摘要:

Reduced preload and afterload to the heart are important effects of angiotensin converting enzyme (ACE) inhibitors in the treatment of congestive heart failure. However, since angiotensin II (Ang II) directly increases the strength of myocardial contraction, suppression of Ang II formation by ACE inhibitors could potentially reduce the beneficial effects of Ang H on the failing heart. To study how ACE inhibition suppresses cardiac Ang II formation in man, we characterized ACE-dependent and ACE-independent Ang II-forming pathways in eight normal and 24 failing human hearts obtained at cardiac transplantation. Ang II-forming activity in left ventricular (LV) membrane preparations was assessed by measuring, the conversion of [125I] angiotensin I (Ang I) to [125I]Ang II. LV [125I]Ang II-forming activity in normal hearts (35.5±2.7 fmol/min/mg, n=8) was not different from that in hearts from patients with ischemic cardiomyopathy (25.5±2.9 fmol/min/mg,n=9) and was 48% lower (p< 0.001) in hearts from patients with idiopathic cardiomyopathy (18.5±+1.9 fmol/min/mg,n=15). In LV tissue from normal hearts and in hearts from patients with idiopathic and ischemic cardiomyopathy, the ACE inhibitor captopril (1 mM) inhibited total [125I]Ang II-forming activity by 11±4%, 11±3%, and 4±3%, respectively (p< 0.05 for each group), illustrating that ACE is not the major Ang II-forming enzyme in the LV. In LV tissue from normal hearts and in hearts from patients with idiopathic and ischemic cardiomyopathy, the serine proteinase inhibitor (soybean trypsin inhibitor, 100 μg/ml) inhibited total [125I]Ang II-forming activity by 80±3% in all three groups (p< 0.001 for each group), further illustrating that the majority of [125I]Ang II-forming activity in the LV is due to one or more membrane-bound serine proteinases. In normal human serum (n=5), [125I] Ang II formation was completely inhibited by 1 mM captopril and was not inhibited by 100 μg/ml soybean trypsin inhibitor. These in vitro studies suggest that chronic ACE inhibitor therapy may decrease angiotensinergic input to the vessels by inhibiting Ang II formation in blood. Since plasma Ang I levels are markedly elevated during chronic ACE inhibitor therapy and our studies show that the heart's major enzymatic pathway for Ang II formation is not blocked by ACE inhibitors, it seems likely that cardiac Ang II formation is not abolished during chronic therapy. The latter suggests sustained or even enhanced inotropic benefit of angiotensin in the heart in the face of circulating renin-angiotensin system blockade with ACE inhibitors.

ISSN:0009-7330    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

We examined the hypothesis that the positive inotropic effect of angiotensin I (Ang I) may be retained in the presence of angiotensin converting enzyme inhibitors so that it may have a direct beneficial effect on the heart. Accordingly, isolated perfused hearts (Langendorff preparation) of 300-day-old cardiomyopathic hamsters (a model of spontaneous cardiomyopathy) and age-matched normal hamsters (controls) were infused with Ang I in the presence of captopril; propranolol was added to the perfusing medium to block catecholamine-mediated effects of angiotensins on the heart. Left ventricular developed pressure and the rate of increase in left ventricular developed pressure increased significantly (p< 0.01) in both the cardiomyopathic and the normal hamster heart despite concomitant reduction in myocardial flow rate favoring a direct inotropic effect of Ang I in both normal and myopathic hearts; these changes were significantly higher by almost threefold in the cardiomyopathic than in the normal hamsters (p< 0.01) and were blocked by the angiotensin II (Ang II) antagonist [Sar1,Thr8]Ang II. Comparing dose-left ventricular contractility response curves for Ang I and Ang II, ED50for responses was identical in both normal and myopathic hearts, whereas peak responses to Ang II were double those to Ang I in normal hearts but were almost identical in the myopathic hearts. Binding of [125I]Ang II in six cardiomyopathic and four normal hamster hearts was of high affinity, but there was no evidence for Ang I-saturable high-affinity binding sites. Therefore, we suggest that the positive inotropic effect of Ang I, in the presence of captopril, is not via a direct effect on either Ang I or Ang II receptors but most probably via conversion of Ang I to Ang II or another intermediate peptide that was mediated by an alternative converting enzyme. The positive inotropic effect of Ang I and, to a lesser extent, Ang II was accentuated in the myopathic compared with the normal hamster hearts; this finding suggests that Ang I conversion is increased in the diseased heart and that elevated levels of circulating Ang I during therapy with angiotensin converting enzyme inhibitors may be of direct benefit to the failing heart.

ISSN:0009-7330    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Knowledge about the distribution and origins of peptide-containing nerves in the innervated and transplanted heart is lacking. Immunohistochemical and histochemical techniques were used to visualize human cardiac innervation before and after transplantation. In the recipient heart cardiac nerve fibers and fascicles displayed immunoreactivity for general neural (protein gene product 9.5 and synaptophysin) and Schwann cell markers (S-100). A major proportion of cardiac nerves displayed neuropeptide tyrosine and tyrosine hydroxylase immunofluorescence staining. Subpopulations of nerves contained somatostatin, vasoactive intestinal polypeptide, calcitonin gene-related peptide, substance P- or neurokinin-like immunoreactivity, and acetylcholinesterase activity. Tissues from cardiac allografts (5 weeks to 63 months after transplantation) contained nerves and ganglion cells that were acetylcholinesterase positive and immunoreactive for the general neural markers. These nerves were less numerous than in recipient hearts and rarely displayed neuropeptide immunostaining. Atrial natriuretic peptide immunoreactivity was localized to myocardial cells in transplanted hearts as well as explanted recipient and postmortem hearts. While most human cardiac allografts remain functionally extrinsically denervated, they appear to contain viable intrinsic nerves, and myocardial cells retain the capacity to produce atrial natriuretic peptide.

ISSN:0009-7330    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

We have shown previously that preconditioning myocardium with four 5-minute episodes of ischemia and reperfusion dramatically limited the size of infarcts caused by a subsequent 40-minute episode of sustained ischemia. The current study was undertaken to assess whether the same preconditioning protocol slowed the loss of high energy phosphates, limited catabolite accumulation, and/or delayed ultrastructural damage during a sustained ischemic episode. Myocardial metabolites and ultrastructure in the severely ischemic subendocardial regions were compared between control and preconditioned canine hearts. Hearts (four to 10 per group) were excised after 0, 5, 10, 20, or 40 minutes of sustained ischemia. All groups had comparable collateral blood flow. Preconditioned hearts developed ultrastructural injury more slowly than controls; evidence of irreversible injury was observed after 20 minutes in controls but not until 40 minutes in preconditioned hearts. Furthermore, after 40 minutes of ischemia, irreversible injury was homogeneous in controls but only focal in preconditioned myocardium. Preconditioning reduced starting levels of ATP by 29%. Nevertheless, it also slowed the rate of ATP depletion during the episode of sustained ischemia, so that after 10 minutes of ischemia, preconditioned hearts had more ATP than controls. However, after 40 minutes, ATP contents were not significantly different between groups. Preservation of ATP resulted from reduced ATP utilization and was not due to increased ATP production. Accumulation of purine nucleosides and bases (products of adenine nucleotide degradation) was limited in preconditioned myocardium. Accumulation of glucose-1-phosphate, glucose-6-phosphate, and lactate also was reduced markedly by preconditioning, due to reduced rates of glycogen breakdown and anaerobic glycolysis. We propose that preconditioning reduces myocardial energy demand during ischemia, which results in a reduced rate of high energy phosphate utilization and a reduced rate of anaerobic glycolysis. Either preservation of ATP or reduction of the cellular load of catabolites may be responsible for delaying ischemic cell death.

ISSN:0009-7330    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

The platelets from 74 patients with acute myocardial infarction or with unstable angina showed decreased prostaglandin E1/I2receptor activity when compared with that of 56 normal volunteers by using [3H]prostaglandin E1as a probe. In normals, Scatchard analyses showed the presence of one high-affinity-low-capacity (KD1=9.0±1.2 nM [mean±SD];n1=120±30 sites/cell) and one low-affinity-high-capacity (KD2=1.1±0.5 μM;n2=1,460±250 sites/cell) prostaglandin E1/I2receptor population in platelets. In contrast (p< 0.01), platelets from patients showed decreased ligand binding (n1=40±20 sites/cell;n2=800±210 sites/cell) with little change in the affinity of the receptors (KD1=7.50±1.6 nM;KD2=0.68±0.24 μM). On the other hand, the platelets from the patients with dilated cardiomyopathy (n=7) who were hospitalized for acute chest pain but had normal coronary arteries did not show any impairment of the receptor activity. The plasma prostacyclin level of the patients with acute ischemic heart disease was similar to that of normal volunteers; this finding indicated that the defective receptor function was not related to the prostaglandin receptors occupancy in vivo. The impaired receptor activity was temporary in nature. The follow-up studies showed that the prostaglandin receptor activity of the patients' platelets improved to “normal” levels within 2–8 weeks. The decreased prostaglandin E1binding to its receptors in the platelets from acute ischemic heart disease also resulted in the similar reduction of the formation of cyclic AMP by 1.0 μM prostaglandin E1(7.5±2.0 pmol/108cells [mean±SD]) when compared with the control platelets (16.35±0.91 pmol/108cells). These results show that the defective prostaglandin E1/I2receptors of platelets are probably pathophysiologically more important than the altered synthesis of prostacyclin in acute ischemic heart disease.

ISSN:0009-7330    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

The role of hemodynamics on platelet thrombus formation was studied in venules and arterioles of the rat mesentery. Thrombus formation was induced by the fluorescent dye/light method for examination of the following factors: 1) the effect of wall shear rate on thrombus initiation, 2) the effect of wall shear rate on the growth of thrombi, and 3) the relation between platelet thrombus initiation and intraluminal velocity profile. The range of wall shear rate was up to approximately 1,000 l/sec in venules and from 640 to 2,900 l/sec in arterioles. Platelet thrombus initiation occurred more rapidly at higher wall shear rate in venules and at lower wall shear rate in arterioles. Thrombus initiation time was shortest around a wall shear rate of 900 1/sec in venules and around 700 l/sec in arterioles. Thrombus growth rate in venules was greatest at a wall shear rate of 1,500–2,000 1/sec. Thrombus initiation and its relation to blood flow was also examined in branched and curved microvessels. In these vessels platelet thrombi were also first initiated at the sites of higher wall shear rate in venules and of lower wall shear rate in arterioles.

ISSN:0009-7330    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

The effect of ischemia on cholinergic presynaptic inhibition of exocytotic norepinephrine release was studied in the innervated perfused rat heart. In normoxic hearts, vagal nerve stimulation significantly reduced exocytotic norepinephrine overflow to 75% of control values. This inhibitory effect was not affected by 3 minutes of low-flow ischemia (67% of control overflow values), but was attenuated or abolished by 10-minute low-flow ischemia or by 1-, 3-, and 5-minute stop-flow ischemia (107%, 85%, 101%, and 120% of control overflow values, respectively). The α-adrenergic antagonist phentolamine could completely or partly restore the failure of vagally induced inhibition of norepinephrine overflow in hearts with 1-, 3-, and 5-minute stop-flow ischemia (72%, 73%, and 85% of control overflow values, respectively). The muscarinic agonist methacholine substantially inhibited norepinephrine overflow to 18% of control overflow values in normoxic hearts. This effect was also significantly attenuated by 10-minute low-flow ischemia or by 1-, 3-, and 5-minute stop-flow ischemia (46%, 38%, 53%, and 55% of control overflow values, respectively). The cholinesterase inhibitor physostigmine did not restore the methacholine-induced inhibition of norepinephrine overflow after 3-minute stop-flow ischemia to normoxic level (55% vs. 17%). These results indicate that myocardial ischemia interferes with endogenous and exogenous cholinergic presynaptic inhibition of norepinephrine overflow in the rat heart. The extent of this attenuation depends on the severity and duration of ischemia. Reduced exocytotic acetylcholine release, which is at least in part due to an enhanced adrenergic presynaptic modulation, and dysfunction of presynaptic muscarinic receptors are suggested as two possible mechanisms.

ISSN:0009-7330    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Elevation of cellular cyclic AMP by agents such as isoproterenol plus 3-isobutyl-1-methylxanthine produced rapid and reversible dendritic formation of bovine pulmonary artery endothelial cells in the monolayer. The effect did not occur with exposure of the cells to a variety of other vasoactive agents, calcium ionophore, phorbol ester, or cyclic GMP. The cyclic AMP-induced configurational change was completely inhibited by 2.5 mMN-phenylanthranilic acid or 145 mM sodium gluconate (Cl−channel inhibitors) and was partially inhibited by 2.5 mM 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS), but it was not affected by deprivation of Ca2+or Na+ion, 1 mM bumetanide (Cl−cotransport inhibitor), 1 mM amiloride (Na+/H+exchange inhibitor), 0.1 mM verapamil (Ca2+channel inhibitor), or 5 mM BaCl2(K+channel inhibitor), by change in cellular pH, or by pertussis toxin. Trifluoperazine (calmodulin inhibitor, 50 μM), 1 mM EGTA plus 100 μM 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8, intracellular Ca2+antagonist), and 5 μM cytochalasin B also produced cellular retraction, but these changes were not blocked by chloride channel inhibition. In the presence of 0.1 mM ouabain plus 0.1 mM bumetanide,36Cl−uptake was decreased by isoproterenol plus isobutylmethylxanthine while its efflux was enhanced.N-Phenylanthranilic acid inhibited the stimulated efflux. We conclude that cyclic AMP induces a configurational change of endothelial cells that is related to Cl−efflux from the cells; the cellular effects may play a role in vascular function.

ISSN:0009-7330    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

We evaluated the processes controlling the accumulation of collagen and elastin in main pulmonary arteries of rats during an episode of hypoxic pulmonary hypertension. Explant cultures of main pulmonary arteries were incubated with [3H]proline to measure collagen and protein synthesis and percent collagen synthesis. Elastin synthesis was measured by [14C] valine incorporation into insoluble elastin. Relative collagen synthesis increased twofold (from 1.1±0.2×103to 2.0±1.0×103disintegrations per minute [14C]hydroxyproline/vessel/hr/mg protein), relative collagen synthesis doubled (from 2% to 4–5% of total protein synthesis), and elastin synthesis increased ninefold (from 0.4±0.2×104to 3.6±0.6×104dpm [14C]valine/vessel/hr/mg protein) in early hypertension. The level of pro αl(I) collagen RNA paralleled the relative collagen synthetic rate during the study period. Within 7 days of recovery from hypoxia, collagen and elastin contents were normal. We conclude that collagen and elastin in main pulmonary arteries are synthesized rapidly during an episode of hypoxic pulmonary hypertension and that collagen and elastin are rapidly removed from the hypertensive vessel during normoxic recovery.

ISSN:0009-7330    

出版商:OVID    

年代:1990

数据来源: OVID

摘要:

Although pressure overload induces cardiac hypertrophy and reexpression of contractile protein isogenes, the molecular mechanism of both is not well understood. We demonstrated the early change in the translational activity of specific cardiac messenger RNA by two-dimensional gel electrophoresis of in vitro translational products. A total of over 400 translational products were detected by fluorography, and the relative predominance of eight species was increased by pressure overload whereas that of two translational products was decreased. We cloned four pressure-overload-responsive complementary DNA clones, pPO-1, −4,−5, and −6, by differential dot blot hybridization. Two clones were increased from the early period after the imposition of pressure overload; the other two were decreased. The expression pattern of each complementary DNA clone in the pressure-overloaded hearts was similar to that in fetal hearts. Pressure overload also induced the additional messenger RNA, which hybridized with pPO-4. This mRNA was also recognized in fetal, neonatal, and adult spontaneously hypertensive rat hearts. The induction of this transcript by pressure overload was not suppressed but, rather, stimulated by cycloheximide. These results suggest that there are some genes that rapidly respond to pressure overload and that may play some role in the development of cardiac hypertrophy.

ISSN:0009-7330    

出版商:OVID    

年代:1990

数据来源: OVID