ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Effects of [Ca2+] on isometric tension and unloaded shortening velocity were characterized in single chemically skinned myocytes from frog atrium and in mechanically disrupted myocardium from rat ventricle. The preparations were attached to a force transducer and piezoelectric translator and were viewed with an inverted microscope to allow continuous monitoring of sarcomere length during mechanical measurements. Unloaded shortening velocity was determined by measuring the time required to take up various amounts of slack imposed at one end of each preparation. Ca2+sensitivity of isometric tension was assessed as pCa50, i.e., the Ca2+concentration at which tension was 50% maximal, and was greater for frog atrial myocytes (pCa506.17) than for rat ventricular myocytes (pCa506.06). This difference in Ca2+sensitivity may be due to variations in myofibrillar protein isoform composition in the two preparations. Inclusion of caffeine in the activating solutions substantially increased the Ca2+sensitivity of tension, which may be a manifestation of a direct effect of caffeine on the myofibrillar proteins. Unloaded shortening velocity during maximal activation averaged 4.32 muscle lengths per second in frog atrial myocytes and 4.46 muscle lengths per second in rat ventricular myocytes. When [Ca2+] was reduced, unloaded shortening velocity decreased substantially in both preparations. Possible mechanisms for the effect of Ca2+on shortening velocity in myocardium include Ca2+dependence of the rate of ADP dissociation from actomyosin complexes or a shortening-dependent internal load involving structures such as C protein or long-lived myosin cross-bridges. (Circulation Research1992;70:885–892)

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

We examined the mechanism(s) of hypotensive action of platelet-activating factor (PAF) in anesthetized dogs. PAF (0.5 μg/kg i.v.) caused a biphasic hypotension; the first phase was transient and was accompanied by a decrease in systemic vascular resistance and an increase in cardiac output. Aspirin-DL-lysine, a cyclooxygenase inhibitor, had no effect on this phase. The second phase was characterized by a sustained hypotension caused by a reduction in cardiac output and was accompanied by an increase in systemic and pulmonary vascular resistance. The plasma concentrations of 6-ketopros-taglandinF,. and thromboxane B2also increased. These changes were markedly attenuated by aspirin. Both atrial pressures decreased during the second phase, thereby indicating that the PAF-induced reduction in cardiac output was related to a hindrance in venous return. The hematocrit increased, and aspirin did not affect this change. The extravasation of plasma probably plays a minor role, whereas venodilation would be the primary mechanism of the second-phase hypotension. S-1452, a prostaglandin H2/thromboxane A2antagonist, abolished the PAF-induced pulmonary vasoconstriction but did not block the hypotensive action of PAF. OKY-046, a thromboxane A2synthetase inhibitor, almost completely abolished the PAF-induced pulmonary vasoconstriction and the increase in plasma thromboxane B2level, whereas it potentiated the hypotension and the increase in the plasma concentrations of prostaglandins; aspirin abolished this potentiation. These results suggest that PAF causes hypotension by two different mechanisms: 1) dilatation of resistance vessels independent of prostaglandins and 2) reduction of venous return due to venodilation, as mediated by prostaglandin(s). (Circulation Research1992;70:893–901)

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Recent work has shown that alterations in the dynamic atrioventricular (AV) nodal response to changes in heart rate can significantly modify AV nodal function. The present study was designed to evaluate the nature and potential importance of sympathetic regulation of the rate-dependent properties of the AV node. Selective stimulation protocols and mathematical formulations were used to independently quantify AV nodal recovery, facilitation, and fatigue in 12 morphine-chloralose-anesthetized dogs. Vagal effects were prevented by bilateral vagal transection and intravenous atropine, and the sinus node was crushed to allow a broader range of pacing cycle lengths. In seven dogs with sympathetic nerves intact, β-adrenergic receptor blockade increased the recovery time constant (τrec) for the conduction of premature test beats from 47 ± 2 (mean ± SEM) msec (control) to 62 ± 1 msec (p < 0.001), whereas isoproterenol decreased τrecto 38 ± 1 msec (p<0.001). In addition, β-blockade increased the maximum amount of rate-dependent AV nodal fatigue from 7 ± 1 msec (at a cycle length of 198 ± 9 msec [control]) to 17 ± 2 msec (p<0.001). In five dogs with decentralized stellate ganglia, τrecwas decreased from 71 ± 3 msec (control) to 57 ± 4 msec and 48 ± 2 msec (p< 0.001 for each) by left stellate ganglion stimulation at 5 and 10 Hz, respectively. Maximum fatigue was similarly reduced from 16 ± 1 msec (control) to 12 ± 2 msec (p=NS) and 8 ± 1 msec (p<0.01), respectively. Stellate ganglion stimulation, isoproterenol, and β-blockade did not alter AV nodal facilitation. A mathematical model incorporating quantitative indexes of AV nodal function accurately accounted for tachycardia-dependent increases in the atrial-His activation interval, which were enhanced by β-adrenergic receptor blockade and reduced by isoproterenol. Furthermore, this model showed that β-adrenergic effects were increased by increasing heart rate, with the majority of the rate-dependent action being due to changes in the time course of AV nodal recovery. We conclude that β-adrenergic receptor stimulation alters functional properties that govern the AV nodal response to changes in heart rate. These changes in functional properties alter the ability of the AV node to conduct impulses during tachycardia and, as such, could play a major role in the ability of sympathetic stimulation to promote and β-adrenergic receptor blockade to prevent the occurrence of AV nodal reentrant arrhythmias. (Circulation Research1992;70:902–911)

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

We studied the therapeutic efficacy of an intravenously injected antifibrotic agent encapsulated in liposomes on inhibiting collagen accumulation in hypertensive blood vessels.cis-4-Hydroxy-l-proline (cHyp) in liposomes was injected into rats exposed to 10% O2, and drug effect was evaluated by measuring right ventricular pressure and hydroxyproline content of the pulmonary artery. Right ventricular pressure was 11 ± 1 mm Hg (mean ± SEM) 5 days after a single intravenous injection of 200 mg/kg cHyp in liposomes compared with 14 ± 1 mm Hg in rats injected with empty liposomes; hydroxyproline content was also reduced by cHyp treatment (87 ± 6 versus 107 ± 7 μg per vessel) (p<0.05 for both,n=6–9). Injections of cHyp in liposomes every 5 days partially prevented hypertension and vascular collagen accumulation during a 3-week exposure to hypoxia, and the dose required was one tenth the dose of unencapsulated cHyp. Therapeutic doses of cHyp in liposomes injected for 6 months affected tensile properties of main pulmonary artery and aorta, but there were no apparent histological effects on other organs. Liposomes injected intravenously were identified in pulmonary artery endothelial cells. The prolonged effect of a single injection of cHyp in liposomes may be due to uptake of the liposomes by the endothelium. Liposome delivery of drugs to the arterial wall may be useful in the study and treatment of hypertensive vascular disease. (Circulation Research1992;70:912–922)

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Analysis of velocity acceleration proximal to a regurgitant valve has been proposed as a method to quantify the regurgitant flow rate (Qo). Previous work has assumed inviscid flow through an infinitesimal orifice, predicting hemispheric isovelocity shells, with calculated flow rate given by Qc=2πrN2vN, where vNis user-selected velocity of interest and rNis the distance from that velocity to the orifice. To validate this approach more rigorously and investigate the impact of finite orifice size on the assumption of hemispheric symmetry, numerical and in vitro modeling was used. Finite-difference modeling demonstrated hemispheric shape for contours more than two orifice diameters from the orifice. More proximal than this (where the measured velocity vNexceeded 3% of the orifice velocity vo), flow was progressively underestimated, with a proportional error ΔQ/Qonearly identical to the ratio of contour velocity to orifice velocity, vN/vo. For the in vitro investigations, flow rates from 4.3 to 150 cm3/sec through 0.3 and 1.0 cm2circular orifices were imaged with color Doppler with aliasing velocities from 19 to 36 cm/sec. Overall, the calculated flow (assuming hemispheric symmetry) correlated well with the true flow, Qc=0.88Qo-7.82 (r=0.945, SD=12.2 cm3/sec,p<0.0001,n=48), but progressively underestimated flow when the vNapproached the orifice velocity vo. Applying a correction factor predicted by the numerical modeling, ΔQ was improved from −13.81 ± 13.01 cm3/sec (mean ± SD) to +1.54 ± 5.67 cm3/sec. These data indicate that flow can be accurately calculated using the hemispheric assumption as Qc=2πrN2vNwhen vN<<vo. For larger vN, flow is systematically underestimated, but a more accurate estimate may be obtained by multiplying Qcby vo/(vo-vN). These observations lend additional support for the clinical use of the proximal acceleration concept and suggest a simple correction factor to make a more accurate estimation of valvular regurgitation. (Circulation Research1992;70:923–930)

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

Hearts with compensatory pressure-overload hypertrophy show an increased intracardiac activation of angiotensin II that may contribute to ischemic diastolic dysfunction. We studied whether pressure-overload hypertrophy in response to aortic banding would result in exaggerated diastolic dysfunction during low-flow ischemia and whether the specific inhibition of the cardiac angiotensin converting enzyme by enalaprilat would modify systolic and diastolic function during ischemia and reperfusion in either hypertrophied or nonhypertrophied hearts. Isolated, red blood cell-perfused isovolumic nonhypertro-phied and hypertrophied rat hearts were subjected to enalaprilat (2.5 × 10-−7M final concentration) infusion during 20 minutes of baseline perfusion and during 30 minutes of low-flow ischemia and 30 minutes of reperfusion. Coronary flow per gram was similar in nonhypertrophied and hypertrophied hearts during baseline perfusion, ischemia, and reperfusion. At baseline, left ventricular developed pressure was higher in hypertrophied than nonhypertrophied hearts in untreated groups (224 ± 8 versus 150 ± 9 mm Hg;p<0.01) and in enalaprilat-treated groups (223 ± 9 versus 145 ± 8 mm Hg;p<0.01). During low-flow ischemia, left ventricular developed pressure was depressed but similar in all groups. All groups showed deterioration of diastolic function; however, left ventricular end-diastolic pressure increased to a significantly higher level in untreated hypertrophied than in nonhypertrophied hearts (65 ± 7 versus 33 ± 3 mm Hg;p<0.001). Enalaprilat had no effect in nonhypertrophied hearts, but it significantly attenuated the greater increase in left ventricular end-diastolic pressure in hypertrophied hearts treated with enalaprilat compared with no drug (65 ± 7 versus 50 ± 5 mm Hg;p<0.01). The beneficial effect could not be explained by differences in coronary blood flow per gram left ventricular weight, glycolytic flux as reported by lactate production, myocardial water content, oxygen consumption, and tissue levels of glycogen and high energy phosphate compounds. During reperfusion, all hearts showed a partial recovery of developed pressure to 70–74% of initial values. No effect of enalaprilat could be detected during reperfusion on systolic and diastolic function or restoration of tissue levels of high energy compounds. In conclusion, our experiments show that hypertrophied red blood cell-perfused hearts manifest a severe impairment of left ventricular diastolic relaxation in response to low-flow ischemia in comparison with control hearts. Further, our experiments support the hypothesis that the enhanced conversion of angiotensin I to angiotensin II in rats with pressure-overload hypertrophy contributes to the enhanced sensitivity of hypertrophied hearts to diastolic dysfunction during low-flow ischemia. (Circulation Research1992;70:931–943)

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The volume and pressure of one ventricle have been demonstrated to modulate the volume and pressure in the contralateral chamber during systole and diastole. To quantitate the isolated systolic effects of left ventricular (LV) pressure on right ventricular (RV) mechanics, we rapidly withdrew blood from the LV immediately after diastole via an apex cannula during a single cardiac cycle in eight open-chest, open-pericardium anesthetized pigs (45 kg) and studied the effects on the RV. Reductions in LV pressure of up to 75 mm Hg were achieved in midsystole without changing LV or RV diastolic volume or pressure. Resultant changes in RV flow and pressure development during these single unloaded beats may therefore be considered to result from pure systolic interaction. The instantaneous left-to-right systolic pressure gain [G(t)] was determined as the ratio of RV pressure change to LV pressure change as a function of time during systole, and the mean LV-to-RV systolic pressure gain was determined as the ratio of changes in mean systolic RV pressure to changes in mean systolic LV pressure. During LV unloading, there was an average reduction of 62.6 ± 12.3%in the mean systolic LV pressure, which resulted in decreases of 13.6 ± 6.4% in mean RV systolic pressure, 17.9 ± 10.4% in RV stroke volume, and 27.0 ± 113% in RV stroke work. G(t) was found to vary significantly within systole, reaching a minimum of 0.042 ± 0.014 mm Hg/mm Hg at normalized time 0.70 of the systolic duration and a maximum of 0.079 ± 0.029 at the end of RV ejection. The midsystolic value for G(t) was 0.055 ± 0.028, and the mean systolic gain was 0.054 ± 0.017 mm Hg/mm Hg. These results demonstrate that, independent of diastolic conditions, there is a substantial transmission of systolic forces from the LV that contributes to RV ejection and that the pressure interaction gain varies within the systolic portion of the cardiac cycle. (Circulation Research1992;70:944–951)

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The purpose of this study was to examine whether neutral endopeptidase and angiotensin I-converting enzyme, two membrane-bound metalloenzymes that are widely distributed in the microcirculation, play a role in bradykinin-induced increase in vascular permeability in the hamster cheek pouch. Changes in vascular permeability were quantified by counting the number of leaky sites and by calculating the clearance of fluorescein isothiocyanate (FITC)-dextran (molecular mass, 70,000 d) during suffusion of the cheek pouch with bradykinin. Bradykinin produced a concentration- and time-dependent increase in the number of leaky sites and clearance of FITC-dextran. The selective, active site-directed neutral endopeptidase inhibitors phosphoramidon (1.0 μM) and thiorphan (10.0 μM) and the selective angiotensin I-converting enzyme inhibitor captopril (10.0 μM) each shifted the concentration-response curve to bradykinin significantly to the left. During suffusion with bradykinin (1.0 μM) and phosphoramidon, the number of leaky sites increased significantly from 17 ± 2 to 27 ± 4 sites per 0.11 cm2(mean ± SEM,p<0.05), and FITC-dextran clearance increased significantly from 1.0 ± 0.2 to 2.1 ± 0.3 ml/sec × 10-−6. During suffusion with bradykinin (1.0 μM) and captopril, the number of leaky sites increased significantly from 10 ± 2 to 41 ± 3 sites per 0.11 cm2, and FITC-dextran clearance increased significantly from 0.8 ± 0.3 to 3.2 ± 0.8 ml/sec × 10–6. During suffusion with bradykinin (1.0 μM) and thiorphan, the number of leaky sites increased significantly from 15 ± 3 to 47 ± 7 sites per 0.11 cm2, and FITC-dextran clearance increased significantly from 0.8 ± 0.2 to 4.7 ± 0.6 ml/sec × 10–6. Suffusion of both phosphoramidon and captopril was associated with an additive effect on bradykinin-induced responses. Other proteinase inhibitors had no significant effect on bradykinin-induced increase in vascular permeability. In addition, adenosine (1.0 μM)-induced increase in leaky site formation was not potentiated by phosphoramidon and captopril. We conclude that neutral endopeptidase and angiotensin 1-converting enzyme each play an important role in modulating bradykinin-induced increase in vascular permeability in vivo. (Circulation Research1992;70:952–959)

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID

摘要:

The present study tested the hypothesis that a reduction in calcium flux across the sarcolemma or the sarcoplasmic reticulum at the onset of reperfusion could attenuate subsequent mechanical “stunning” (postischemic myocardial dysfunction). The isolated working rat heart was subjected to 20 minutes of total global ischemia, reperfused in the Langendorff mode for 5 minutes, and then made to work again for 10 minutes. During the early reperfusion period (first 2 minutes), the effects of agents thought to increase cytosolic calcium (high external calcium [modified Tyrode's solution replaced Krebs-Henseleit buffer as the perfusatel, isoproterenol, forskolin, and Bay K 8644) were tested. All these interventions worsened stunning. The cardiac output (CO) of control hearts recovered to 74.7 ± 3.4%, whereas recovery was 56.3 ± 3.7% (p<0.05) for high calcium (10 mM), 53.4 ± 3.6% (p<0.05) for isoproterenol, 43.4 ± 4.1% (p<0.05) for Bay K 8644, and 62.7 ± 2.4% (p<0.002) for forskolin. Interventions aimed at limiting calcium flux during early reperfusion, such as reperfusion with a low extracellular calcium or the addition of ryanodine (3 × 10–9M), nisoldipine (10–8M), or the inorganic blockers Mn2+(2 mM) or Mg2+(16 mM), were also tested. Low extracellular calcium (0.75 mM) improved CO to 91.8 ± 0.8% (p<0.05). Reperfusion with ryanodine and nisoldipine gave CO recoveries of 103.6 ± 1.8% (p<0.002) and 99.0 ± 2.8% (p<0.002), respectively. The addition of Mn2+and Mg2+resulted in CO recoveries of 88.9 ± 2.4% (p<0.05) and 91.9 ± 1.4% (p<0.002), respectively. Ryanodine and nisoldipine pretreatment changed CO recoveries to 97.5 ± 1.8% (p<0.002) and 84.8 ± 5.2% (p=NS), respectively. In conclusion, the use of organic or inorganic calcium antagonists or ryanodine at the onset of reperfusion attenuated reperfusion stunning in the isolated rat heart. Agents thought to promote calcium influx and/or to increase cytosolic calcium levels exaggerated the severity of stunning. These data support the hypothesis that the development of myocardial mechanical stunning can be related to cytosolic calcium overload at the onset of reperfusion. (Circulation Research1992;70:960–967)

ISSN:0009-7330    

出版商:OVID    

年代:1992

数据来源: OVID