摘要:

&NA;Pinacidil belongs to a novel group of compounds that enhance the potassium permeability of vascular smooth muscle. Evidence also exists that this drug enhances the potassium permeability of cardiac tissue. The purpose of the present investigation was to determine if pinacidil alters potassium‐channel activity in heart and, if so, which potassium channel is the target. We used the whole‐cell arrangement of the patch voltage clamp to record membrane currents from isolated guinea pig ventricular cells. In solutions designed to isolate potassium currents, pinacidil enhances a time‐independent current positive to the potassium equilibrium potential. Current measured at voltages negative to the potassium equilibrium potential are essentially unaltered by the drug. The potassium sensitivity of outward current indicates that the target for the drug is a potassium channel. Experiments designed to test for voltage‐dependent channel gating strongly suggest that the pinacidil‐sensitive current is not voltage gated. Pinacidil‐sensitive current is blocked by externally applied Ba2+, Cs+, and tetraethylammonium ion. In addition, it is potently blocked after external application of 100 nM glibenclamide. Taken along with the time‐ and voltage‐independent properties of pinacidil‐sensitive current, this pharmacology strongly suggests that the target for pinacidil in heart is the ATP‐sensitive potassium channel. (Circulation Research1989;65:436‐445)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

&NA;The relation between functional properties of the contractile apparatus, such as shortening velocity and ATPase activity, and myosin isoenzyme composition was studied in ventricular myocardium of adult (60‐90‐day‐old) rats and of newborn (3‐day‐old) and young (10‐ and 20‐day‐old) rats. In adult animals, variations of isomyosin pattern were produced by reducing food intake and by changing the thyroid state. Hyperthyroidism was induced with triiodothyronine daily injection for 15 days; hypothyroidism was induced with iodine‐free diet and KCIO4in drinking water for 50‐60 days. The following parameters were studied: 1) calciummagnesium‐activated and magnesium‐activated ATPase activity of washed and purified myofibrils, 2) calcium‐activated ATPase activity of purified myosin, 3) isomyosin composition and relative content of &agr;‐myosin heavy chains (&agr;‐MHCs), and 4) force‐velocity curve of left and right ventricle papillary muscles. To take into account the difference in excitation‐contraction coupling between newborn and adult myocardium, the determination of the force‐velocity curve was repeated in Krebs' solution with normal [CaCl2] (2.5 mM) and in Krebs' solution with high [CaCl2] (10 mM). During postnatal growth, the relative content of &agr;‐MHC increased and reached a maximum at about 20 days. Pronounced increases of myofibrillar and myosin ATPase activity and in shortening velocity occurred during the same period. In adult hyperthyroid rats, &agr;‐MHC content as well as enzymatic activity and shortening velocity were higher than in control adult animals. Hypothyroidism and food deprivation caused a decrease of &agr;‐MHC content and a reduction of both enzymatic activities and shortening velocity. The study of the relations between &agr;‐MHC relative content and functional parameters showed that 1) in ventricular myocardium of adult rats a linear relation existed between &agr;‐MHC content and myosin and myofibrillar ATPase activity and shortening velocity, and 2) in newborn and young rat ventricular myocardium, both enzymatic activities and shortening velocity were lower than would have been expected on the basis of the linear relation described above. This latter observation could be accounted for by a variation in specific activity of myosin during postnatal development or by the presence of peculiar isomyosins that cannot be detected with usual electrophoretic techniques. (Circulation Research1989;65:446‐457)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

&NA;The purpose of this study was to determine whether the behavior of sonicated albumin microbubbles accurately mimics red blood cell flow in the microcirculation and is thus consistent with their use as in vivo tracers of red blood cell flow during myocardial contrast echocardiography. Accordingly, microbubbles prepared from fluorescein‐conjugated albumin and fluorescently labeled red blood cells were injected intravascularly in eight golden hamsters. Their intravascular distribution, velocities, arteriolar‐to‐venular transit times, and flux ratios at branch points were determined in the microcirculation of the cheek pouch. Albumin microbubbles (mean diameter, 4.9±3.6 &mgr;m) and red blood cells displayed a similar frequency of distribution across the arteriolar lumen (33% in the central 20% of the arterioles), and their arteriolar velocities were also similar (2.5±0.7 mm/sec and 2.3±0.7 mm/sec,p=NS). The mean velocities of microbubbles correlated well with those of red blood cells at baseline and after adenosine application (r=0.97 andr=0.89, respectively), as did the calculated maximum velocity (r=0.98 andr=0.80, baseline and adenosine, respectively). The velocity profiles across the lumen of the vessels for albumin microbubbles and red blood cells were similar at baseline and after adenosine‐induced velocity changes. The flux ratios at branch points also correlated well (r=0.92,p<0.001). Arteriolar‐to‐venular transit times of albumin microbubbles were similar to those of red blood cells in vessels ranging in size from 22 &mgr;m to 45 &mgr;m. We conclude that the behavior of albumin microbubbles in the microcirculation mimics that of red blood cells and supports their use as intravascular tracers of red blood cell flow during myocardial contrast echocardiography. (Circulation Research1989;65:458‐467)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

&NA;We used intraneural recordings of sympathetic nerve activity in conscious humans to determine if central command increases sympathetic discharge to resting skeletal muscle during static exercise. In nine healthy subjects, we measured arterial pressure, heart rate, and muscle sympathetic nerve activity with microelectrodes in the peroneal nerve of the resting leg during 1) static handgrip at 15% and 30% maximal voluntary contraction and 2) attempted handgrip during partial neuromuscular blockade produced by systemic administration of tubocurarine chloride (0.075 mg/kg i.v.). During curare, subjects reported that they used near‐maximal motor effort to attempt a sustained handgrip contraction, but they generated almost no force. Without sustained contraction, the intent to exercise alone, that is, central command, caused statistically significant (p<0.05) increases in muscle sympathetic nerve activity as well as in arterial pressure and heart rate. However, the increases in muscle sympathetic nerve activity (+56±16% over control) and in mean arterial pressure (+12±2 mm Hg) during attempted handgrip were much smaller (p<0.05) than the sympathetic nerve response (+217±37% over control) and pressor response (+25±3 mm Hg) during an actual static handgrip at 30% maximal voluntary contraction. In contrast, heart rate increased as much during the attempted contraction (+18±2 beats/min) as during the actual contraction at 30% maximal voluntary contraction (+16±4 beats/min). In 11 additional subjects, the heart rate responses during curare were greatly attenuated (p<0.05) by atropine but were not significantly affected by propranolol. From these observations, we conclude that during static handgrip in humans central command plays a major role in the regulation of parasympathetic outflow to the sinus node and a minor role in the activation of sympathetic outflow to nonexercising skeletal muscle. The new concept suggested by these data is that central command governs vagally mediated increases in heart rate at all levels of static exercise but contributes to activation of skeletal muscle sympathetic outflow only at near‐maximal levels of static handgrip. (Circulation Research1989;65:468‐476)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

&NA;Amiodarone has multiple pharmacological effects in heart. Electrophysiological data suggest that among its other effects, amiodarone is a sodium channel blocker. Using a radioligand assay, we determined whether amiodarone interacted with a previously described receptor for type I agents associated with the cardiac sodium channel. The radioligand was [3H]batrachotoxinin A 20&agr;‐benzoate ([3H]BTXB), a toxin that binds to the activated state of the sodium channel. We have previously shown that class I antiarrhythmic drugs inhibit [3H]BTXB binding. The purpose of this study was to assess whether amiodarone and other class III agents interact with this receptor. Amiodarone inhibited [3H]BTXB binding in a dose‐dependent fashion, with an estimated IC50value of 3.6 &mgr;M. This IC50value is similar to reported clinically effective serum concentrations of amiodarone. In contrast to amiodarone, the IC50values for other class III drugs (bretylium, sotalol, bethanidine,N‐acetylprocainamide) were much higher than their therapeutic concentrations and bore no relation to them. Scatchard analysis of [3H]BTXB binding showed that amiodarone reduced the maximal binding for [3H]BTXB; this finding indicates irreversible inhibition or (more likely) allosteric inhibition by amiodarone. The latter agrees with electrophysiological data suggesting that amiodarone binds to inactivated sodium channels. Sodium channel blockade by amiodarone may contribute to its overall electrophysiological effect. (Circulation Research1989;65:477‐482)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

&NA;To investigate coupling between the heart and arterial system in normal subjects and cardiac patients, we determined both the slope of the left ventricular end‐systolic pressure‐volume relation (ventricular elastance) and the slope of the arterial end‐systolic pressure‐stroke volume relation (effective arterial elastance) in three groups of subjects: group A, 12 subjects with ejection fraction of 60% or more; group B, seven patients with ejection fraction of 40‐59%; and group C, nine patients with ejection fraction of less than 40%. We also determined the left ventricular stroke work, end‐systolic potential energy, and the ventricular work efficiency defined as stroke work per pressure‐volume area (stroke work+potential energy). In group A, ventricular elastance was nearly twice as large as arterial elastance. This is a condition for a maximal mechanical efficiency. In group B, ventricular elastance was almost equal to arterial elastance. This is a condition for maximal stroke work from a given end‐diastolic volume. In group C, ventricular elastance was less than one half of arterial elastance, which resulted in increased potential energy and decreased work efficiency. Thus, the present study suggests that ventriculoarterial coupling is normally set toward higher left ventricular work efficiency, whereas in patients with moderate cardiac dysfunction, ventricular and arterial properties are so matched as to maximize stroke work at the expense of the work efficiency. Neither the stroke work nor the work efficiency is near maximum for patients with severe cardiac dysfunction. (Circulation Research1989;65:483‐493)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

&NA;The mammalian myocardium responds to stretch by increasing both contractility and the release of atrial natriuretic peptide. These effects are observed in isolated perfused heart preparations as well as in vivo. That atrial natriuretic peptide release can be stimulated by activation of the phosphatidylinositol turnover pathway suggests a possible mechanism by which stretch might activate a biological response. Accordingly, experiments were performed to examine the effect of dilatation of the right atrium on the phosphatidylinositol turnover pathway measured in isolated perfused hearts. Dilatation of the right atrium caused a stimulation of the phosphatidylinositol turnover pathway as measured by an increase in the accumulation of inositol phosphates. In right atria, increases were detected after 1 minute of dilatation, and maximal increases were observed after 10 minutes. Dilatation for 10 minutes caused an increase in inositol monophosphate, inositol bisphosphate, and inositol trisphosphate from 23.3±0.9, 15.4±0.4, and 9.5±0.3 cpm/mg tissue (mean±SEM,n=7) to 74.6±2.3, 20.2±1.3, and 13.6±1.5 cpm/mg tissue (n=8), respectively (p<0.01 for all inositol phosphates). Smaller increases were observed in the other chambers of the hearts. Perfusion with propranolol, prazosin, and atropine (all 1 &mgr;M) did not alter the inositol phosphate response to dilatation, indicating that it was not secondary to release of norepinephrine or acetylcholine. Dilatation of the right ventricle also caused a stimulation of inositol phosphate accumulation, but this was lower than after dilatation of the right atrium. These results show that the myocardium can respond to dilatation by an activation of the phosphatidylinositol turnover pathway. Such a mechanism has implications for the release of atrial natriuretic peptide and also provides a potential mechanism for the enhanced contractility after increased venous return. (Circulation Research1989;65:494‐501)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

&NA;We infused recombinant human tumor necrosis factor alpha (rhTNF&agr;), lymphotoxin (rhLT), andEscherichia coli0111:B4 lipopolysaccharide (LPS) into anesthetized sheep with a lung lymph fistula to compare their effects on systemic and pulmonary hemodynamics, lung lymph dynamics, and eicosanoid release. rhTNF&agr;(25‐150 &mgr;g/kg,n=6 sheep), but not rhLT (25 &mgr;g/kg,n=3), rapidly increased lung lymph and plasma levels of 6‐keto‐prostaglandin F1&agr;(6‐k‐PGF1&agr;) and caused profound systemic vasodilation and hypotension. Meclofenamate pretreatment (10 mg/kg) of three other sheep given 25 &mgr;g/kg rhTNF&agr;prevented the increase of lymph and plasma 6‐k‐PGF1&agr;levels, systemic vasodilation, and the early (<2 hrs) but not the late (4‐6 hours) hypotension caused by rhTNF&agr;. LPS (1 &mgr;g/kg,n=11) induced a briefer increase of lymph 6‐k‐PGF1&agr;levels than did rhTNF&agr;while plasma 6‐k‐PGF1&agr;levels did not increase. LPS induced more gradual hypotension than did rhTNF&agr;but did not cause systemic vasodilation. LPS and rhTNF&agr;, but not rhLT, increased lymph thromboxane B2(TXB2) levels during the first hour of study, whereas only LPS acutely increased plasma TXB2levels. LPS caused acute pulmonary vasoconstriction and greater acute pulmonary artery hypertension than did either rhTNF&agr;or rhLT. Whereas LPS‐treated sheep required less fluid transfusion than rhTNF&agr;‐treated sheep to maintain mean systemic arterial pressure greater than 50 mm Hg, LPS infusion caused a greater increase of lung lymph protein clearance. rhTNF&agr;caused minimal alterations of lung microvascular permeability. We conclude that eicosanoid mediators contribute importantly to differences of systemic and pulmonary hemodynamics caused by these agents in sheep. rhTNF&agr;cannot account for all of the LPS‐induced hemodynamic, lung lymph, and eicosanoid responses in sheep. (Circulation Research1989;65:502‐514)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

&NA;The actin dependence of the rate and magnitude of the initial phosphate burst was measured using both quench‐flow and stopped‐flow kinetic techniques. These studies revealed that even at high actin concentrations the magnitude of the phosphate burst was a significant fraction of the magnitude that exists in the absence of actin. Furthermore, it was shown that the rate of the burst rises rapidly as a function of the actin concentration. Detailed modeling with the four‐state model revealed that if the predicted Vmaxis constrained to be approximately equal to the extrapolated value (double reciprocal plot) and if the apparent dissociation constant of subfragment‐1 to actin divided by the apparent activation constant of the actin‐activated myosin ATPase activity (Kbinding/KATPase) is constrained to be considerably different from one, then the model is unable to simultaneously account for the ATPase activity and the rate and magnitude of the initial inorganic phosphate burst. (Circulation Research1989;65:515‐525)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID

摘要:

&NA;This study examined the possibility that the postischemic mechanical depression observed in the “stunned” myocardium is a result of an alteration in the control of intracellular calcium. Regional myocardial stunning was produced in five open‐chest dogs by eight to twelve 5‐minute occlusions of the left anterior descending coronary artery, alternated with 10‐minute reflow periods and followed by a final 60‐minute period of reperfusion. Systolic segment shortening in the postischemic zone, measured by sonomicrometry, fell from 14.9% at baseline to −1.1% at the end of reperfusion. Sarcoplasmic reticulum isolated from stunned myocardium demonstrated a 17% reduction in oxalate‐supported45Ca2+transport compared with sarcoplasmic reticulum from normal myocardium (0.93 vs. 1.12 &mgr;mol Ca2+/mg protein/min,p<0.005). There was also a 20% decrease in the maximal activation by Ca2+of the sarcoplasmic reticulum Ca2+,Mg2+‐ATPase (2.46 vs. 1.96 &mgr;mol Pi/mg protein/min,p<0.005), and a downward shift in the Ca2+‐activation curve of the Ca2+,Mg2+‐ATPase. These results indicate that myocardial stunning is associated with damage to the calcium‐transport system of the sarcoplasmic reticulum. Altered intracellular control may contribute to the inability of the stunned heart to maintain normal mechanical function. (Circulation Research1989;65:526‐530)

ISSN:0009-7330    

出版商:OVID    

年代:1989

数据来源: OVID