Biomedical subjects

J T Shepherd

Publications and source records attributed to J T Shepherd.

At least 55 records · Page 3Linked to original sources

PubMed1986

Aggregating human platelets cause direct contraction and endothelium-dependent relaxation of isolated canine coronary arteries. Role of serotonin, thromboxane A2, and adenine nucleotides.

Aggregating human platelets contract isolated rings of canine coronary artery without endothelium, but relax rings with intact endothelium. We performed experiments to identify the substances released from platelets responsible for these effects. The contraction in rings without endothelium was reduced by treating the platelets with thromboxane synthetase inhibitor, dazoxiben, or treating the vessels with the thromboxane-receptor antagonist, SQ 29548. The serotonergic antagonist, methiothepin, also reduced the platelet-induced contraction. The combination of methiothepin plus dazoxiben or SQ 29548 caused a further inhibition. The endothelium-dependent relaxation to platelets during contractions evoked by prostaglandin F2 alpha was nearly abolished by the ADP- and ATP-scavenger, apyrase. It was not inhibited by methiothepin, which antagonizes endothelium-dependent relaxations to serotonin. Thus, both serotonin and thromboxane A2 contribute to the direct activation of coronary smooth muscle by aggregating human platelets, whereas adenine nucleotides are the principal mediators of the endothelium-dependent relaxation.

Adenine Nucleotides↗

PubMed1986

Oxytocin causes endothelium-dependent relaxations of canine basilar arteries by activating V1-vasopressinergic receptors.

Experiments were designed to study the effects of oxytocin on canine basilar and femoral arteries and to compare these with the effects of vasopressin. Rings of the arteries were suspended in physiological salt solution for isometric tension recording. Oxytocin and vasopressin caused endothelium-dependent relaxation of basilar arteries contracted with prostaglandin F2 alpha. Vasopressin was more potent than oxytocin. In the femoral artery, the two hormones caused endothelium-independent contractions with the same order of potency. The relaxations of the basilar artery occurred at lower concentrations of each substance than the contractions of the femoral artery. The relaxations in response to both agonists were inhibited competitively, and the contractions noncompetitively, by the V1-vasopressinergic antagonist d(CH2)5Tyr(Me)AVP; the antagonist did not affect endothelium-dependent relaxations in response to bradykinin. Thus, both oxytocin and vasopressin cause endothelium-dependent relaxation of the basilar artery by activating V1-vasopressinergic receptors; the contractions of femoral arteries that they cause also may be mediated in part by V1-vasopressinergic receptors.

Animals↗

PubMed1985

Circulatory response to beta-adrenergic blockade at rest and during exercise.

The beta adrenoceptors involved in the regulation of the cardiovascular system include the beta 1 subtype in the heart, coronary arteries and juxtaglomerular cells of kidney, and the beta 2 subtype in skeletal muscle resistance vessels and on terminals of sympathetic nerves. The beta 1 receptors are activated primarily by norepinephrine released from the sympathetic nerves, the beta 2 by circulating epinephrine from the adrenal medulla. The function of these receptors is to adjust the circulation to meet the stresses imposed by gravitational forces including those that occur in changing from supine to standing position, in muscular exercise and during emotional stress. In normal subjects, other systems can compensate if the beta receptors are prevented from functioning. Thus, during beta-adrenergic blockade it is only when the cardiovascular system is taxed severely that deficiencies in its performance become apparent. In patients with cardiovascular diseases, other effects of beta blockers, not yet understood, may also be important.

Animals↗

PubMed1985

Spasm of the coronary arteries: causes and consequences (the scientist's viewpoint).

Both beta 1- and alpha 1-adrenoceptors are present on canine coronary arteries, and they are accessible to norepinephrine released from the sympathetic nerves. Under normal conditions, these arteries relax because of the predominance of the beta 1-adrenoceptors, whereas constriction prevails in the presence of beta 1-adrenoceptor antagonists. The coronary arteries also have cholinergic nerves. When activated, these nerves release acetylcholine, which acts on muscarinic receptors on the sympathetic nerve terminals to reduce the output of norepinephrine and thereby lessen the relaxation mediated by beta 1-adrenoceptors. Thus, muscarinic agonists can precipitate coronary artery spasm. If the smooth muscle cells of the coronary arteries become hypoxic, their responsiveness to beta-adrenergic stimulation is lost and constrictor responses are exaggerated. Cardiac glycosides prevent the predominance of the beta-adrenergic effects of norepinephrine. Therefore, after treatment with ouabain, release of norepinephrine from the sympathetic nerves leads not to relaxation but to further contraction of coronary arteries. The endothelium of the coronary arteries inhibits platelet aggregation by the formation and release of prostacyclin, and it reacts to platelet products by causing relaxation of the underlying smooth muscle. In addition, if any thrombin is formed, it also causes endothelium-mediated relaxation. If the endothelium is damaged, these protective mechanisms are lost. Patients with coronary artery spasm usually have morphologic changes in the artery at the site of the spasm. Platelets can aggregate at this site and release vasoactive substances, which--aided by formation of thrombin--cause contraction. Thus, the blood supply to the myocardium is reduced; the ensuing hypoxia augments the constriction. Acute myocardial ischemia caused by coronary vasospasm may precipitate acute cardiac rhythm disturbances and sudden death by ventricular tachycardia or fibrillation.

Adrenergic beta-Agonists↗

PubMed1985

The heart as a sensory organ.

Three groups of receptors in the heart are activated by changes in pressure in the cardiac chambers. Those at the venous-atrial junctions with myelinated vagal afferent nerves indicate changes in heart rate and degree of atrial filling. A second group, present in all the cardiac chambers, served by unmyelinated vagal afferent nerves, signals changes in ventricular preload, afterload and cardiac contractility. A third group, also present in all the cardiac chambers, has both myelinated and unmyelinated afferent nerves that pass to the spinal cord. Their normal function is unknown. Abnormal activation of the cardiac mechanoreceptors during myocardial ischemia may be important in the genesis of life-threatening arrhythmias.

Arrhythmias, Cardiac↗

PubMed1985

Modulation of postjunctional alpha-adrenergic responsiveness by local changes in temperature.

In canine cutaneous veins, local moderate warming (37 degrees-41 degrees C) augments the responsiveness to postjunctional alpha 1-adrenergic stimulation but depresses that to postjunctional alpha 2-adrenergic activation. Moderate cooling (37 degrees-24 degrees C) has the opposite effect. The effects of warming and cooling on alpha 1-adrenergic responses are buffered by a large receptor reserve, allowing for the predominance of alterations in alpha 2-adrenergic responsiveness.

Adrenergic alpha-Agonists↗

PubMed1985

Local modulation of adrenergic neurotransmission in blood vessels.

Norepinephrine, released from sympathetic nerve terminals, has a key role in adjusting continuously the performance of the cardiovascular system. Although the amount of transmitter released depends primarily on the degree of activation of postganglionic sympathetic fibers, local metabolites and circulating vasoactive substances, in addition to affecting smooth-muscle cells directly, alter the amount of norepinephrine released. Thus, metabolic acidosis, an increase in potassium ions and in osmolality reduce the output of norepinephrine in the face of a constant frequency of stimulation of the postganglionic fibers. Many receptors have been identified on the prejunctional nerves which, when activated, can increase or decrease transmitter release. Those agonists which decrease it include adenosine and the adenine nucleotides, and norepinephrine, acetylcholine, histamine, and serotonin, acting on purinergic, alpha 2-adrenoceptors, muscarinic, H2-histaminergic and S1-serotoninergic receptors, respectively. Those that increase transmitter release include epinephrine (acting on beta 2-adrenoceptors) and angiotensin II. Part of the action of certain drugs is due to their prejunctional effects. Thus, cardiac glycosides cause a release of norepinephrine, and the antidepressant drug amitriptyline causes inhibition of prejunctional alpha-adrenoceptors and muscarinic receptors. Local changes in temperature also have complex actions on the neuroeffector junction and the vascular smooth muscle, which are of prime importance for cutaneous vessels.

Acetylcholine↗

PubMed1985

Adenine nucleotides, serotonin, and endothelium-dependent relaxations to platelets.

Aggregating platelets cause an endothelium-dependent relaxation of isolated contracted canine coronary arteries. The role of adenine nucleotides and of 5-hydroxytryptamine in causing this relaxation was determined. Rings of these arteries were suspended in organ chambers filled with physiological salt solution and contracted with prostaglandin F2 alpha. Adenosine diphosphate relaxed rings with intact endothelium but had no effect on endothelium-denuded rings. The relaxation was attenuated by the enzyme, apyrase, which hydrolyzes adenosine tri- and diphosphate. 5-Hydroxytryptamine (5-HT) exerted a direct contractile effect mediated by the endothelium. The latter was prevented by the 5-HT1 serotonergic antagonist, methiothepin, but not by the 5-HT2 serotonergic antagonist, ketanserin. The endothelially mediated relaxation to aggregating platelets was prevented by apyrase but not by methiothepin or ketanserin. Responses to platelets were unaltered by the inhibitor of cyclooxygenase, meclofenamate. These experiments demonstrate the key role of adenine nucleotides in mediating the endothelium-dependent relaxation of canine coronary arteries to aggregating platelets.

Adenine Nucleotides↗

PubMed1985

Cooling and alpha 1- and alpha 2-adrenergic responses in cutaneous veins: role of receptor reserve.

Experiments were designed to determine the effects of cooling on alpha 1- and alpha 2-adrenergic responses in isolated canine cutaneous veins. Rings of saphenous veins were suspended for isometric tension recording in physiological salt solution. Cooling (from 37 to 24 degrees C) augmented contractions to norepinephrine under control conditions and after alpha 1-adrenergic blockade (prazosin) but not following alpha 2-adrenergic blockade (rauwolscine). Cooling augmented contractions evoked by the alpha 2-adrenergic agonists B-HT 920 and UK 14304 but did not affect responses to the full alpha 1-adrenergic agonist phenylephrine. These experiments suggest that cooling augments alpha 2-adrenergic responsiveness without affecting alpha 1-adrenergic responsiveness. However, the contractions evoked by the partial alpha 1-adrenergic agonist St 587 were virtually abolished by cooling. Moreover, following partial irreversible blockade of the alpha 1-adrenoceptors with phenoxybenzamine, cooling also reduced the contractions evoked by phenylephrine. Therefore, cooling reduces alpha 1-adrenergic responsiveness in canine cutaneous veins, but in the case of full alpha 1-adrenergic agonists such as norepinephrine and phenylephrine the inhibitory effect of cooling is buffered by an alpha 1-adrenoceptor reserve. With norepinephrine, this permits the potentiating effect of cooling on the alpha 2-adrenergic component of the response to predominate.

Adrenergic alpha-Agonists↗

PubMed1985

Adrenergic pharmacology of human and canine peripheral veins.

A comparison has been made of the factors concerned with the response of canine and human saphenous veins to adrenergic stimulation. Both vessels have prejunctional muscarinic and beta-adrenergic receptors. When activated by appropriate agonists these receptors decrease and increase the output, respectively, of norepinephrine from the nerve endings. Both vessels have postjunctional alpha 1 and alpha 2 adrenoceptors and postjunctional beta adrenoceptors. Activation of the former two receptors leads to contraction of the smooth muscle, and of the latter to relaxation. There are, however, qualitative differences. In the human veins the responsiveness of the prejunctional beta adrenoceptors exceeds that of the postjunctional, whereas the reverse is true in the dog. As a consequence, in the human vein beta-adrenergic agonists augment, and in the canine veins they depress, the contractile response to sympathetic nerve stimulation.

Acetylcholine↗

PubMed1984

Prolonged vibration of cutaneous artery: absence of persisting aftereffects.

1-3 h after prolonged (3-16 h) vibration (120 Hz, 0.2-0.3 mm amplitude) of rings of canine saphenous arteries there was no significant change in the contractile response to electrical stimulation, exogenous norepinephrine or of neuronal uptake of tritium labeled norepinephrine. These results did not provide evidence for persistent aftereffects of prolonged vibration.

Animals↗

PubMed1984

Role of arterial and cardiopulmonary mechanoreceptors in the regulation of arterial pressure during rest and exercise in conscious dogs.

Techniques have been developed to study the role of arterial and vagally innervated cardiopulmonary mechanoreceptors in conscious dogs during rest, exercise, and anxiety or emotional stress. These techniques involve, among others, bilateral reversible vascular isolation of the carotid sinuses and acute reversible interruption of the aortic baroreflex. The carotid sinus, the aortic arch, and the cardiopulmonary receptors tonically inhibit the vasomotor center in the resting dog. The arterial receptors, but not the cardiopulmonary receptors, minimize the lability in arterial pressure at rest and during exercise. During exercise, the arterial baroreceptors are reset to a higher operating point, limit the increase in arterial blood pressure that develops with increasing severity of exercise, and act to return the pressure quickly to the resting level when exercise ceases. The effects on arterial blood pressure are due to reflex changes in total systemic vascular resistance; cardiac output and heart rate are controlled independently of the arterial and cardiopulmonary mechanoreflexes. The cardiopulmonary reflexes have no evident role in the control of arterial pressure during exercise but, in the chronic absence of the arterial baroreflexes, act to decrease the total systemic vascular resistance when exercise ceases.

Afferent Pathways↗

PubMed1984

Endothelium and asymmetrical responses of the coronary arterial wall.

Changes in isometric tension due to intra- or extraluminal addition of vasoactive agents were determined in isolated perfused segments of canine left circumflex coronary artery. Segments denuded of endothelium were more sensitive to the contractile action of 5-hydroxytryptamine and potassium during intraluminal addition. In segments with intact endothelium, the sensitivity to intraluminal, but not extraluminal, 5-hydroxytryptamine was decreased in comparison to denuded segments; that to potassium was unchanged. In segments with intact endothelium contracted with prostaglandin F2 alpha, intraluminal, but not extraluminal, acetylcholine, adenosine diphosphate, or thrombin caused relaxation. Intraluminal 5-hydroxytryptamine and aggregating platelets caused relaxation or attenuated contractions in a majority of vessels studied; extraluminal addition caused only contractions. Thus the endothelium is responsible for opposite smooth muscle responses to intra- versus extraluminal vasoactive substances released from aggregating platelets. During intraluminal thrombosis the endothelium may inhibit smooth muscle contraction by responding to 5-hydroxytryptamine and adenosine diphosphate released from platelets and to thrombin; where the endothelium is damaged, the luminal aspect of the blood vessel wall, which is more sensitive to 5-hydroxytryptamine, may become the site of coronary spasm.

Acetylcholine↗

PubMed1984

Cardiopulmonary reflexes and blood pressure in exercising sinoaortic-denervated dogs.

To examine the role of cardiopulmonary receptors in arterial blood pressure regulation during and after exercise, conscious dogs with chronic sinoaortic denervation were subjected to 12 min of light exercise and 12 min of exercise that increased in severity every 3 min. Hemodynamic measurements were made before and after interruption of cardiopulmonary afferents by bilateral cervical vagotomy. During both exercise protocols, after an initial transient decrease, the arterial blood pressure remained close to resting values before and after vagotomy. On cessation of the graded exercise, the arterial blood pressure did not change before, but a rapid and sustained increase in pressure occurred after vagotomy. At the time of this increase the cardiac output and heart rate were returning rapidly to the resting level. The study demonstrates that in the chronic absence of arterial baroreflexes, vagal afferents prevent a rise in arterial blood pressure after vigorous exercise presumably by the action of cardiopulmonary receptors causing a rapid dilatation of systemic resistance vessels.

Animals↗

PubMed1984

The effect of warming on adrenergic neurotransmission in canine cutaneous vein.

The effect of warming on adrenergic neurotransmission was examined in canine cutaneous veins. Isometric tension was recorded from rings of saphenous veins of the dog in organ chambers filled with physiological salt solution. During contractions caused by potassium or prostaglandin F2 alpha, warming from 37 to 41 degrees C caused an augmentation. During contractions caused by stimulation of the adrenergic nerves, and by exogenous norepinephrine, warming caused a relaxation. The relaxation with warming was not altered by the beta-adrenergic antagonist, propranolol, or by inhibitors of extraneuronal and neuronal uptake of norepinephrine. During contractions evoked by the alpha 2-adrenergic agonists, alpha-methyl norepinephrine and B-HT 920, warming caused a relaxation, whereas during contractions due to the alpha 1-adrenergic agonists, cirazoline , methoxamine, ST 587, and phenylephrine, it caused an augmentation. The relaxation caused by warming during norepinephrine-induced contractions was prevented by the preferential alpha 2-antagonists yohimbine and rauwolscine, but not by the preferential alpha 1-antagonist, prazosin. In strips of saphenous vein incubated with [3H] norepinephrine , warming did not affect the release of labeled transmitter evoked by nerve stimulation. These experiments indicate that warming directly enhances contractility of vascular smooth muscle, while depressing the responsiveness of cutaneous vessels to sympathetic nerve activation by a selective inhibitory effect on postjunctional alpha 2-adrenoceptors. Relaxation with warming is greater during nerve stimulation than during administration of exogenous norepinephrine, which may be due to a predominance of postjunctional alpha 2-adrenoceptors in the neuromuscular junction.

Animals↗

PubMed1984

Vasopressin causes endothelium-dependent relaxations of the canine basilar artery.

The effect of synthetic 8-arginine vasopressin (vasopressin) was studied in isolated canine basilar, left circumflex coronary, and femoral arteries of the dog. Vascular rings with and without endothelium were suspended for isometric tension recording in physiological salt solution. The removal of the endothelium was confirmed by the absence of relaxations induced by either thrombin (basilar arteries) or acetylcholine (coronary and femoral arteries). In the basilar artery, vasopressin induced concentration-dependent inhibition of myogenic tone. In basilar and coronary arteries, the hormone caused concentration-dependent relaxations during contractions evoked by prostaglandin F2 alpha. In femoral arteries, vasopressin caused contraction. After removal of the endothelium, the inhibitory responses to vasopressin were abolished in basilar arteries and significantly reduced in left circumflex coronary arteries. The contractions of femoral arteries were not affected by endothelium removal. The V1-vasopressinergic antagonist d(CH2)5Tyr(Me)AVP prevented the inhibitory response to vasopressin, but did not alter endothelium-dependent relaxations of basilar arteries caused by adenosine diphosphate. These results demonstrate that the endothelial cells mediate relaxation induced by vasopressin via specific V1-vasopressinergic receptors.

Adenosine Diphosphate↗

PubMed1984

Cooling augments platelet-induced contraction of peripheral arteries of the dog.

The effect of cooling on platelet-induced contractions was studied. Rings of canine saphenous arteries were suspended for isometric tension recording in organ baths filled with aerated physiological salt solution. Norepinephrine, 5-hydroxytryptamine, and autologous aggregating platelets all caused contractions that were augmented by cooling the bath content from 37 to 24 degrees C. These contractions were inhibited, in a concentration-dependent manner, by the serotonergic antagonist ketanserin. The alpha 1-adrenergic antagonist, prazosin, in concentrations causing progressive inhibition of contractions evoked by norepinephrine did not affect the response to either 5-hydroxytryptamine or platelets. Aggregating platelets were found to release 5-hydroxytryptamine in sufficient amounts to account for the observed contractions. Pretreatment of platelets with the cyclo-oxygenase inhibitor meclofenamate reduced the amount of thromboxane liberated by aggregating platelets but did not influence evoked contractions. These observations suggest that aggregating platelets cause contraction of the canine saphenous artery by releasing 5-hydroxytryptamine. They demonstrate that cooling markedly augments contractions of peripheral arterial smooth muscle caused by aggregating platelets.

Animals↗

PubMed1984

Vasopressin induces endothelium-dependent relaxations of cerebral and coronary, but not of systemic arteries.

Vasopressin causes relaxations of isolated basilar and left circumflex coronary arteries of the dog. After removal of the endothelium the inhibitory effect of vasopressin is abolished in the basilar and reduced in the coronary arteries. By contrast, vasopressin causes contractions of femoral arteries, which are not affected by the removal of endothelium. Indomethacin, nordihydroguaiaretic acid, atropine, propranolol and cimetidine do not reduce the inhibitory effect of vasopressin in basilar arteries. However, the V1-vasopressinergic antagonist d(CH2)5Tyr(Me)AVP blocks the vasopressin-induced relaxations, indicating that the effect of the hormone on the endothelium is mediated by activation of specific V1-vasopressinergic receptors.

Animals↗