and after the administration of either epinephrine or milrinone. MEASUREMENTS AND MAIN RESULTS: Measurements included pulse-wave Doppler analysis of mitral inflow and pulmonary vein and left ventricular outflow tract velocities. Left ventricular inflow velocity of propagation measured with color M-mode and tissue Doppler assessment of early mitral annulus velocity were used to evaluate left ventricular relaxation. Values of velocity of propagation and mitral annulus velocity improved significantly after bypass, suggesting improved relaxation. The administration of either epinephrine or milrinone did not result in further improvement in left ventricular relaxation. CONCLUSIONS: After cardiopulmonary bypass, left ventricular relaxation was significantly improved. Neither epinephrine nor milrinone exhibited favorable lusitropic effects after bypass.

Oximetry-derived perfusion index for intraoperative identification of successful thoracic sympathectomy.

BACKGROUND: Endoscopic thoracic sympathectomy treats patients with hyperhidrosis. Laser Doppler flow and changes in palmar temperature have been advocated for intraoperative monitoring. The pulse oximetry-derived perfusion index (PI) is used to quantify pulsatile blood flow at the pulse oximeter. Upper limb sympathectomy is associated with increased flow to the ipsilateral extremity; thus we postulate that it will increase PI. We evaluated changes in intraoperative PI as a monitor of successful thoracic sympathectomy. METHODS: After institutional review board approval and informed consent, 10 adult patients undergoing bilateral endoscopic thoracic sympathectomy under general anesthesia were studied. Finger pulse-oximetry probes were placed on each hand, and reference probes on each earlobe. Hemodynamic variables and PI were continuously monitored. Data were collected immediately before and every minute after sympathectomy for 5 minutes. Anesthetic management remained constant throughout. A successful sympathectomy was defined by a twofold increase in PI on the ipsilateral arm. Data were analyzed with analysis of variance and Student's t tests; a p < 0.05 was considered significant. RESULTS: Baseline oximetric waveforms were adequate in all subjects. Right sympathectomy was associated with a 372% increase in PI (p < 0.0001), and left sympathectomy with a 316% increase in PI (p < 0.029). This occurred as early as 1 minute after transection of the sympathetic chain. The PI in the reference probes as well as the hemodynamics remained constant. All patients had postoperative resolution of their hyperhidrosis symptoms. CONCLUSIONS: In patients with hyperhidrosis of the upper extremity, the intraoperative PI derived from pulse oximetry is an additional indicator of successful thoracic sympathectomy.

Oral sildenafil reduces pulmonary hypertension after cardiac surgery.

BACKGROUND: Treatment of postoperative pulmonary hypertension with intravenous (IV) pulmonary vasodilators is hampered by the lack of selectivity. Inhaled nitric oxide produces selective pulmonary vasodilation; however, it requires a special device, and weaning can cause rebound. Oral sildenafil is a phosphodiesterase type V inhibitor. Sildenafil can produce sustained pulmonary vasodilatation in patients with hypoxic or primary pulmonary hypertension; however, experience with postoperative pulmonary hypertension is limited. We report our initial experience with eight patients who received oral sildenafil as adjunctive therapy for postoperative pulmonary hypertension METHODS: We reviewed the charts of eight adult patients with postoperative pulmonary hypertension who received oral sildenafil (25 to 50 mg) to facilitate weaning of IV (milrinone, nitroglycerine, and sodium nitroprusside) and inhaled (nitric oxide) pulmonary vasodilators. Hemodynamic data were recorded before and 30 and 60 minutes after the initial dose of sildenafil. RESULTS: After the initial dose of sildenafil, mean pulmonary artery pressure was reduced by 20% and 22% at 30 and 60 minutes, respectively (p < 0.05). Pulmonary vascular resistance index decreased by 49% and 44% at 30 and 60 minutes, respectively (p < 0.05). Sildenafil had no clinically significant effects on cardiac index, mean arterial pressure, or systemic vascular resistance. Subsequent doses of sildenafil were administered at regular intervals, allowing successful weaning of concomitant pulmonary vasodilators. CONCLUSIONS: Oral sildenafil is an effective agent for treatment of postoperative pulmonary hypertension and can be used to facilitate weaning of inhaled and IV pulmonary vasodilators.

Milrinone increases middle cerebral artery blood flow velocity after cardiopulmonary bypass.

OBJECTIVE: To evaluate the effects of milrinone on middle cerebral artery blood flow velocity (Vmca) and pulsatility index (PI) during normocapnia and hyperventilation in adults after cardiopulmonary bypass (CPB). DESIGN: A prospective study. SETTING: University-affiliated hospital and Veterans Affairs Medical Center. PARTICIPANTS: Twenty-five adults with left ventricular ejection fraction >40% undergoing coronary artery bypass graft surgery. INTERVENTIONS: After separation from CPB, using transcranial Doppler ultrasonography, peak and mean Vmca and PI were recorded before and after the administration of 50 microg/kg of milrinone under normocapnia and with hyperventilation. MEASUREMENTS AND MAIN RESULTS: Heart rate, arterial blood pressure, central venous pressure, and cardiac output were documented after each study period. Compared with baseline, milrinone increased peak Vmca by 20%, increased mean Vmca by 19%, and decreased PI by 16% (p < 0.001). Before the administration of milrinone, hyperventilation decreased peak Vmca by 20%, decreased mean Vmca by 26%, and increased PI by 24% (p < 0.01). After milrinone administration, hyperventilation also decreased peak Vmca by 22%, decreased mean Vmca by 21%, and increased PI by 19% (p < 0.01). Milrinone increased cardiac index and decreased mean arterial pressure and systemic vascular resistance (p < 0.05); however, heart rate and central venous pressure remained unchanged. CONCLUSIONS: The administration of milrinone increases cerebral blood flow after CPB most likely as a result of cerebral vasodilation. The response to hyperventilation seems to be partially preserved.

Measurement of cardiac output before and after cardiopulmonary bypass: Comparison among aortic transit-time ultrasound, thermodilution, and noninvasive partial CO2 rebreathing.

OBJECTIVES: A noninvasive continuous cardiac output system (NICO) has been developed recently. NICO uses a ratio of the change in the end-tidal carbon dioxide partial pressure and carbon dioxide elimination in response to a brief period of partial rebreathing to measure CO. The aim of this study was to compare the agreement among NICO, bolus (TDCO), and continuous thermodilution (CCO), with transit-time flowmetry of the ascending aorta using an ultrasonic flow probe (UFP) before and after cardiopulmonary bypass (CPB). DESIGN: Prospective, observational human study. SETTING: Veterans Affairs Medical Center Hospital. PARTICIPANTS: Sixty-eight patients. METHODS: Matched sets of CO measurements between NICO, TDCO, CCO, and UFP were collected in 68 patients undergoing elective CABG at specific time periods before and after separation from CPB. After anesthetic induction, all patients had an NICO sensor attached between the endotracheal tube and the breathing circuit, a PAC floated into the pulmonary artery for TDCO and CCO monitoring, and a UFP positioned on the ascending aorta and used for the reference CO. Bland-Altman analysis was used to compare the agreement among the different methods. MEASUREMENTS AND MAIN RESULTS: Bland-Altman analysis of CO measurements before CPB yielded a bias, precision, and percent error of 0.04 L/min +/- 1.07 L/min (44.8%) for NICO, 0.18 L/min +/- 1.01 L/min (41.7%) for TDCO, and 0.29 L/min +/- 1.40 L/min (57.5%) for CCO compared with simultaneous UFP CO measurements, respectively. After separation from CPB (average 29 mins), bias, precision, and percent error were -0.46 L/min +/- 1.06 L/min (37.3%) for NICO, 0.35 L/min +/- 1.39 L/min (46.1%) for TDCO, and 0.36 L/min +/- 1.96 L/min (64.7%) for CCO compared with UFP CO measurements, respectively. CONCLUSIONS: Before initiation of CPB, the accuracy for all 3 techniques was similar. After separation from CPB, the tendency was for NICO to underestimate CO and for TDCO and CCO to overestimate it. NICO offers an alternative to invasive CO measurement.

Effects of a new phosphodiesterase enzyme type V inhibitor (UK 343-664) versus milrinone in a porcine model of acute pulmonary hypertension.

BACKGROUND: Perioperative pulmonary hypertension remains a clinical challenge. The phosphodiesterase enzyme type III inhibitor milrinone produces pulmonary vasodilation but lacks selectivity. Sildenafil, a phosphodiesterase enzyme type V inhibitor, can also induce relaxation of the pulmonary vasculature; however, only the oral formulation is presently available. This study evaluated the effects of a new intravenous sildenafil analogue--UK 343-664--compared with milrinone during acute pulmonary hypertension in a porcine model of thromboxane-induced pulmonary hypertension. METHODS: After acute pulmonary hypertension, 24 adult swine were randomized to 3 groups. Group 1 (n = 9) received an intravenous dose of 500 microg of UK 343-664, group 2 (n = 8) received milrinone 50 mg/kg, and group 3 (n = 7) received 10 mL of normal saline solution. All agents were administered for more than 5 minutes. Data were recorded continuously for 30 minutes. RESULTS: Both milrinone and UK 343-664 partially reversed thromboxane-induced pulmonary hypertension, with a notable decrease in mean pulmonary artery pressure and pulmonary vascular resistance and a concomitant increase in cardiac output. In addition, milrinone improved right ventricular contractility but produced marked systemic vasodilatation. In contrast, the administration of UK 343-664 was associated with pulmonary vasodilatation, without appreciable changes in systemic arterial pressure or vascular resistance. CONCLUSIONS: Milrinone and UK 343-664 were equally effective as pulmonary vasodilators; however, only UK 343-664 exhibited a high degree of pulmonary selectivity. Potential uses for this new phosphodiesterase enzyme type V inhibitor warrant further study.

Treatment of ethanol-induced acute pulmonary hypertension and right ventricular dysfunction in pigs, by sildenafil analogue (UK343-664) or nitroglycerin.

In patients at risk for sudden ethanol (ETOH) intravascular absorption, prompt treatment of pulmonary hypertension (PHTN) will minimise the risk of cardiovascular decompensation. We investigated the haemodynamic effects of intravenous ETOH and the pulmonary vasodilatory effects of a sildenafil analogue (UK343-664) and nitroglycerin (NTG) during ETOH-induced PHTN in pigs. We studied pulmonary and systemic haemodynamics, and right ventricular rate or time derivate of pressure rise during ventricular contraction ( =dP/dT), as an index of contractility, in 23 pigs. ETOH was infused at a rate of 50 mg/kg/min, titrated to achieve a twofold increase in mean pulmonary arterial pressure (MPAP), and then discontinued. The animals were randomised to receive an infusion of 2 ml/kg ( n = 7) normal saline, a 500-microg/kg bolus of UK343-664 ( n = 8), or NTG 1 microg/kg ( n = 8); each was given over 60 seconds. Following ETOH infusion, dP/dT decreased central venous pressure (CVP), and MPAP increased significantly, resulting in significantly increased pulmonary vascular resistance (PVR). Within 2 minutes after treatment with either drug, CVP, heart rate (HR), and the systemic vascular resistance-to-pulmonary vascular resistance (SVR/PVR) ratio returned to baseline. However, at that time, only in the UK343-664 group, MPAP and dP/dT partially recovered and were different from the respective values at PHTN stage. NTG and UK343-664 decreased PVR within 2 minutes, from 1241+/-579 and 1224+/-494 dyne . cm/sec 5 , which were threefold-to-fourfold increased baseline values, to 672+/-308 and 538+/-203 dyne . cm/sec 5 respectively. However, only in the UK343-664 group, changes from baseline PVR values after treatment were significant compared to the maximal change during target PHTN. Neither drug caused a significant change in SVR. In this model of ETOH-induced PHTN, both UK343-664 and NTG were effective pulmonary vasodilators with a high degree of selectivity. However, the changes from baseline values of PVR, and the partial recovery of systemic pressure and RV contractility compared to the maximal change during target PHTN, were significant only in the sildenafil analogue group.

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.

Treating metabolic impairment and myocardial stunning with phosphodiesterase inhibitor type III, milrinone, administered prior to coronary artery occlusion in the presence of calcium channel blockade in pigs.

This study examined milrinone effects on ischaemic myocardial metabolism and function with calcium blockade. We studied 15 pigs in 3 groups: group C received no drugs; group D received diltiazem 5 mg bolus followed by infusion; group D+M received diltiazem and milrinone (50microg/Kg). The left anterior descending (LAD) artery was then occluded for 15 minutes. Left ventricular (LV) function data obtained included rate, pressures, output, Emax, and dP/dT. Blood lactate was obtained from the LAD and circumflex vessels at baseline, end of occlusion, early (15 min) and late (1 hour) reperfusion. In group D+M, less depression of LV function occurred during ischaemia and early reperfusion. Lactate extraction in the LAD region was less negative in D+M group than in the group without milrinone during ischaemia and late reperfusion. We conclude the preemptive administration of milrinone prior to ischaemia added to calcium blockade improved myocardialfunction and ischaemic metabolic effects.