calcimycin and Cardiac-Output--Low

Alterations of vasoreactivity are a well-known phenomenon in chronic heart failure (CHF), and activation of the endogenous endothelin (ET) system is suspected to contribute significantly. Regional differences in alterations of vasoreactivity exist; however, nothing is known about cerebrovascular reactivity in CHF. This is of interest in view of increased stroke risk in CHF. Therefore, 12 weeks after coronary artery ligation to induce CHF in rats, studies of vasoreactivity of the isolated basilar artery (BA) were performed and compared with third-order branches (MA-A3) and the main trunk (MA) of the superior mesenteric artery. Some of the animals received long-term ET-receptor antagonism by 11 weeks of treatment with the selective ET(A)-receptor antagonist LU 135252 or the mixed ET(A)/ET(B)-receptor antagonist bosentan. In rats with CHF, endothelium-dependent relaxation by acetylcholine and A23187 as well as endothelium-independent relaxation by sodium nitroprusside (SNP) was largely unaffected in BA or MA. However, in MA-A3, potency of SNP was diminished without change of maximal effect. ET-1-induced contraction did not differ in arteries from CHF and control rats, either in placeboor ET-receptor antagonist-treated animals. In summary, there was essentially no change of vascular reactivity in similar sized arteries obtained from brain and mesentery. This is in contrast to results on arteries from a variety of vascular regions published previously, thus supporting the concept of organ- and probably time-related changes of vascular function in the development of CHF. The absence of significant alteration of cerebral vasoreactivity may be taken to indicate that changes in cerebral blood flow and increased incidence of ischemic stroke in patients with CHF are caused not by local alterations of vascular function.

Topics: Acetylcholine; Animals; Basilar Artery; Calcimycin; Cardiac Output, Low; Chronic Disease; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Male; Mesenteric Arteries; Nitroprusside; Rats; Rats, Wistar; Vasoconstriction; Vasodilation; Vasodilator Agents

We have previously shown that ANG II increases microvascular permeability in normal dog lungs but not after pacing-induced heart failure. This study investigated how ANG II induces permeability in isolated blood-perfused canine lung lobes and what alterations occur during heart failure. In normal lobes, the protein kinase C (PKC) inhibitors staurosporine (500 nM) or chelerythrine (10 microM) did not modify ANG II-induced increases in the capillary filtration coefficient (Kf,c, ml . min-1 . cmH2O-1 . 100 g-1; an index of microvascular permeability), suggesting that PKC is not involved. Thapsigargin (150 nM) was used to stimulate capacitative Ca2+ entry in lobes from control dogs and dogs paced at 245 beats/min for 4 wk to induce heart failure. In control lobes, Kf,c rose after thapsigargin, from 0.06 +/- 0.01 to 0.17 +/- 0.03 ml . min-1 . cmH2O-1 . 100 g-1 (mean +/- SE, P < 0.05) but did not change in the paced group. A Ca2+ ionophore, A-23187, increased Kf,c in both control (10 microM; 0.05 +/- 0.01 to 0.17 +/- 0.05 ml . min-1 . cmH2O-1 . 100 g-1, P < 0.05) and pace (5 microM; 0.06 +/- 0.01 to 0. 21 +/- 0.07 ml . min-1 . cmH2O-1 . 100 g-1, P < 0.05) lobes, indicating that increasing intracellular Ca2+ is sufficient to induce pulmonary microvascular permeability after pacing. We conclude that during heart failure, Ca2+ signaling within the pulmonary microvascular endothelium is altered.

Topics: Alkaloids; Angiotensin II; Animals; Benzophenanthridines; Calcimycin; Calcium; Capillary Permeability; Cardiac Output, Low; Cardiac Pacing, Artificial; Dogs; Endothelium, Vascular; Enzyme Inhibitors; Ionophores; Lung; Phenanthridines; Protein Kinase C; Signal Transduction; Staurosporine; Thapsigargin; Vascular Resistance

Abnormalities in vasomotor tone, including enhanced vasoconstriction at rest and diminished vasodilation in response to various stimuli, develop as a consequence of chronic heart failure. This study was undertaken to evaluate whether a specific local mechanism, namely endothelium-derived relaxing factor (EDRF) activity, might be impaired in an experimental model of chronic heart failure. Segments of thoracic aorta (TA) and pulmonary artery (PA) were isolated from a group of rats that had hemodynamic evidence of heart failure 10 weeks after ligation of the left coronary artery (n = 25) and from a group of sham-operated control rats (n = 18). Both endothelium-dependent and endothelium-independent vascular responses were assessed by exposing arterial segments to increasing concentrations of agonists. All studies were performed in the presence of 10 microM indomethacin to avoid the influence of vasoactive prostanoids. The dose-response curve for EDRF-mediated relaxation to acetylcholine was shifted rightward in rats with heart failure, and the concentrations of acetylcholine required to achieve 50% maximal relaxation (EC50) were increased compared with those of control rats in both TA and PA segments. Additionally, the dose-response curve for relaxation to ADP was shifted rightward with significantly increased EC50 in PA segments from rats with heart failure. In contrast, EDRF-mediated relaxation to the calcium ionophore A23187 was similar in the groups. Endothelium-independent relaxation to nitroglycerin was slightly increased in TA but not PA segments in the heart-failure group. Basal EDRF activity, as assessed by the increase in force after exposure to hemoglobin, was diminished in PA segments from rats with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylcholine; Adenosine Diphosphate; Animals; Aorta, Thoracic; Calcimycin; Cardiac Output, Low; Chronic Disease; Heart; Hemodynamics; Male; Nitric Oxide; Pulmonary Artery; Rats; Rats, Inbred Strains; Vasodilation