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Biomedical subjects

G Heusch

Publications and source records attributed to G Heusch.

At least 163 records · Page 9Linked to original sources
PubMed1992

[Poor reproducibility of parameters of heart rate variations].

The analysis of heart rate variability is supposed to be a marker of autonomic cardiac activity and is used for risk stratification of post-infarction patients. Analysis of heart rate variability in the frequency domain may permit a differentiation of vagal and sympathetic control; for such analyses only short time intervals characterized by a steady-state autonomic balance can be used. Yet, it is unclear whether single determinations of heart rate variability indices derived from short time intervals yield reproducible results. Therefore, the reproducibility of heart rate variability indices was studied with weekly measurements in 10 healthy volunteers under the following defined conditions: 13 min supine rest, 10 min standing, 13 min sitting, and 15 min cycle ergometry followed by a 14 min recovery period. Heart rate variability was determined in the frequency domain (fast Fourier transformation) and in the time domain. The reproducibility was estimated by the coefficient of variation (CV). Additionally, the reproducibility of heart rate, blood pressure, and the expiratory-inspiratory ratio of heart rate was determined. The reproducibility of the frequency domain indices (36.6-74.9% CV) and of the time domain indices (19.6-32.8% CV) was considerably worse than that of heart rate (5.2-8.2% CV), blood pressure (5.1-8.2% CV) and the expiratory-inspiratory ratio of heart rate (4.6% CV). The reproducibility of heart rate variability indices was not improved by orthostatic or ergometric challenge. This poor reproducibility does not permit a reliable interpretation of heart rate variability on the basis of single measurements in healthy volunteers. Given the wide range and scatter of the measured parameters, the diagnostic and prognostic value of heart rate variability indices derived from short recording periods appears questionable.

Arrhythmias, Cardiac↗
PubMed1992

Characterization of "hibernating" and "stunned" myocardium with focus on the use of calcium antagonists in "stunned" myocardium.

In the initial seconds after a sudden reduction in coronary blood flow, a temporary mismatch between myocardial energy demand and supply exists. The mechanisms underlying the rapidly ensuing reduction in contractile function in the ischemic myocardium are still unknown. In the presence of some residual blood flow, a state of "perfusion-contraction matching" develops. The metabolic status of such hypoperfused myocardium improves, since myocardial lactate production is attenuated and creatine phosphate (CP), after an initial reduction, returns toward control values. The hypoperfused myocardium responds to inotropic stimulation by dobutamine. The recruitment of an inotropic reserve implies increased energy utilization. During inotropic stimulation, after partial normalization, lactate production is again increased, and CP is decreased again. Thus, a supply-demand imbalance that had been at least partially corrected by the ischemia-induced decrease in regional contractile function is precipitated again. A situation of chronic contractile failure in viable myocardium that normalizes upon reperfusion has been termed myocardial "hibernation." Myocardial "stunning" is characterized by a reversible postischemic contractile dysfunction despite full restoration of blood flow. The details of the underlying mechanisms are not clear. An inadequate energy supply and impaired sympathetic neurotransmission have been excluded. Potential mechanisms, which are not mutually exclusive, may include (a) damage of membranes by free radicals, (b) an increase in free cytosolic calcium during ischemia and reperfusion, and (c) a decrease in the calcium sensitivity of the myofibrils. The equally pronounced increases in regional contractility in normal and "stunned" myocardium during postextrasystolic potentiation and the infusion of calcium or the calcium-sensitizing agent AR-L-57, however, suggest an unchanged calcium sensitivity of reperfused myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium↗
PubMed1992

The calcium antagonist nisoldipine improves the functional recovery of reperfused myocardium only when given before ischemia.

It is unclear whether the protective effects of calcium antagonists on reperfused myocardium are secondary to increased blood flow during ischemia (anti-ischemic action) or reperfusion (Gregg phenomenon), or are mediated through altered calcium kinetics in ischemic or reperfused myocardium. To study the effect of the calcium antagonist nisoldipine on the functional recovery of stunned myocardium, 32 enflurane-anesthetized dogs were subjected to 15 min of occlusion of the left circumflex coronary artery and subsequent 4 h of reperfusion. Eight dogs served as placebo controls (group I), and eight dogs received nisoldipine (5 micrograms/kg i.v.) before occlusion (group II), eight dogs at 10 min of occlusion (group III), and eight dogs at 4 min of reperfusion (group IV). The mean aortic pressure was kept constant with an intra-aortic balloon, and the heart rate did not change. In group I, posterior systolic wall thickening (WT, sonomicrometry) decreased from 18.3 +/- 2.4% (mean +/- SD) during control conditions to -3.0 +/- 2.0% at 13 min of occlusion. At 10 min of reperfusion, WT was 1.7 +/- 3.9% and did not recover further (-1.2 +/- 3.7% at 4 h of reperfusion). Posterior transmural blood flow (BF, colored microspheres) decreased from 1.42 +/- 0.43 ml/min/g during control conditions to 0.26 +/- 0.08 ml/min/g at 13 min of occlusion. BF was 2.07 +/- 0.93 ml/min/g at 10 min and 0.95 +/- 0.31 ml/min/g at 4 h of reperfusion. In groups III and IV, the WT and BF were not different from those in group I throughout the experimental protocol. In group II, however, the WT, although similar to the WT of group I before and during ischemia, recovered from 2.7 +/- 4.3% at 10 min to 11.8 +/- 6.0% at 4 h of reperfusion (p less than 0.05 vs. groups I, III, and IV). The BF in group II decreased from 2.52 +/- 0.66 ml/min/g after administration of nisoldipine to 0.22 +/- 0.14 ml/min g at 13 min of occlusion. The BF was 1.31 +/- 0.51 ml/min/g at 10 min and 1.33 +/- 0.43 ml/min/g at 4 h of reperfusion. Nisoldipine exerts no beneficial effect when given immediately before or after the onset of reperfusion. The improved functional recovery of reperfused myocardium in dogs pretreated with nisoldipine cannot be attributed to an increased regional myocardial blood flow during ischemia or reperfusion. The better myocardial recovery, therefore, appears to be related to an attenuated myocardial calcium overload during the first few minutes of ischemia.

Analysis of Variance↗
PubMed1992

[Hibernation, stunning, ischemic preconditioning--new paradigms in coronary disease?].

Myocardial ischemia has traditionally been characterized as an imbalance between energy supply and demand. In the initial seconds after a sudden reduction of coronary blood flow, myocardial energy demand most certainly exceeds the reduced energy supply. This temporary mismatch, however, is an inherently unstable condition because regional contractile dysfunction ensues. The mechanisms responsible for the rapid reduction in contractile function of the acutely ischemic myocardium are still poorly understood. If some residual blood flow exists, a state of "perfusion-contraction matching" can be maintained without the development of irreversible damage. The metabolic status of such hypoperfused myocardium improves as myocardial lactate production is attenuated and creatine phosphate, after an initial reduction, returns towards control values. The hypoperfused myocardium can respond to inotropic stimulation by dobutamine with increased function. The recruitment of an inotropic reserve implies increased energy utilization. In fact, the partially normalized lactate production is again increased, and creatine phosphate is decreased again. Apparently, the inotropic challenge once again precipitates a supply-demand imbalance which had been at least partially corrected by the ischemia-induced decrease of regional contractile function. A situation of chronic contractile failure in viable myocardium which normalizes upon reperfusion has been termed myocardial "Hibernation". Myocardial "Stunning" is characterized by a reversible post-ischemic contractile dysfunction despite full restoration of blood flow. The underlying mechanisms are not clear in detail. An inadequate energy supply and an impaired sympathetic neurotransmission have been excluded. Potential mechanisms, which are not mutually exclusive, may include (1) damage of membranes and enzymes by free radicals, (2) an increase in free cytosolic calcium during ischemia and reperfusion, and (3) a decrease of the calcium sensitivity of the myofibrils. The equally pronounced increases in regional contractility in normal and "stunned" myocardium during intracoronary calcium infusion, postextrasystolic potentiation and the infusion of the calcium-sensitizing agent AR-L-57, however, suggest an unchanged calcium sensitivity of reperfused myocardium. Interventions to reduce free radical formation or to increase their elimination attenuate myocardial stunning. Likewise, pretreatment with calcium antagonists before ischemia attenuates myocardial stunning. This effect is probably related to an attenuated myocardial calcium overload during early ischemia. The potential benefit from calcium antagonists when given after established reperfusion remains controversial.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Pressure-flow characteristics in the right and left ventricular perfusion territories of the right coronary artery in swine.

Regional pressure-flow relationships within the right coronary artery (RCA) circulation of swine were determined. Enflurane-anaesthetized swine (n = 7) were studied during step-wise reductions of RCA perfusion pressure using an extracorporeal circuit. Regional blood flow was measured using microspheres and contractile function of the right ventricle was measured using sonomicrometry. The RCA perfusion territory was divided into its anatomic components: right ventricular free wall (RV), interventricular septum (with further division in transmural thirds; SEP-LV, SEP-MID and SEP-RV) and right atrium (RA). Pressure-flow relations were constructed for each region and autoregulatory capacity assessed through calculation of an autoregulatory index (AI, closed-loop gain). The pressure-flow relationship for the entire RCA exhibited autoregulation down to a pressure of 40 mmHg. The SEP-LV exhibited a similar relationship with loss of autoregulation at approximately 40 mmHg. The pressure-flow relationship of the RV, however, showed autoregulation to a pressure of 30 mmHg with a decrease of blood flow only at a pressure of 20 mmHg. Little autoregulation was observed in the RA. Autoregulatory gain assessed by AI was similar in RV, SEP-LV and SEP-RV as pressure was reduced from 90 to 55 mmHg (RV = 0.54 +/- 0.41; SEP-LV = 0.58 +/- 0.36; SEP-RV = 0.83 +/- 0.36). With further reductions of pressure, AI was highest in the RV, followed by the SEP-RV and then SEP-LV.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Postextrasystolic potentiation does not distinguish ischaemic from stunned myocardium.

Myocardial function is impaired by ischaemia, and it remains depressed during reperfusion following short periods of ischaemia (stunned myocardium). We tested whether ischaemic and reperfusion dysfunction, in particular the time course of its recovery, can be distinguished by postextrasystolic potentiation (PESP). In eight open-chest dogs, posterior systolic wall thickening (sonomicrometry) was reduced by graded occlusion of the left circumflex coronary artery (LCX) from 17.4 +/- 6.8% (SD) during control conditions to 10.7 +/- 1.3% (mild ischaemic dysfunction), 7.2 +/- 2.3% (moderate ischaemic dysfunction), 3.6 +/- 1.4% (severe ischaemic dysfunction), and -4.4 +/- 3.6% (complete coronary occlusion). Extrasystoles with constant prematurity and a fully compensated postextrasystolic interval were induced after at least 4 min steady-state ischaemia. After each ischaemic period full recovery of posterior systolic wall thickening was assured. During 8 h of reperfusion following a 15-min LCX occlusion, extrasystoles were induced when posterior systolic wall thickening was comparable to one degree of the preceding ischaemic dysfunction. The increases in posterior systolic wall thickening induced by PESP were 10.5 +/- 5.8% during control conditions, during ischaemia they were 11.5 +/- 3.5% (mild dysfunction), 12.3 +/- 4.6% (moderate dysfunction), 12.6 +/- 4.1% (severe dysfunction) and 10.4 +/- 4.4% (complete coronary occlusion), and during reperfusion they were 12.8 +/- 8.2% (severe dysfunction), 13.0 +/- 9.7% (moderate dysfunction) and 10.7 +/- 2.2% (mild dysfunction).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Control of coronary vasomotor tone in ischaemic myocardium by local metabolism and neurohumoral mechanisms.

There is no doubt that under normal conditions powerful local metabolic regulation adjusts coronary blood flow to myocardial oxygen consumption. However, despite substantial experimental efforts the responsible mediators are still largely unknown. Adenosine, a purported mediator of local metabolic control of coronary blood flow, is probably only involved in transient flow adaptations but not in steady state coronary autoregulation. Even below the autoregulatory range a substantial vasodilator reserve persists, and recruitment of such a vasodilator results in improved regional myocardial blood flow and attenuated regional ischaemic dysfunction. Beta-adrenergic coronary dilation is of minor functional importance. Alpha-adrenergic coronary constriction acts to attenuate increases in coronary blood flow during sympathetic activation under normal conditions, so that myocardial oxygen extraction increases to match the increased oxygen consumption. Alpha-adrenergic coronary constriction remains operative in ischaemic myocardium, thus precipitating or contributing to acute myocardial ischaemia during sympathetic activation and exercise in experimental animals, as well as in patients with stable angina. The vagal transmitter acetylcholine-upon exogenous intracoronary infusion-induces critical constriction of epicardial coronary arteries with endothelial dysfunction and atherosclerosis. However, a vagal initiation of coronary spasm or myocardial ischaemia has not been documented so far. Similarly, peptide hormones/transmitters such as NPY, vasopressin and angiotensin can induce myocardial ischaemia upon exogenous administration. Their pathophysiological role in myocardial ischaemia, however, remains to be established.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Measurement of regional myocardial blood flow with multiple colored microspheres.

BACKGROUND: The use of radioactive microspheres (RM) for the measurement of regional myocardial blood flow (RMBF) is limited and inaccessible to many investigators due to radiation safety concerns and radioactive waste disposal problems. Therefore, a new method for the measurement of RMBF using colored microspheres (CM) was developed. METHODS AND RESULTS: Polystyrene spheres (diameter, 15 +/- 0.1 [SD] micron; density, 1.09 g/ml) were dyed with one of five colors. With the injection of CM into the left atrium or into a coronary perfusion line, RMBF and its distribution can be determined. CM are extracted from the myocardium and blood by digestion with potassium hydroxide and subsequent microfiltration. The dyes are then recovered from the CM within a defined volume of a solvent, and their concentrations are determined by spectrophotometry. The separation of composite absorbance spectra by spectrophotometry with the CM technique was as good as the separation of energy spectra by a gamma-counter using the RM technique. Leaching of dye from the CM was less than 0.1% during a 2-month period in vitro. Significant leaching of dye from the microspheres also did not occur during 8 hours in the blood and myocardium of four anesthetized dogs in vivo. For further validation of this method, pairs of CM and RM (15.5 +/- 0.1 [SD] microns) were simultaneously injected under five different RMBF conditions (range, 0-10 ml/[min.g]) into the left anterior descending coronary artery of four anesthetized pigs, with coronary inflow as a flow reference, or into the left atrium of four anesthetized dogs using aortic blood withdrawal as a reference. The relation between RMBF determined by CM and RM was CM = 0.01 + 1.00.RM (r = 0.98, n = 1,080 data points) in the pigs, and CM = -0.19 + 0.92.RM (r = 0.97, n = 1,813 data points) in the dogs. CONCLUSIONS: Measurement of RMBF with CM yields values very similar to those of RM. Their use is less expensive and avoids all the disadvantages related to radioactivity, thus offering an alternative method for as many as five RMBF measurements in a single experiment.

Animals↗
PubMed1991

No effect of coronary perfusion on regional myocardial function within the autoregulatory range in pigs. Evidence against the Gregg phenomenon.

BACKGROUND: The hypothesis that increases in coronary perfusion increase ventricular performance independently from providing enhanced oxygen supply ("Gregg phenomenon") remains controversial. METHODS AND RESULTS: To study the physiological significance of changes in coronary perfusion on global and regional myocardial function in situ, the left anterior descending coronary artery of isoflurane-anesthetized swine was cannulated, and perfusion was varied. In one group of swine (n = 5), coronary arterial pressure was increased in four steps from 88 +/- 11 to 186 +/- 11 mm Hg by increasing the speed of the pump circuit providing coronary blood flow. No changes in left ventricular end-diastolic pressure, peak pressure, or maximum left ventricular dP/dt were observed. Subendocardial blood flow (by radiolabeled microspheres) increased from 0.96 +/- 0.27 to 2.04 +/- 0.73 ml/min/g without any increase in systolic wall thickening (by sonomicrometry) or myocardial oxygen consumption of the anterior myocardium. In a second group of swine (n = 8), coronary arterial pressure was kept constant and coronary blood flow was increased stepwise by intracoronary adenosine infusion. End-diastolic pressure, peak pressure, and maximum left ventricular dP/dt remained unchanged when coronary blood flow increased from 21.7 +/- 9.8 to 93.8 +/- 34.1 ml/min. Subendocardial blood flow increased from 0.89 +/- 0.26 to 3.28 +/- 1.02 ml/min/g, again without any increase in systolic wall thickening (45.6 +/- 8.6 versus 42.6 +/- 9.8%) and myocardial oxygen consumption (5.75 +/- 1.18 versus 5.87 +/- 1.67 ml/min/100 g). In a third group of swine (n = 10), coronary arterial pressure was lowered by intracoronary adenosine infusion during constant coronary inflow. Left ventricular hemodynamics remained unchanged. With a decrease in coronary arterial pressure from 130 +/- 25 to 71 +/- 14 mm Hg, no decreases in subendocardial blood flow and systolic wall thickening were observed. Only when coronary arterial pressure was further reduced to 57 +/- 13 mm Hg did systolic wall thickening fall to 25.7 +/- 9.9% (control, 31.1 +/- 11.1%), associated with a decrease in subendocardial blood flow from 1.17 +/- 0.39 to 0.87 +/- 0.52 ml/min/g. CONCLUSIONS: Thus, the Gregg phenomenon plays no significant role within or above the autoregulatory pressure-flow range normally seen in anesthetized swine in situ.

Animals↗
PubMed1991

Effect of alpha-adrenergic stimulation on regional contractile function and myocardial blood flow with and without ischemia.

BACKGROUND: The effect of alpha-adrenergic receptor activation on regional contractile function and transmural myocardial blood flow is controversial. Accordingly, the effects of selective alpha 1-(methoxamine) and alpha 2-(BHT 933) receptor stimulation on regional contractile function and transmural myocardial blood flow distribution were studied in 15 anesthetized open-chest dogs. METHODS AND RESULTS: The alpha-adrenergic agonists were separately infused into the cannulated left circumflex coronary artery during control and ischemic conditions in the same animal. Mean coronary perfusion pressure was held constant by a servocontrolled pump in an extracorporeal circuit. Ischemia was created by reducing coronary perfusion pressure to the level at which percent systolic wall thickening (%WT) decreased by 54%. Contractile function during control conditions was unchanged, whereas under ischemic conditions a further significant decrease in %WT of 27% occurred with either alpha 1- or alpha 2-receptor stimulation without any change in the anterior (control) wall function. Both alpha 1- and alpha 2-receptor stimulations during control conditions resulted in a relatively uniform transmural decrease in blood flow with no change in the subendocardial-to-subepicardial blood flow ratio. With alpha 1-stimulation during ischemia (n = 13), there was a tendency toward decreased subepicardial blood flow with no change in subendocardial flow, resulting in an increased subendocardial-to-subepicardial blood flow ratio (0.61 +/- 0.23 to 0.82 +/- 0.40, p less than 0.05). alpha 2-Receptor stimulation during ischemia (n = 12) produced a significant decrease in subepicardial blood flow (0.45 +/- 0.20 to 0.35 +/- 0.12 ml/min/g, p less than 0.01) with no change in subendocardial blood flow, also resulting in an increased subendocardial-to-subepicardial blood flow ratio. CONCLUSIONS: These results indicate the selective vasoconstriction in outer wall layers during ischemia mediated by either alpha 1- or alpha 2-receptors can cause a decrease in regional contractile function despite unchanged subendocardial blood flow and improved subendocardial-to-subepicardial flow ratio. This suggests an adverse effect of alpha-adrenergic vasoconstriction during ischemia in this coronary perfusion pressure-controlled canine model.

Adrenergic alpha-Agonists↗
PubMed1991

[A two-stage regulatory system for pressure-constant perfusion of coronary vessels].

This paper describes a double-loop servo-controlled pump system for the constant-pressure perfusion of a coronary artery. Due to the transient nature of changes in coronary vasomotor tone, such a perfusion system must have a fast regulatory response. In the first stage, a servo-controlled pump primes a windkessel having a volume of 35 ml with blood. The pumping rate is electronically controlled to maintain a constant pressure within the windkessel max. 700 mmHg. The maximal flow rate is 300 ml/min. To reduce the high pressure in the windkessel to the desired coronary perfusion pressure, a variable flow resistance, comprising a clamped thin-walled silicone tube, is provided in the output line of the system. A fast servo-motor drives the clamp and is controlled by an electronic regulator, using a second feedback loop from the pressure signal measured at the tip of the perfusion cannula. The system stabilizes the coronary perfusion pressure within 300 ms. An additional modulation of the setpoint signal in synchrony with the cardiac cycle improves the phasic pattern of the blood flow, and thus prevents changes in transmural blood flow distribution. The dead volume of the overall system is about 60 ml. Hemolysis caused by this system during five hours of perfusion in vivo is negligible.

Animals↗
PubMed1990

Alpha-adrenergic regulation of myocardial performance in the exercising dog: evidence for both presynaptic alpha 1- and alpha 2-adrenoceptors.

New evidence supporting both presynaptic alpha 1- and alpha 2-adrenoceptors playing a role in the regulation of myocardial contractile performance in the exercising dog is reviewed. Studies utilized chronically instrumented dogs having sonomicrometers for the measurement of regional wall thickening and transducers for the measurement of left ventricular and systemic hemodynamics. During steady state exercise, either the selective alpha 1-adrenoceptor blocker prazosin (80 micrograms/kg) or the selective alpha 2-adrenoceptor blocker idazoxan (80 micrograms/kg) was infused into the left atrium while exercise continued. Immediately following the administration of either alpha-adrenoceptor blocking agent, there were substantial increases in heart rate, left ventricular dP/dt and regional contractile function as assessed using sonomicrometers, and norepinephrine release by the myocardium increased substantially. beta-adrenergic blockade prevented the heart rate and contractile effects of either alpha 1- or alpha 2-adrenoceptor blocker whereas norepinephrine release was further enhanced. These effects could not be attributed to baroreceptor unloading. In dogs studied under resting conditions with norepinephrine infusion to produce an increase in dP/dt similar to that observed during treadmill exercise, no sympathetic augmentation was observed following either alpha-blocker. Together, these studies provide evidence that both alpha 1- and alpha 2-adrenoceptors participate in the modulation of sympathetic neuronal norepinephrine release in the canine myocardium.

Adrenergic alpha-Antagonists↗
PubMed1990

Mechanisms of benefit in the ischemic myocardium due to heart rate reduction.

The studies reviewed here examine the role of heart rate reduction in the beneficial effect observed following beta-adrenoceptor blockade during exercise-induced ischemia in conscious dogs. To further study the effects of heart rate reduction on regional blood flow in an ischemic bed without collateral circulation, anesthetized swine with controlled coronary perfusion were also studied. Measurements of regional myocardial blood flow (microspheres) and contractile function (sonomicrometers) during steady state exercise in dogs with chronic coronary artery stenosis indicated the existence of severe regional contractile dysfunction and subendocardial ischemia. The administration of beta-adrenoceptor blockade (1.0 mg/kg atenolol) improved regional contractile function when heart rate was reduced from 220 to 165 beats/min. Atrial pacing during exercise to prevent the bradycardia following beta-adrenoceptor blockade eliminated the improved regional function and blood flow. Thus, the beneficial effect of beta-blockade was only apparent when exercise heart rate was reduced. In anesthetized swine with constant inflow coronary perfusion, two levels of coronary hypoperfusion were examined at heart rates of 91 beats/min or 55 beats/min. Bradycardia was produced using the bradycardic agent UL-FS 49 (0.3 mg/kg). Regional contractile function and subendocardial blood flow were markedly improved at the lower heart rate for either level of reduced coronary perfusion, indicating a redistribution of blood flow towards the subendocardium. The improvement in contractile function was larger than predicted on the basis of the improvement in blood flow per min to the subendocardium. Independent relationships between regional contractile function and the subendocardial blood flow per min were observed for each heart rate. Thus, the studies in conscious exercising dogs indicated that heart rate reduction is an essential mechanism for the improvement of ischemic regional myocardial contractile function during exercise by beta-blockade. This is likely the result of the marked improvement in subendocardial blood flow per beat which accompanies the reduced heart rate; regional myocardial blood flow per beat appears to be a predictor of regional contractile function during ischemia both at rest and during exercise.

Animals↗
PubMed1990

Contribution of postsynaptic alpha 2-adrenoceptors to reflex sympathetic constriction of stenotic coronary vessels.

Increases in the activity of efferent cardiac sympathetic nerves by 35 +/- 9% were induced by 60 s bilateral occlusion of the common carotid arteries (BCO) in anesthetized dogs. Under control conditions the reflex rise in sympathetic nerve activity enhanced left ventricular pressure (115 +/- 4 mm Hg) by 47% and regional myocardial oxygen consumption (9.7 +/- 1.1 ml/min.100 g) by 56%. Simultaneously, end-diastolic circumflex coronary resistance (0.99 +/- 0.11 mm Hg.min.100 g/ml) decreased by 16%. After exhaustion of coronary dilator reserve by production of a severe coronary stenosis, BCO enhanced left ventricular pressure (107 +/- 4 mm Hg) by 49%, oxygen consumption of the poststenotic area (7.6 +/- 0.8 ml/min.100 g) increased by 21%, and circumflex coronary resistance (0.54 +/- 0.05 mm Hg.min.100 g/ml) also increased by 19%. The reflex increase in coronary resistance during BCO was abolished after infusion of the alpha 2-adrenoceptor antagonist rauwolscine (0.2 mg/kg i.v.). Administration of rauwolscine, however, did not prevent the reflex increase of left ventricular pressure and regional myocardial oxygen consumption. Comparable increases in poststenotic coronary resistance during BCO were found in dogs which either received propranolol (2 mg/kg i.v.) or in which the reflex rise in mean aortic pressure was limited to 13 +/- 3 mm Hg. In both experimental groups, rauwolscine also effectively prevented the BCO-induced rise in coronary resistance. In contrast, the reflex increase of total peripheral resistance was not significantly reduced by rauwolscine, but was blunted after additional administration of the selective alpha 1-adrenoceptor antagonist prazosin (1.2 mg/kg i.v.). We conclude that: 1) Poststenotic coronary vasoconstriction occurs during shortlasting increases in efferent cardiac sympathetic discharge within the physiological range. 2) This increase in poststenotic coronary resistance is significantly reduced after administration of the alpha 2-adrenoceptor antagonist rauwolscine. 3) In contrast to poststenotic coronary resistance, functionally innervated alpha 2-adrenoceptors are of minimal importance for the reflex increase in total peripheral resistance.

Animals↗
PubMed1990

Alpha 2-adrenergic coronary constriction in ischemic myocardium during exercise.

The effect of either selective alpha 1- or alpha 2-adrenoceptor blockade on ischemic myocardial blood flow and function was examined in beta-blocked dogs trained to run on a motor-driven treadmill. The animals were instrumented with sonomicrometers for the assessment of regional systolic wall thickening (%WTh) of the left ventricle. For drug infusion, an intracoronary catheter was implanted in the circumflex coronary artery and a hydraulic cuff was placed proximally around the artery. Following systemic beta-blockade with 0.8 mg/kg propranolol, an acute stenosis of the circumflex coronary artery inflated during exercise induced severe dysfunction in the posterior wall. Intracoronary infusion of 80 micrograms/kg of the selective alpha 2-adrenoceptor blocking agent idazoxan improved posterior wall (PW)-%WTh from 5.1 +/- 1.6 to 10.8 +/- 2.8% (p less than 0.06) and regional myocardial blood flow (radiolabelled microspheres) in the subendocardium of the posterior wall from 0.17 +/- 0.05 to 0.45 +/- 0.30 (ml/min)/g (p less than 0.05). No increases in regional blood flow and regional myocardial function were observed after infusion of the selective alpha 1-adrenoceptor blocking agent prazosin (20 micrograms/kg) under the same experimental conditions. It is concluded that during severe ischemia, significant postjunctional alpha 2-adrenoceptor mediated coronary vasoconstriction exists. Regional alpha 2-adrenoceptor blockade, but not alpha 1-adrenoceptor blockade is effective in reducing regional ischemia and dysfunction by attenuating sympathetic vasoconstriction in the conscious dog.

Adrenergic alpha-Antagonists↗
PubMed1990

Prevention of alpha-adrenergic coronary constriction by calcium-antagonists.

This manuscript reviews the experimental evidence for a functional antagonism of Ca-antagonists against alpha-adrenoceptor-mediated increases in coronary vasomotor tone. In studies on anesthetized dogs, intravenous nifedipine effectively prevented the alpha 1-adrenoceptor-mediated increase in epicardial coronary resistance, as well as the increase in end-diastolic resistance mediated by both alpha 1- and alpha 2-adrenoceptors during cardiac sympathetic nerve stimulation. Both intracoronary and intravenous administration of nifedipine also prevented the alpha 2-adrenoceptor-mediated increase in coronary resistance distal to severe stenoses, as well as the resulting ischemic dysfunction and net lactate production during cardiac sympathetic nerve stimulation. Felodipine was equally effective as nifedipine in preventing an alpha 2-adrenoceptor-mediated increase in coronary resistance and the resulting contractile dysfunction distal to severe coronary stenoses. alpha 1- and alpha 2-Adrenergic coronary constriction also contribute to the severity of myocardial ischemia in conscious dogs during treadmill exercise. Again, nifedipine improved regional myocardial blood flow and attenuated regional contractile dysfunction during exercise-induced ischemia in conscious dogs with a chronic coronary stenosis. This beneficial effect of nifedipine was attributed to a recruitment of coronary dilator reserve and not to a reduction in heart rate or afterload. In conclusion, there is solid experimental evidence for a functional antagonism of Ca-antagonists against alpha-adrenergic coronary constriction and its contribution to myocardial ischemia.

Animals↗
PubMed1990

Pain and myocardial ischemia: the role of sympathetic activation.

In a first series, we tested whether the relative ischemia distal to a severe stenosis on the left circumflex coronary (CX) artery increases the activity of cardiac sympathetic (CS) nerves which, in turn, may result in a poststenotic vasoconstriction and an aggravation of ischemia. In 23 anesthetized, vagotomized dogs, an acute stenosis that reduced CX blood flow to 50% of control was produced and maintained for 20 min. The activity of postganglionic CS nerves increased by 23 +/- 4% within 20 min. In parallel, poststenotic coronary resistance increased from 0.48 +/- 0.03 (SEM) to 0.61 +/- 0.03 mm Hg.min.100 g/ml, resulting in a net lactate production after 15 min. The selective alpha 2-adrenoceptor antagonist rauwolscine (0.2 mg/kg i.v.; n = 6) and the calcium antagonist nifedipine (10 micrograms/kg i.v.; n = 6) prevented the progressive increase in poststenotic resistance and the net lactate production, but still permitted an increase in CS activity. Segmental anesthesia of CS nerves with epidural infiltration of procaine at segments C7-T6 (n = 6) prevented the sympathetic activation, the progressive increase in poststenotic resistance and the net lactate production. In six additional dogs with intact vagus nerves, CS activation and a concomitant increase in poststenotic resistance resulting in myocardial ischemia were also found. These data suggest a vicious cycle between poststenotic coronary vasoconstriction and CS activation, resulting in severe myocardial ischemia. In a second series, stimulation of high-threshold somatic afferents (= nociceptive stimulation: NCS) was used to cause reflex CS activation. The superficial peroneal nerve was electrically stimulated in 14 anesthetized, vagotomized dogs. With intact CX arteries, a 1 min stimulation resulted in a pronounced increase in CX blood flow and perfusion pressure. In contrast, NCS in the presence of a severe stenosis on the CX artery increased end-diastolic poststenotic coronary resistance by 96 +/- 15% due to a reflex activation of CS nerve fibers. This activation was markedly reduced after injection of fentanyl (27 micrograms/kg i.v.; n = 6). Injection of naloxone (60 micrograms/kg) restored the original effect. Systolic wall thickening (WT; sonomicrometry) in the CX artery-perfused myocardium was increased during NCS (10.9 +/- 3.9 (SD) vs. 13.6 +/- 5.0%) in additional five dogs with intact coronary arteries. In the presence of a stenosis on the CX artery, systolic WT was reduced to 7.0 +/- 2.5% and was further decreased to 4.6 +/- 2.3% during NCS. The additional deterioration of systolic regional function during NCS was prevented after i.v. injection of fentanyl, as was the increase in poststenotic coronary resistance.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗