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Flow-mediated dilatation (FMD) of conduit arteries is dependent on an intact endothelium, although the mechanisms are not fully understood. Using high-resolution ultrasound, we examined the role of endothelial mediators in radial artery dilatation in response to transient (short period of reactive hyperemia) and sustained (prolonged period of reactive hyperemia, hand warming, or an incremental infusion of acetylcholine into the distal radial artery) hyperemia. After short episodes of reactive hyperemia, FMD was abolished by local infusion of the nitric oxide synthesis inhibitor N:(G)monomethyl-L-arginine (5.3+/-1.2% versus 0.7+/-0.7%, P:<0.001). In contrast, basal vessel diameter and dilatation after prolonged episodes of reactive hyperemia, hand warming, and distal infusion of acetylcholine were not attenuated by nitric oxide synthesis inhibition. Inhibition of cyclooxygenase or local autonomic nervous system blockade also had no effect on FMD. Patients with hypercholesterolemia exhibited reduced FMD in response to transient hyperemia, but the response to sustained hyperemia was normal. These data suggest heterogeneity of endothelial responses to blood flow that are dependent on the characteristics of the flow stimulus. Dilatation after brief episodes of hyperemia is mediated by release of nitric oxide, whereas dilatation during sustained hyperemia is unaffected by NO synthesis inhibition. Hypercholesterolemia seems to differentially affect these pathways with impairment of the nitric oxide-dependent pathway and preservation of non nitric oxide-mediated dilatation to sustained flow stimuli.

We studied the development of selective adrenergic and cholinergic neuroeffector transmission in primary cultures of isolated ventricular muscle cells. Explants of either thoracolumbar 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 chronotropic response, blocked by propranolol, in the sympathetic neuromuscular cultures, but not in the spinal cord neuromuscular cultures. Bethanechol sulfate produced a negative chronotropic response, blocked by atropine, in the spinal cord neuromuscular cultures, but not in the sympathetic neuromuscular cultures. Isolated ventricular 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 chronotropic response. These studies are the first to establish the selective production of functional cholinergic and adrenergic innervation of isolated cardiac muscle cells in vitro.

The purpose of this study was to investigate the nature of the serotonin-induced coronary chemoreflex in the conscious monkey. Ten chronically prepared and four acute monkeys were used in this study. Five chronically prepared animals had catheters in the left atrium, ascending aorta, descending aorta, and, bilaterally, in the common carotid arteries. In addition, Silastic catheters were placed next to both vagi to permit vagal block with 2% lidocaine. Serotonin was injected (12-200 micrograms/kg) into the left atrium, ascending aorta, descending aorta, or, bilaterally, into the carotid arteries while blood pressure, heart rate, and respiratory movements were recorded. Injections of serotonin were associated with hypertension and bradycardia followed by tachycardia, all of which were preceded by a cough response. Atropine blocked the bradycardia, whereas atropine and phentolamine eliminated the cardiovascular components of the reflex. Vagal blockade eliminated the bradycardia but otherwise did not alter the response to left atrial serotonin. Three monkeys were prepared with aortic and left atrial catheters. Subsequently, they were subjected to sinoaortic deafferentation. Serotonin injected into these animals did not alter blood pressure or respiration. The results of this study show that serotonin injected into the left atrium of the conscious monkey produces respiratory and cardiovascular alterations by its effect on aortic and carotid chemoreceptors, and that there is no coronary chemoreflex in the conscious monkey.

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 quiescent 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 beta-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 nitrate 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 alpha 1-adrenergic receptors located on the aortic baroreceptor nerve endings.

The purpose of this study was to determine the behavior of left ventricular mechanoreceptors with myelinated vagal afferents and to compare them with endings with nonmyelinated vagal afferents. Single unit activity was recorded from 13 endings with nonmyelinated vagal afferents (conduction velocity 2.1 +/- 0.3 m/sec) and from 16 endings with myelinated vagal afferents (conduction velocity 7.3 +/- 1.3 m/sec). Resting discharge frequencies of nonmyelinated afferents and of myelinated vagal afferents were 1.7 +/- 0.3 and 2.7 +/- 0.5 imp/sec (P less than 0.1), respectively (at left ventricular end diastolic pressure of 6 mm Hg for both groups). Ten of 16 myelinated vagal afferents had pulse synchronous discharge under basal condition, whereas only 3 of 13 nonmyelinated vagal afferents had such activity. During aortic occlusion, the discharge of myelinated vagal afferents increased 1.7 +/- 0.3 imp/sec per mm Hg, whereas nonmyelinated vagal afferents increased significantly (P less than 0.05) less (0.5 +/- 0.1 imp/sec per mm Hg). Discharge for both groups was linearly related to left ventricular end-diastolic pressure but not to left ventricular systolic pressure. Increases in left ventricular systolic pressure alone did not increase firing for either group. During aortic occlusion, the maximum discharge rates of myelinated vagal afferents (43 +/- 7 imp/sec) were significantly higher than those of nonmyelinated vagal afferents (14 +/- 3 imp/sec) at left ventricular end-diastolic pressure of 30 +/- 2 and 24 +/- 2 mm Hg, respectively. Both groups increased their discharge during volume expansion with myelinated vagal afferents showing greater sensitivity than nonmyelinated vagal afferents. All endings studied were in the inferoposterior wall of the left ventricle. All nonmyelinated vagal afferents were in or near the epicardium. In contrast, myelinated vagal afferents were equally distributed between the endocardium and the epicardium. Myelinated vagal afferents had discrete receptive fields (1-2 mm2) whereas those of nonmyelinated vagal afferents were much larger (1 cm2). In conclusion, the discharge of left ventricular endings with nonmyelinated vagal afferents and myelinated vagal afferents both appear to be determined mainly by changes in left ventricular end-diastolic pressure. They may be located at different depths in the left ventricular wall. Myelinated vagal afferents have greater sensitivity and maximum firing frequencies than nonmyelinated vagal afferents.