Circulation Research

Smith, Thomas W.

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Growth of cultured cells in low potassium medium has been shown to result in an increase in the number of Na,K-ATPase sites. This phenomenon and its physiological and pharmacological consequences were examined in spontaneously beating monolayers of cultured chick heart cells. Growth of cells in 1 MM extracellular potassium, 2 μM ouabain, or 1

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Kirk, Edward S.

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If a coronary artery is ligated and the distal end cannulated, blood flows retrograde from the cannula when vented to the atmosphere. By varying the height of the outflow tubing, and thereby changing the outflow pressure, pressure-flow relationships can be constructed. We used this technique in eight dogs to assess the characteristics of blood flow into ischemic myocardium. Above a back pressure of 10 mm Hg, increasing back pressure resulted in a decrease of retrograde blood flow. However, below a back pressure of about 10 mm Hg (10.7 ± 2.7 mm Hg), alterations in back pressure did not result in changes in retrograde blood flow (back pressure-independent region). The transition at 10 mm Hg is interpreted as the critical waterfall pressure in ischemic myocardium. In another group of eight dogs, the ischemic bed was completely embolized with 25

Jalife, Jose

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A mathematical model of dynamic vagus-sinus interactions was devised based on Hodgkin and Huxley-type equations of time- and voltage-dependent membrane currents. Brief vagal pulses were modeled with a concentration-dependent, acetylcholine-activated, potassium current. Single acetylcholine (“vagal”) pulses scanning the sinus cycle induced changes in pacemaker rhythm that depended on pulse magnitude, duration, and time of occurrence during the cycle. Phase-response curves summarizing these effects are strikingly similar to experimental results. Notably, appropriately timed acetylcholine pulses could produce an acceleratory response. With repetitive acetylcholine input, the model produced various patterns of synchronization of the sinus pacemaker. There was stable entrainment at harmonic (i.e., 1:1, 2:1, etc.) relations, as well as more complex arrhythmic patterns that depended on the relationship between the acetylcholine cycle length and the sinus pacemaker period. In some cases, shortening of the acetylcholine input cycle length led to “paradoxical” acceleration of the sinus pacemaker. Simulations suggest that many clinically observed sinus rhythm disturbances can be explained by dynamic vagus-sinus interactions.

Ribeiro, Mario C. L.

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In studies utilizing the isolated isovolumic blood-perfused canine heart, left ventric ular pressure was measured following a sudden expansion of ventricular volume. An increase in performance occurred in two phases: first, there was an instantaneous rise of developed pressure simultaneous with ventricular distension; in the second phase, developed pressure continued to increase for several minutes until a final steady state was reached. The immediate increase in developed pressure occurred with a prolongation of the time-to-peak pressure, and there was no further change of time-to-peak pressure during the time-dependent increase of developed pres sure. In another series of experiments, systolic pressure was elevated without changing resting volume, and mechanical performance changed in a different manner: after an increase in systolic load, there was a modest and transient decrease of developed pressure; thereafter, ventricular pressure recovered only to original values. The influence of different degrees of ventricular expansion, calcium, and verapamil were studied. Under higher ventricular dilations the immediate as well as the slow increase of contraction were heightened and the time to reach half of the slow increase was shortened. When ventricular dilation was induced during an infusion of calcium chloride, higher values for the immediate pressure increase were observed, whereas the time-dependent increase and the time to reach half of the slow increase did not change in comparison with control studies. Verapamil decreased the immediate and the time-dependent enhancement of contraction. The time-dependent increase in developed pressure occurs more slowly with verapamil. These findings in the intact heart are in accord with the hypothesis that myocardial stretch is followed by an increase in intracellular calcium stores, and with the concept that the Frank-Starling mechanism involves an activation of the contractile state.

Hermsmeyer, Kent

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We studied the development of selective adrenergic and cholinergic neuroeffector transmission in primary cultures of isolated ventricular muscle cells. Explants of either thoraco-lumbar sympathetic ganglia or sacrococcygeal spinal cord were added to newborn rat ventricular cultures harvested prior to the onset of in vivo autonomic innervation. Neuronal growth, migration, and the formation of neuromuscular junctions were observed with light and scanning electron microscopy. Glyoxylic acid histofluorescence, reflecting catecholamine synthesis, was found in only the sympathetic neuromuscular cultures. Choline acetyltransferase activity was detected in both spinal cord and sympathetic neuromuscular cultures, but was significantly higher in the spinal cord neuromuscular cultures. The isolated ventricular muscle cells remained at a constant spontaneous contraction frequency, regardless of the type of culture preparation. Guanethidine sulfate application produced a positive chronorropic response, blocked by propran-olol, in the sympathetic neuromuscular cultures, but not in the spinal cord neuromuscular cultures. Bethanechol sulfate produced a negative chronorropic response, blocked by atropine, in the spinal cord neuromuscular cultures, but not in the sympathetic neuromuscular cultures. Isolated ventric ular muscle cells in the absence of neurons failed to respond to either agent. Direct microelectrode stimulation of adrenergic or cholinergic neurons likewise respectively produced either a positive or negative ventricular muscle cell chronorropic response. These studies are the first to establish the selective production of functional cholinergic and adrenergic innervation of isolated cardiac muscle cells in vitro.

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Wise, Gwendolyn M.

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The threshold sensitivity of cardiovascular tissues to α-adrenergic stimulation is determined largely by the affinity of a-adrenergic receptors for agonists. To determine whether changes in a-adrenergic receptor affinity could contribute to the regulation of cardiac and vascular responsiveness, we used the a-adrenergic-selective radioligands, [

Wit, Andrew L.

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The effects of changing the time course of action potential repolarization on the amplitude and coupling interval of delayed afterdepolarizations were studied in small preparations of coronary sinus atrial fibers exposed to catecholamines. Repolarization was accelerated or retarded by current pulses passed through an intracellular microelectrode in the depolarizing or repolarizing direction. Acceleration of repolarization decreased the amplitude of delayed after-depolarizations, prolonged their coupling interval to the action potential upstroke, and prevented triggered activity. Prolonging the time for repolarization increased afterdepolarization amplitude, shortened the coupling interval, and caused triggered activity. The afterdepolarization amplitude and coupling interval had a linear relationship to the duration of the action potential plateau. In some preparations, the action potential plateau increased spontaneously at stimulation rates that caused afterdepolarization amplitude to increase and triggering to occur, and this may have contributed to the occurrence of triggering. The effects of action potential repolarization on delayed afterdepolarizations suggest that pharmacological agents such as antiarrhythmic drugs which alter action potential duration should influence afterdepolarizations. Drugs which shorten action potential duration might prevent triggered activity from occurring, whereas drugs which prolong duration might cause triggering.

Saum, William R.

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A persistent question with regard to the effects of catecholamines on baroreceptor activity has been whether the adrenergic action is indirectly mediated through an alteration in vessel wall tone or whether it is a direct action on the excitability of baroreceptor nerve endings. The effects of norepinephrine on the pressure-impulse frequency relationship of rat single aortic baroreceptor fibers were studied in vitro. Perfusion of the aortic arch with norepinephrine produced an excitatory response which consisted of: a drug-evoked stimulation of previously quiecent fibers at 0 mm Hg, and a sensitization of the response to pressure. The norepinephrine-induced facilitation was blocked by prazosin but not by yohimbine. Phenylephrine mimicked the effects of norepinephrine, whereas clonidine had no excitatory effects on baroreceptor activity. Baroreceptor activity was unaffected by β-adrenergic agonists or antagonists. Norepinephrine had no effect on the pressure-volume relationship of the aortic arch, but produced a contraction of helical aortic strips. However, there was no correlation between the concentration-response relationship of norepinephrine on aortic smooth muscle and its excitatory action on baroreceptors. 5-Hydroxytryptamine and angiotensin II produced a contraction of helical strips, but had no effect on baroreceptor activity. Sodium nitrite reduced the norepinephrine-induced contractile response by 75%, but did not antagonize the baroreceptor facilitation. It is proposed that the excitatory action of norepinephrine is independent of smooth muscle activity, and is mediated by activation of