The effects of endothelin-A receptor blockade during the progression of pacing-induced congestive heart failure.

OBJECTIVES: We sought to identify the effects of endothelin (ET) subtype-A (ET(A))) receptor blockade during the development of congestive heart failure (CHF) on left ventricle (LV) function and contractility. BACKGROUND: Congested heart failure causes increased plasma levels of ET and ET(A) receptor activation. METHODS: Yorkshire pigs were assigned to four groups: 1) CHF: 240 beats/min for 3 weeks; n=7; 2) CHF/ET(A)-High Dose: paced for 2 weeks then ET(A) receptor blockade (BMS 193884, 50 mg/kg, b.i.d.) for the last week of pacing; n=6; 3) CHF/ET(A)-Low Dose: pacing for 2 weeks then ET(A) receptor blockade (BMS 193884, 12.5 mg/kg, b.i.d.) for the last week, n=6; and 4) CONTROL: n=8. RESULTS: Left ventricle fractional shortening decreased with CHF compared with control (12+/-1 vs. 39+/-1%, p < 0.05) and increased in the CHF/ET(A) High and Low Dose groups (23+/-3 and 25+/-1%, p < 0.05). The LV peak wall stress and wall force increased approximately twofold with CHF and remained increased with ET(A) receptor blockade. With CHF, systemic vascular resistance increased by 120%, was normalized in the CHF/ET(A) High Dose group, and fell by 43% from CHF values in the Low Dose group (p < 0.05). Plasma catecholamines increased fourfold in the CHF group and were reduced by 48% in both CHF/ET(A) blockade groups. The LV myocyte velocity of shortening was reduced with CHF (32+/-3 vs. 54+/-3 microm/s, p < 0.05), was higher in the CHF/ET(A) High Dose group (39+/-1 microm/s, p < 0.05), and was similar to CHF values in the Low Dose group. CONCLUSIONS: ET(A) receptor activation may contribute to the progression of LV dysfunction with CHF.

Changes in L-type calcium channel abundance and function during the transition to pacing-induced congestive heart failure.

OBJECTIVE: The development of congestive heart failure (CHF) is accompanied by left ventricular (LV) and myocyte contractile dysfunction. However, time-dependent cellular and ionic events which contribute to the initiation and progression of CHF remain unclear. This study tested the central hypothesis that changes in L-type Ca2+ channel current (ICa) and abundance (Bmax) are early events in the transition to CHF. METHODS: LV fractional shortening by echocardiography, isolated LV myocyte shortening velocity by videomicroscopy, ICa by voltage-clamp, and Bmax by [3H]nitrendipine binding were determined at each week during the progression of pacing-induced CHF in pigs (240 bpm; n = 6/week for 3 weeks). Myocyte and L-type Ca2+ channel function were determined under basal conditions and after beta-adrenergic receptor stimulation with 25 nM isoproterenol. RESULTS: After 1 week of pacing, myocyte and L-type Ca2+ current responses to beta-adrenergic receptor stimulation were reduced by 20% from control values and was accompanied by over a 210% increase in plasma catecholamine levels. After 2 weeks of pacing, reductions in LV fractional shortening and myocyte shortening velocity from control values (20 +/- 1 vs. 34 +/- 2% and 36.7 +/- 2.9 vs. 50.6 +/- 2.4 microns/s, respectively, P < 0.05) were paralleled by decreased ICa (2.47 +/- 0.10 vs. 3.63 +/- 0.25 pA/pF, P < 0.02) and Bmax (149 +/- 16 vs. 180 +/- 12 fmol/mg, P < 0.03). After 3 weeks of pacing, LV fractional shortening was reduced by over 50%, myocyte shortening velocity by 37%, and ICa and Bmax were reduced by over 25% from control values. Furthermore, after 3 weeks of pacing, the ICa/Bmax ratio was reduced from control values (16.2 +/- 0.9 vs. 20.6 +/- 1.2 [fA/pF]/[fmol/mg], P < 0.03), which suggests functional defects in the remaining L-type Ca2+ channels. CONCLUSIONS: An early event during the transition to pacing-induced CHF was diminished beta-adrenergic receptor augmented L-type Ca2+ current, which was followed by an absolute loss of steady-state L-type Ca2+ current and channel abundance. The development of severe CHF was accompanied by a loss of Ca2+ carrying capacity through residual channels. These unique findings suggest that a contributory molecular mechanism for the initiation and progression of CHF is changes in the structure and function of the L-type Ca2+ channels.

Fate of gelatin-resorcinol-formaldehyde/glutaraldeyde adhesive on femoral vessel morphology.

Several clinical reports have demonstrated that gelatin-resorcinol-formaldehyde/glutaraldehyde (GRFG) glue can be useful in the repair of acute aortic dissection; however, the cellular and extracellular events that follow GRFG application, as well as the mechanisms responsible for the long-term strength and adhesive properties of GRFG, remain unclear. Accordingly, the present study examined the long-term effects of GRFG adhesive application on femoral vessel extracellular structure and composition. The left and right femoral artery and vein were sterilely exposed in adult rats, and GRFG (2 mL) was applied between and around one pair of vessels. An equivalent amount of sterile saline was applied to the contralateral vessels to serve as an intrinsic control. At either 1 (n = 6) or 2 (n = 6) months postoperatively, the lower extremities were perfusion fixed and harvested to preserve the native anatomy and cytoarchitecture of the femoral region. Gross examination of the specimens revealed no evidence of necrosis or wound breakdown. Tissue blocks (4 microm) were then sectioned perpendicular to the treated vessel region and subjected to histomorphometric analysis using computer-assisted microscopy. The perivascular capsule area, relative content of fibrillar collagen, and number of nucleated cells within the interstitial space were computed. At 1 and 2 months following the application of GRFG adhesive, perivascular capsular size increased by 42 and 221%, respectively. Perivascular interstitial collagen content increased by 21% at 1 month and by 50% at 2 months. The nucleated cell number increased by 107% at 1 month and by 166% at 2 months. This cellular infiltrate appeared to be of fibroblastic morphology. Thus, a potential contributory mechanism to the long-term strength and adhesive capacities of GRFG adhesive may be extracellular remodeling and not the intrinsic properties of GRFG glue itself.