Endothelial Dysfunction Providing the Basis for the Treatment of Pulmonary Hypertension: Human Pulmonary Artery Rings

9 Jun
2014

Endothelial Dysfunction Providing the Basis for the Treatment of Pulmonary Hypertension: Human Pulmonary Artery RingsNO would cause pulmonary vasodilatation. Indeed, we were able to prove that this was the case in 1988. In patients with pulmonary hypertension, inhaled NO (unlike IV PGI2) acted as a selective pulmonary vasodilator (Fig 2). Others quickly showed the same response in patients with ARDS and neonatal PPH. Indeed, inhaled NO has been shown in such infants to reduce mortality rates and reduce the need for extracorporeal oxygenation. Pulsing NO during oxygenation may offer a means of treating ambulatory patients with pulmonary hypertension.
Impaired NO Release in Pulmonary Hypertension: The initial studies of the capacity of endothelium to produce NO required stimulating the release of NO with specific agonists such as acetylcholine (ACh) and adenosine diphosphate or nonspecific agonists such as the calcium ionophore, A2317. Buy birth control online add comment Alternatively, it is possible to “block” NOS by means of analogues of L-arginine.
Using these techniques and pulmonary artery rings dissected from explant lungs of patients undergoing transplantation for pulmonary hypertension in isometric organ baths, it proved possible to demonstrate improved “stimulated” release of NO from the endothelium of diseased lungs. Stimulated release of NO with ACh and adenosine diphosphate together with nonspecific calcium ionophore was impaired while the capacity to vasodilate with NO donors was increased (Table 1). This impaired release of NO was also seen in severe pulmonary hypertension. It appeared associated with a low arterial oxygen tension in patients but could not be connected with L-arginine.
Isolated perfused lungs were again obtained as the explant of patients with pulmonary hypertension undergoing transplant surgery with “controls” as donor lungs not required for surgery. We were able to show unimpaired basal release of NO in the diseased lungs. The rise in pulmonary vascular resistance was equivalent in diseased and control lungs when NO release was blocked with L-NAME (Table 2). However, again we demonstrated impaired stimulated release of pulmonary endothelium NO.

Figure 2. Comparison of effects on pulmonary (PVR) and systemic (SVR) vascular resistance of an infusion of PGI2 (0.5 mg in 250 mL) at rates of 4, 8, and 12 mL/h and inhalation of NO (40 ppm in air) with baseline (BL) values in eight patients with pulmonary hypertension. Means ± SEM are shown. Asterisk: p<0.05; double asterisk: p<0.01.

Figure 2. Comparison of effects on pulmonary (PVR) and systemic (SVR) vascular resistance of an infusion of PGI2 (0.5 mg in 250 mL) at rates of 4, 8, and 12 mL/h and inhalation of NO (40 ppm in air) with baseline (BL) values in eight patients with pulmonary hypertension. Means ± SEM are shown. Asterisk: p<0.05; double asterisk: p<0.01.

Table 1—Vascular Responses of Human Pulmonary Artery Rings

ResponseTest RingsControlRingsStatisticalSignificance
Precontraction in response to phenylephrine, g2.1±0.1(n=34)1.3±0.1(n=23)p<0.001
Maximal relaxation in response to vasodilators, %
Acetylcholine40±4(n=34)78±4(n=22)p<0.001
Adenosine diphosphate52±4(n=20)84±2 (n = 17)p<0.001
Calcium ionophore A2318736+6(n=12)87±7(n=6)p<0.001
Sodium nitroprusside99±1(n=8)90±3(n=6)p<0.01

Table 2—Constant Flow Experiments: Characteristics of Patients Undergoing HLT

DiagnosisAge, yr/SexFIo2Pa02, mm Hgpvrb,mm Hg/mL/ min/kgAPVR,mm Hg/ mL/min/kgInhibitor
Donor41/M0.35146.50.11+0.09L-NAME
Donor17/M0.451710.13+0.15L-NAME
Donor47/F0.451690.10+ 1.14L-NAME
Donor23/M0.451740.14+0.27L-NAME
Donor30/M0.351330.19+0.24L-NAME
CF19/M0.21520.27+0.82MB
CF31/M0.21400.34+0.40MB
PPH40/M0.21541.4+ 1.61MB
PPH47/F0.21481.58+ 1.32MB
ES33/F0.21611.48+0.34L-NAME
ES35/F0.21551.15+0.33L-NAME
ES44/F0.21650.88+0.19L-NAME
CF29/F0.21580.41+0.27L-NAME
CF24/F0.21480.39+0.23L-NAME
COAD47/M0.21630.63+0.66L-NAME
top