摘要:

&NA;Prolonged stimulation of tissues by adrenergic agonists may lead to diminished responsiveness of the tissues to subsequent activation by catecholamines; this phenomenon has been termed desensitization or tachyphylaxis. We have examined the in vivo consequences of prolonged stimulation of vascular &agr;‐adrenergic receptors in rats harboring pheochromocytoma, a tumor that secretes catecholamines. In both early (3‐4 weeks after implantation) and late (6‐7 weeks after implantation) stages of tumor development, New England Deaconess Hospital rats with transplanted pheochromocytomas developed hypertension and tachycardia and had plasma dopamine and norepinephrine concentrations markedly greater than controls. In both these stages of pheochromocytoma, pressor responses to several vasoconstrictors were examined after pithing. Rats with the tumor were found to become progressively subsensitive to &agr;‐adrenergic agonists. In the early phase of pheochromocytoma, loss in sensitivity was found for both &agr;1‐ and &agr;2‐adrenergic agonists, whereas responsiveness to the nonadrenergic vasoconstrictors Arg‐vasopressin and angiotensin‐II was intact (homologous desensitization). However, in the later stage of pheochromocytoma, pressor responses to all these vasoconstrictive agents and also to stimulation of the complex sympathetic outflow were found to be subsensitive (heterologous desensitization). In plasma membranes prepared from mesenteric arteries of early stage tumor‐bearing rats, [3H]prazosin binding sites were significantly decreased to 150 ± 12 fmol/mg vs. 234 ± 19 fmol/mg in controls. [3H]Yohimbine binding sites were not significantly altered. Our results show that both postjunctional &agr;1‐ and &agr;2‐adrenergic receptor‐mediated vasopressor responses can be specifically attenuated in the presence of chronically elevated endogenous catecholamine levels produced by pheochromocytoma and that each &agr;‐receptor subtype may be differentially regulated in the development of desensitization. (Circulation Research1987;61:86‐98)

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

&NA;This study investigated whether excision of either the right or left atrial appendage of rats alters their natriuretic response and the release of atrial natriuretic factor during acute blood volume expansion or reduction. These animals were subjected to a thoracotomy and either had their right or left atrial appendages removed or underwent a right or left atrial sham appendectomy for comparative, control purposes. Intrajugular vein, intracarotid artery, and intravesical catheters were installed 3‐4 weeks later under sodium pentobarbital anesthesia. Then, when the rats were conscious, blood volume was expanded using blood from donor rats once every 15 minutes in 3 increments of 10% of the calculated total blood volume at a rate of 5 ml/kg/min. Blood and urine samples were collected before volume expansion and at the end of each 15‐minute period, with the withdrawn blood being replaced. A maximal fourfold increase in urinary volume, urinary sodium excretion, and plasma atrial natriuretic factor was observed in all but the right‐atrial‐appendectomized animals. Plasma atrial natriuretic factor, urinary volume, and urinary sodium excretion were correlated in all 4 groups. No significant changes in blood pressure or hematocrit were noted. Plasma vasopressin, measured at the end of volume expansion, was significantly lower in animals subjected to left atrial appendectomy. Highperformance liquid chromatography of plasma from the control groups indicated that most of the released ANF during blood volume expansion corresponded to a high molecular weight peptide. Additional rats, processed as above, were subjected to 10% blood volume decrements. Urine and blood were collected before the blood volume reduction and at 15‐minute intervals after each of the 3 decrements of 10% volume. A gradual and marked decline in urinary volume and sodium excretion was seen in all 4 groups but only the control groups showed a significant lowering of plasma atrial natriuretic factor. Plasma vasopressin was equally high in all groups. A significant but negative correlation was evident between the plasma levels of atrial natriuretic factor and vasopressin (r= −0.51,p<0.01). Left atrial appendectomy induced a chronic elevation of systemic arterial blood pressure, which may represent a new model of experimental hypertension whose mechanisms remain to be investigated. It can be concluded that the right atrium, probably by releasing atrial natriuretic factor, may be involved in the short‐term regulation of blood volume, but other neural and hormonal systems (such as vasopressin) may play more important roles in volume conservation during hemorrhage. (Circulation Research1987;61:99‐106)

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

&NA;Left ventricular hypertrophy (LVH) was produced in guinea pigs after aortic stenosis (AS). The percentage of LVH in AS was determined by normalizing left ventricular (LV) weight by the mean LV weight of sham‐operated controls (n= 12). After 3 weeks of cardiac overload, a mild LVH (30 ± 3%) was induced in 17 animals and a relatively severe LVH (56 ± 3%) was induced in 7 animals. LV papillary muscles were rapidly excised for mechanical studies. No significant differences were observed between control and mild hypertrophy groups. In contrast, a marked decrease in myocardial performance was seen in the more severe cardiac hypertrophy group and was expressed as a percentage of sham‐operated levels (Vmax, 22%; active isometric force/mm2, 23%; + dF/dt max/mm2, 26%). Relaxation in this group was still more impaired than contraction (peak lengthening velocity, 14%; ‐ dF/dt max/mm2, 19%). Moreover, the load sensitivity of relaxation was present in both sham‐operated controls and mild hypertrophy but almost disappeared in more severe hypertrophy. Isometric relaxation was delayed in the latter group, as shown by the 15% increase of the half‐time of the decline of isometric relaxation (t½). On the other hand, acute hypoxia (95% N2‐5% CO2for 20 minutes) also induced a fall in contractility and the disappearance of the load sensitivity of relaxation but with a 67% decrease of t½. Thus, the mechanical analysis of relaxation allows the effects of chronic overload in relatively severe cardiac hypertrophy to be separated from those of acute hypoxia. Moreover, in severe cardiac hypertrophy, the impairment of the load sensitivity of relaxation with increased t½ strongly suggests alterations of the sarcoplasmic reticulum, especially since the moderate decrease in the myofibrillar ATPase activity, which has been observed previously in guinea pig pressure overload, cannot account completely for the marked fall in myocardial performance. (Circulation Research1987;61:107‐116)

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

&NA;The effects of exogenous and endogenous adenosine on exocytotic noradrenaline release were studied in rat hearts perfused in situ. Exocytotic release of endogenous noradrenaline (determined by high pressure liquid chromatography) was induced by electrical stimulation of the left cervicothoracic ganglion. Exogenous adenosine significantly reduced noradrenaline overflow from the heart. This suppression of noradrenaline overflow was not influenced by desipramine, indicating a mechanism independent from noradrenaline reuptake. The A1subtype specific agonists cyclohexyladenosine and R‐phenylisopropyladenosine had inhibitory effects at lower concentrations than adenosine and S‐phenylisopropyladenosine, suggesting the relevance of presynaptic inhibitory adenosine receptors of the A1subtype. Short ischemic periods of 3 minutes resulted in a marked coronary venous overflow of adenosine during reperfusion. This was accompanied by an inhibition of noradrenaline release evoked by nerve stimulation during ischemia. The adenosine antagonists theophylline and 8‐phenyltheophyl‐line prevented this suppression of noradrenaline release. Blockade of oxidative phosphorylation by cyanide in combination with glucose‐free perfusion induced an increased formation of endogenous adenosine and suppression of stimulation‐evoked noradrenaline overflow. Again, in the presence of the adenosine antagonists theophylline or 8‐phenyltheophylline, this suppression was abolished. These results indicate that adenosine is a potent inhibitor of exocytotic noradrenaline release in the heart with relevance during conditions of increased endogenous adenosine formation such as myocardial ischemia. (Circulation Research1987;61:117‐123)

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

&NA;Aftercontractions, delayed afterdepolarizations, and automaticity occurred in guinea pig papillary muscles that were reoxygenated after hypexic conditioning. The emergence of dysfunction was dependent on the severity of hypoxic conditioning and on stimulation during reoxygenation. After 60 minutes of substrate‐free hypoxia, reoxygenation induced automaticity in a high proportion of stimulated muscles; the automaticity appeared within 1 minute and lasted for 10‐20 minutes. After similar conditioning, muscles reoxygenated for 7‐15 minutes were stimulated at various cycle lengths. The incidence of automaticity and the amplitudes of delayed events had W‐shaped dependencies on cycle length (200‐1,000 msec), whereas coupling intervals had M‐shaped dependencies. In ventricular myocytes that displayed automaticity after reoxygenation, extrasystolic upstrokes arose smoothly from delayed afterdepolarizations that reached threshold. In tissue, extrasystolic upstrokes usually rose sharply from delayed afterdepolarizations that were distinctly subthreshold. Thus, threshold was reached elsewhere in the tissue. Further evidence of electrical heterogeneity was obtained from surface mapping of delayed‐afterdepolarization amplitude in reoxygenated muscle. There were no detectable aftercontractions, delayed afterdepolarizations, or signs of automaticity in quiescent reoxygenated muscles or in stimulated reoxygenated muscles that were treated with 1 μM ryanodine. We conclude that the dysfunction precipitated by reoxygenation is due to synchronized spontaneous releases of calcium from overloaded sarcoplasmic reticulum. (Circulation Research1987;61:124‐133)

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

&NA;Previous studies have indicated that the hypotensive effects of atrial natriuretic factor were enhanced in renin‐dependent hypertensive rats, suggesting that the atrial peptides may antagonize the vasoconstrictor effects of the renin‐angiotensin system. The present study was designed to define further the interaction between atrial natriuretic factor and the renin‐angiotensin system by examining the hemodynamic effects of Wy‐47,663, a synthetic human atrial natriuretic factor, in conscious normotensive rats, in renin‐dependent (aortic‐ligated) hypertensive rats, and in rats made hypertensive by chronic infusion of angiotensin II. Changes in renal and mesenteric blood flow were continuously monitored in the rats using pulsed Doppler flow probes chronically implanted in the animals one week prior to testing. Infusion of increasing doses of Wy‐47,663 caused dose‐dependent reductions in mean arterial pressure in all three groups of rats, but the depressor responses were significantly greater in renal hypertensive and angiotensin II‐infused rats. Renal blood flow tended to increase during the infusion of the atrial peptide in the angiotensin II‐treated rats, and renal vascular resistance fell significantly (− 37 ± 6%). However, Wy‐47,663 significantly reduced renal blood flow in the normotensive and renal hypertensive rats, while renal vascular resistance was increased (29 ± 6%) and unchanged (3 ± 9%), respectively. Mesenteric blood flow was reduced significantly, and mesenteric vascular resistance was increased markedly in all three groups of rats during infusion of the atrial peptide. In a separate group of renal hypertensive rats, the hemodynamic effects of complete blockade of the renin‐angiotensin system were assessed by injection of an angiotensin II converting enzyme inhibitor (Wy‐44, 655). In contrast to the hemodynamic effects of Wy‐47,663, inhibition of converting enzyme activity in the renal hypertensive rats significantly increased renal and mesenteric blood flow and reduced regional vascular resistance in both vascular beds. Since renal vasodilation and hypotension were observed during infusion of Wy‐47,663 into rats whose hypertension was mediated purely through the pressor effects of angiotensin II, these data suggest that the atrial peptides are capable of suppressing the renal vasoconstrictor actions of angiotensin II in conscious rats. However, the data indicate further that overall hemodynamic responses to Wy‐47,663 in the renal hypertensive rats were not mediated solely through antagonism of the vasoconstrictor actions of the renin‐angiotensin system, as typified by converting enzyme inhibition. (Circulation Research1987;61:134‐140)

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

&NA;Ultrarapid freezing has been applied to monitor the structure of the freeze‐fractured myocardial sarcolemma. Our two goals were 1) to demonstrate that large areas of membrane can be preserved free of visible ice crystal damage and, thus, be amenable to quantitative analysis and 2) to compare the structure of directly frozen myocardial membranes with conventionally prepared tissue. The E face was most affected by lack of chemical pretreatment. First, our laboratory reported an increase in E face particle density from 379 ± 30/μm2in conventional fixed tissue to 489 ± 18/μm2in unpretreated tissue. Discrete arrays of 12‐15 nm particles on the E face were a striking feature of the unfixed sarcolemma. However, P face intramembrane particle (IMP) density remained unchanged from previous estimates in fixed tissue. Specialized regions of the sarcolemma were enhanced in ultrarapidly frozen tissue. Particle domains of the adherens junctions were very prominent in forming a cap alongside the gap junctions. Both the P and E faces of the gap junctions were highly ordered into hexagonal arrays. Caveolae in the membrane were infrequent in both P and E faces. (Circulation Research1987;61:141‐147)

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

摘要:

&NA;[Ca2+]itransients, elicited by voltage‐clamp depolarization of single guinea pig cardiac ventricular cells, were observed through use of the fluorescent Ca2+indicator, fura‐2. Individual cells, loaded with fura‐2 either by internal perfusion or by exposure to fura‐2/AM, were studied with the use of an inverted microscope that was equipped with ultraviolet epifluorescence illumination, an intensified silicon intensifier target camera, and a photomultiplier tube. Variation of membrane voltage and exposure of cells to verapamil (a Ca2+channel blocker) and ryanodine (which was assumed to abolish selectively the release of Ca2+from the sarcoplasmic reticulum) were used to investigate the cellular processes that determine the [Ca2+]itransient. The principal results of the study are: 1) When appropriate methods are used, the properties of cytosolic fura‐2 inside guinea pig cells are similar to those of fura‐2 in solution, irrespective of the method of loading. 2) The amplitude (at 100 msec) of verapamil‐sensitive fluorescence transients elicited by pulse depolarization (range ‐30 to 80 mV) has a bell‐shaped dependence on membrane voltage (maximum at 10 mV). 3) Rapid, ryanodine‐sensitive and verapamil‐sensitive “tail transients” are elicited on repolarization from membrane potentials greater than 30 mV; their amplitude increases as the amplitude of the preceding pulse increases. 4) The amplitude of slow fluorescence transients that are insensitive to verapamil and ryanodine increases continuously with membrane potential throughout the range − 20 to 80 mV. The voltage dependence and pharmacology of the rapid transients elicited by pulse depolarization or by repolarization are consistent with their having arisen from Ca2+released from the sarcoplasmic reticulum, via Ca2+‐induced Ca2+release. The [Ca2+]itransients remaining in the presence of ryanodine and verapamil may arise from Ca2+entering via the sodium‐calcium exchanger. (Circulation Research1987;61:148‐154)

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID

ISSN:0009-7330    

出版商:OVID    

年代:1987

数据来源: OVID