Altered pulmonary microvascular reactivity to norepinephrine in canine pacing-induced heart failure.

Abstract

Pulmonary hypertension in congestive heart failure causes medial hypertrophy in pulmonary vessels and thickening of the endothelial basement membrane. In this study, the functional consequences of such pulmonary vascular adaptations were evaluated. Heart failure was induced in dogs by rapid ventricular pacing (240 beats per minute) for 28 days, at which time left ventricular shortening fraction was decreased by 57% compared with that at baseline. Lung lobes from paced (n=56) and control dogs (n=68) were isolated and perfused with autologous blood. Total, arterial (Ra), and venous (Rv) vascular resistances were significantly increased and vascular capacitance decreased in lobes from paced animals compared with controls. Increments in Ra and Rv after intra-arterial boluses of norepinephrine were measured before and after sequential addition of the al-and a2-receptor antagonists prazosin (16 ,umol/L) and yohimbine (0.1 gmol/L) in the presence or absence of propranolol (5 ,umol/L). Nor-epinephrine (1 to 40 jig) had little effect on Ra in the absence of propranolol, a pattern that persisted in control lobes after propranolol. However, when lobes from paced animals were pretreated with propranolol, norepinephrine increased Ra. Rv was increased after norepinephrine in control lobes, an effect that was enhanced in the paced group. In both groups, the increment in Rv was greater after propranolol. Irrespective of propranolol pretreatment, prazosin significantly attenuated, if not abolished, the response to norepinephrine. The enhancement in venous vascular reactivity in lobes from paced animals remained when venous pressure was elevated to 20 cm H20. In control lobes under conditions of elevated tone or when endothelium-dependent relaxing factor was blocked, responses to norepinephrine did not mimic those observed in the paced group. Microvascular permeability, as measured by the capillary filtration coefficient, was not altered in the paced group. We conclude that the pulmonary adaptations to 4 weeks of rapid ventricular pacing include functional changes in pulmonary hemodynamics and vascular reactivity but not in microvascular permeability. (Circ Res. 1994;75:347-356.) Key Words * congestive heart failure * pulmonary venous hypertension * pulmonary circulation * isolated lung * yohimbine * prazosin * propranolol C ongestive heart failure is associated with chronic exposure of the lung to high pulmonary vascular pressures. In part, this may be due to the increased circulating levels of humoral vasoconstrictors such as catecholamines and angiotensin II observed in animal models of heart failure and in humans with congestive heart failure.1-3 Although pulmonary capillary pressure (Pc), and therefore transcapillary fluid flux, would be predicted to be increased as a result, not all patients with congestive heart failure or high pulmonary vascular pressures secondary to mitral stenosis develop pulmonary edema.3 Several mechanisms could potentially contribute to protection of the lung against edema formation and a...

Role of EETs in regulation of endothelial permeability in rat lung

“…Kf,c was determined by dividing the rate of lung weight gain measured 13-15 min after increasing P v by 7-10 cmH2O by the resultant increment in capillary pressure (Pc) (43) and normalizing the result per gram dry lung weight. This rate of weight gain was corrected for any nonisogravimetric rate of weight gain during the period just preceding the K f,c maneuver.…”

“…Kf,c measurements were made at baseline and at specific time points (30-90 min) after treatment, as described under experimental protocols. Using measures of P a, Pc, and Pv, we determined not only total vascular resistance (Rt) but also arterial (Ra) and venous (Rv) vascular resistance (41,43).…”

Mechanisms and Limits of Induced Postnatal Lung Growth

“…Whereas CHF increases transendothelial water flux in lungs (189)(190)(191), interstitial or alveolar edema does not always develop (192)(193)(194). This adaptive response involves structural remodeling of the alveolar-capillary barrier, septal interstitium, extra-alveolar pulmonary vasculature, as well as functional remodeling of signaling pathways regulating endothelial barrier function.…”

“…Septal remodeling in response to chronic capillary congestion serves a protective role by raising the pressure required to induce stress failure of the blood-gas barrier (48,196,198). Despite early thickening of the septal barrier and increased resistance to stress failure, basal endothelial permeability remains normal (192,196,199), and the endothelium is refractory to injury (200) after 1-2 months of pacinginduced CHF. The more extensive alveolar septal remodeling seen in the aortic banding model is actually associated with decreased endothelial permeability (195).…”

“…However, chronic pulmonary capillary congestion alters the interstitial pressure-fluid volume relationship in a way that maintains a normal interstitial fluid pressure in the face of lung edema and does not change the lung content of glycosaminoglycans, hyaluronan, or collagen relative to bloodfree dry mass (203). However, because blood-free dry lung mass increases significantly in CHF (192,199,200,209), matrix deposition likely also increases. In acute lung injury or pulmonary fibrosis, glycosaminoglycan deposition precedes deposition of mature collagen; myofibroblasts in regions of increased glycosaminoglycan deposition also contain type I procollagen (210).…”