Showing papers by "Lewis J. Rubin published in 1998"

Dysfunctional Voltage-Gated K+ Channels in Pulmonary Artery Smooth Muscle Cells of Patients With Primary Pulmonary Hypertension

Abstract: Background—Primary pulmonary hypertension (PPH) is a rare disease of unknown cause. Although PPH and secondary pulmonary hypertension (SPH) share many clinical and pathological characteristics, their origins may be disparate. In pulmonary artery smooth muscle cells (PASMCs), the activity of voltage-gated K+ (KV) channels governs membrane potential (Em) and regulates cytosolic free Ca2+ concentration ([Ca2+]cyt). A rise in [Ca2+]cyt is a trigger of vasoconstriction and a stimulus of smooth muscle proliferation. Methods and Results—Fluorescence microscopy and patch clamp techniques were used to measure [Ca2+]cyt, Em, and KV currents in PASMCs. Mean pulmonary arterial pressures were comparable (46±4 and 53±4 mm Hg; P=0.30) in SPH and PPH patients. However, PPH-PASMCs had a higher resting [Ca2+]cyt than cells from patients with SPH and nonpulmonary hypertension disease. Consistently, PPH-PASMCs had a more depolarized Em than SPH-PASMCs. Furthermore, KV currents were significantly diminished in PPH-PASMCs. Bec...

Molecular basis and function of voltage-gated K+ channels in pulmonary arterial smooth muscle cells

Abstract: K+-channel activity-mediated alteration of the membrane potential and cytoplasmic free Ca2+ concentration ([Ca2+]cyt) is a pivotal mechanism in controlling pulmonary vasomotor tone. By using combin...

Successful use of chronic epoprostenol as a bridge to liver transplantation in severe portopulmonary hypertension.

Abstract: Background. Portopulmonary hypertension, defined as mean pulmonary artery pressure >25 mmHg in the presence of a normal pulmonary capillary wedge pressure and portal hypertension, is a known complication of end-stage liver disease that has been associated with high morbidity and mortality at the time of liver transplantation. We have recently reported the successful treatment of portopulmonary hypertension with chronic intravenous epoprostenol and now report the first patient with severe portopulmonary hypertension successfully treated with epoprostenol who subsequently underwent successful liver transplantation. Methods. A patient with severe portopulmonary hypertension was treated with intravenous epoprostenol, 23 ng/kg/min, for a 4-month period, after which the portopulmonary hypertension resolved and the patient underwent successful liver transplantation. Results. The patient was discharged, continues to do well, and at 3 months is off epoprostenol with near normal pulmonary artery pressures. Conclusions. Chronic epoprostenol, in conjunction with a multidisciplinary, well-planned perioperative evaluation and treatment plan, may be the answer to a heretofore untreatable disease. Portopulmonary hypertension (PPHTN*), defined as a mean pulmonary artery pressure (MPAP) .25 mmHg with a normal pulmonary capillary wedge pressure (PCWP) in the presence of portal hypertension, is a known yet uncommon complication of chronic liver disease. Despite its low prevalence, PPHTN has received increasing attention as its pres

The influence of continuous intravenous prostacyclin therapy for primary pulmonary hypertension on the timing and outcome of transplantation.

Abstract: Background: Primary pulmonary hypertension (PPH) is a progressive disease with a median survival of less than 3 years from diagnosis. Medical management has typically consisted of anticoagulation and oral calcium channel blocking agents, whereas lung transplantation (LT) has been reserved for patients who are unresponsive to medical therapy. Continuous intravenous prostacyclin was introduced for patients who did not respond to calcium channel blockers and who would have required LT. We reviewed our experience with prostacyclin in LT candidates to study its effects on the timing and outcome of LT. Methods: We retrospectively reviewed the clinic and hospital records of patients with PPH who were both treated with prostacyclin and evaluated for LT. Additional information was obtained from the pulmonary vascular disease and lung transplantation databases. Results: A total of 42 patients were identified who received prostacyclin for the treatment of PPH and were evaluated for LT. Thirty-seven patients were accepted as LT candidates, 22 at The University of Maryland Medical Center (UMMC), 15 at other LT programs. Overall, 70% (27/37) of LT candidates were removed from the LT waiting list or had listing for LT deferred because of clinical improvement. In patients listed for LT before initiation of prostacyclin therapy, 55% (12/22) were removed from the active waiting list for 27.2 ± 17 months (range 8 to 60), and 92% (11/12) remain on the inactive status. In patients who received prostacyclin before listing for LT, listing for LT was deferred in 94% (14/15) for 17.4 ± 9 months (range 6 to 33 months) because of clinical stability or improvement. In all, 93% of patients (39/42) experienced an improvement in 1 or more New York Heart Association functional class. The hemodynamic profiles of the eight patients removed from the active waiting list at UMMC demonstrated increases of 55% ± 18% in cardiac output, and decreases of 14.3% ± 4.9% in mean pulmonary artery pressure and 36% ± 8.3% in total pulmonary resistance (p < 0.05). The 1-year survival rate for LT after prostacyclin therapy was 88% (7/8) at UMMC and 60% (3/5) at the other centers. Conclusion: We conclude that prostacyclin therapy is an effective means of delaying, possibly indefinitely, the need for LT in patients with PPH and that excellent results can be obtained when LT is performed after prostacyclin therapy. Consideration should be given to initiating prostacyclin therapy in all patients whose conditions do not respond to conventional therapy before proceeding with transplantation. J Heart Lung Transplant 1998;17:679-85.

Artery Smooth Muscle Cells of Patients With Primary Pulmonary Hypertension

Abstract: Background—Primary pulmonary hypertension (PPH) is a rare disease of unknown cause. Although PPH and secondarypulmonary hypertension (SPH) share many clinical and pathological characteristics, their origins may be disparate. Inpulmonary artery smooth muscle cells (PASMCs), the activity of voltage-gated K

Short-term outcome and predictors of adverse events following pulmonary thromboendarterectomy.

Abstract: p < 0.05). Mild mixed acidosis present at ICU admission resolved prior to discharge ( p = 0.002). The length of mechanical ventilation time was positively correlated with the absolute post-CPB PVR and negatively correlated with the relative change in central venous pressure (CVP) from pre-CPB to post-CPB values ( r = 0.75, p = 0.037). Of the pre-CPB anthropometric variables, only body mass index was significantly higher in nonsurvivors ( p = 0.037). Pulmonary artery pressures and vascular resistance fall significantly after PTE. A lower post-CPB PVR and a relatively decreased (i.e., from pre-CPB values) CVP predict reduced length of postoperative ventilation but not of the hospital stay. Mortality appears increased in patients with a large body habitus.

Roles of K+ and Cl- Channels in cAMP-induced pulmonary vasodilation

Abstract: Increase in intracellular adenosine 3', 5'-cyclic monophosphate (cAMP) is a common pathway for many clinically used drugs to cause pulmonary artery (PA) relaxation. Activity of sarcolemmal K+ and Cl(-)-channels is an important determinant of membrane potential (Em), which, in turn, plays a critical role in regulating pulmonary vascular tone. Whether K+ and Cl- channels were involved in cAMP-induced PA relaxation was tested using isolated rat PA rings. Raising extracellular K+ concentration from 20 to 142.7 mM increased the K(+)-evoked contraction, but significantly decreased the relaxation induced by the adenylate cyclase activator, forskolin (FSK, 2.5 microM), suggesting that FSK-induced PA relaxation depended on transmembrane K+ gradient. Indeed, the FSK-induced relaxation was inhibited by 4-aminopyridine (4-AP, 10 mM), a voltage-gated K+ (Kv) channel blocker. Neither the Ca(2+)-activated K+ channel blocker, charybdotoxin, nor the ATP-sensitive K+ channel blocker, glibenclamide, had this effect. Furthermore, reducing extracellular Cl- concentration from 142.7 to 50 mM significantly decreased the FSK-induced relaxation in PA rings precontracted with 142.7 mM K+ (Ek approximately 0 mV), but negligibly affected the evoked contraction. This indicates that transmembrane Cl- gradient also regulates FSK-induced PA relaxation. Indeed, the Cl- channel blocker, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB, 10 microM), significantly inhibited the FSK-induced relaxation in PA rings preconstricted by 142.7 mM K+. In summary, the data suggest that the cAMP-induced PA relaxation is attributable, at least partly, to both activation of the 4-AP-sensitive Kv channels and stimulation of the NPPB-sensitive Cl- channels.