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Biomedical subjects

J T Shepherd

Publications and source records attributed to J T Shepherd.

At least 73 records · Page 4Linked to original sources
PubMed1984

Neurogenic cholinergic prejunctional inhibition of sympathetic beta adrenergic relaxation in the canine coronary artery.

Electrical stimulation of isolated canine coronary arteries causes release of norepinephrine and subsequent relaxation by activation of beta adrenoceptors. The purpose of the present study was to determine if this beta adrenergic relaxation was influenced by a concomitant release of acetylcholine. Rings of epicardial coronary arteries of the dog were studied in organ chambers filled with physiological salt solution. The tetrodotoxin-sensitive, beta adrenergically mediated relaxation induced by electrical stimulation was studied during contractions evoked by prostaglandin F2 alpha. The relaxation to low-frequency stimulation was inhibited and augmented, respectively, by acetylcholine and atropine, suggesting that release of acetylcholine may modulate the beta adrenergic response to sympathetic nerve stimulation. The relaxation caused by high-frequency stimulation was not affected by atropine or removal of the endothelium, indicating that endogenously released acetylcholine does not act directly on the smooth muscle or initiate an endothelium-dependent vasodilator response. In superfused strips of coronary artery preincubated in [3H]norepinephrine, acetylcholine depressed the stimulated overflow of [3H]norepinephrine, indicating prejunctional cholinergic receptors on adrenergic nerve endings. Atropine augmented the overflow, suggesting that endogenous acetylcholine, released during stimulation, inhibits the release of norepinephrine. These observations suggest that prejunctional inhibition of norepinephrine release, which limits the sympathetic beta adrenergic relaxation of the smooth muscle, is the primary neurogenic cholinergic effect in canine epicardial coronary arteries.

Acetylcholine↗
PubMed1984

Effects of the adrenergic transmitter on epicardial coronary arteries.

Rings of isolated epicardial coronary arteries made to contract with prostaglandin F2 alpha relax when their sympathetic nerves are stimulated. This response, which is the opposite of that seen in other systemic blood vessels, results from activation by norepinephrine (NE) of beta 1 adrenoceptors, which predominate over alpha 1 adrenoceptors in the main coronary arteries. A modest contraction occurs only when the beta 1 adrenoceptors are blocked. As each branch leaves the main artery, only beta 1 adrenoceptors are present, so that the sole effect of NE is to cause relaxation. Like the terminations of other sympathetic nerves, those to the main coronary arteries or their branch vessels contain alpha 2 adrenoceptors that when activated reduce the output of neurotransmitter. When these prejunctional receptors are inhibited with phentolamine, there is a greater relaxation in response to activation of the sympathetic nerves, which is caused by increased release of NE. Thus, the in vivo observation that phentolamine increases coronary blood flow may be explained by the action of this drug on prejunctional alpha 2 adrenoceptors rather than on alpha 1 adrenoceptors on the smooth muscle cells themselves.

Animals↗
PubMed1983

Inhibitory role of the endothelium in the response of isolated coronary arteries to platelets.

Aggregating autologous platelets caused contraction of isolated rings of canine left circumflex arteries. The contractions were augmented after removal of the endothelium and were attenuated by serotonergic antagonists. During contraction caused by prostaglandin F2 alpha, aggregating platelets caused a transient increase in tension followed by a profound relaxation of arteries with endothelium, but caused only further contraction of arteries without endothelium. These observations demonstrate the importance of the vascular endothelium in opposing the constriction of coronary vessels caused by 5-hydroxytryptamine and other substances released from aggregating platelets.

Animals↗
PubMed1983

Prejunctional beta-adrenoceptors in human and canine saphenous veins.

Experiments were designed to compare the functional importance of prejunctional beta-adrenoceptors in human and canine blood vessels. Rings of saphenous veins were mounted for isometric tension recording in organ chambers filled with physiological salt solution. Isoproterenol caused concentration-dependent relaxations of comparable magnitude during contractions of canine veins caused by electrical stimulation or norepinephrine. In the human veins, isoproterenol caused smaller relaxations during norepinephrine-induced contractions, and augmented the contractile response to electrical stimulation. Helical strips of veins were incubated with [3H]norepinephrine and mounted for superfusion and isometric tension recording. Isoproterenol augmented the release of intact labeled transmitter during electrical stimulation more in the human than in the canine vein. In veins from both species the effects of isoproterenol were inhibited by propranolol. These experiments demonstrate that the adrenergic nerves of the human saphenous vein have a greater responsiveness to prejunctional beta-adrenergic activation than those of the corresponding canine vessel. As a consequence, in the human vein, beta-adrenergic agonists augment, rather than depress the contractile response to activation of the adrenergic nerve endings.

Animals↗
PubMed1983

Muscarinic and beta-adrenergic prejunctional modulation of adrenergic neurotransmission in the blood vessel wall.

Many prejunctional inhibitory and excitatory receptors have been described on adrenergic nerve endings in animal arteries and veins, and studies to date have identified some of these in human blood vessels. The latter include muscarinic receptors in cutaneous veins which when activated by acetylcholine inhibit the evoked release of norepinephrine, and beta-adrenoceptors which when stimulated by isoproterenol or epinephrine facilitate it. Animal studies suggest that cholinergic vasodilatation can result from prejunctional inhibition of adrenergic neurotransmission. The human saphenous vein appears to contain more prejunctional beta-adrenoceptors than the canine, with a consequential greater enhancement of norepinephrine release when these receptors are activated.

Acetylcholine↗
PubMed1983

Effect of cold on the blood vessel wall.

The effect of cold has been studied on isolated canine and human blood vessels. These have led to the following conclusions concerning the phenomenon of the hunting reaction seen in human extremities on their exposure to severe cold. (1) On exposure to cold there is a marked increase in the affinity of the postjunctional alpha-adrenoceptors for norepinephrine. This results in a powerful constriction of the blood vessels and a cessation of blood flow to the distal tissue. As the temperature of the tissues rapidly falls, sympathetic nerve conduction is interrupted and vasodilatation occurs, due to the cessation of norepinephrine release and the depressor action of cold on the contractile machinery. The resultant return of blood flow rewarms the tissue, nerve conduction is reestablished, and this combined with the increased affinity of the alpha-adrenoceptors for norepinephrine leads to renewed vasoconstriction. Repetition of this cycle could result in the hunting reaction. (2) There appears to be a difference between the cutaneous artery and vein, in that the latter remains constricted at lower temperatures. (3) Preliminary experiments suggest that the response of the human cutaneous vein to cold is qualitatively similar to the dog vein, although some quantitative differences are present.

Animals↗
PubMed1983

5-Hydroxytryptamine can mediate endothelium-dependent relaxation of coronary arteries.

5-Hydroxytryptamine caused contractions of isolated canine coronary artery rings. These contractions were larger in the absence of the endothelium, whereas those caused by phenylephrine, potassium chloride, and prostaglandin F2 alpha were not. When coronary arteries were contracted with prostaglandin F2 alpha, 5-hydroxytryptamine caused relaxation in some rings with endothelium but only further contraction in all rings without endothelium. The inhibitory action of 5-hydroxytryptamine mediated by the endothelium was unaffected by blockade of monoamine oxidase or cyclooxygenase. In rings with endothelium, aggregating platelets, which released 5-hydroxytryptamine and thromboxane A2, caused relaxation. The relaxations caused by 5-hydroxytryptamine and aggregating platelets were antagonized by methysergide but not by ketanserin. These observations suggest that the response to 5-hydroxytryptamine is the net result of a direct contractile action on coronary smooth muscle and an inhibitory action mediated by the endothelium. In some vessels the endothelium-dependent inhibitory responses to aggregating platelets may be mediated in part by released 5-hydroxytryptamine. The serotonergic receptors on endothelial cells may be of a different subtype than those mediating contractions of the smooth muscle cells.

Animals↗
PubMed1983

Prejunctional and postjunctional actions of endogenous norepinephrine at the sympathetic neuroeffector junction in canine coronary arteries.

The effects of endogenous and of exogenous norepinephrine were studied in isolated rings of canine left circumflex coronary artery and its first ventricular branch. Norepinephrine was released from adrenergic nerve endings by transmural electrical stimulation and by tyramine. In rings contracted with prostaglandin F2 alpha, transmural electrical stimulation resulted in frequency-dependent relaxations which were blocked by propranolol or tetrodotoxin; tyramine and exogenous norepinephrine caused concentration-dependent relaxations which were blocked by propranolol. The tyramine-induced relaxations also were inhibited by cocaine. The left circumflex artery was less sensitive than its branch to beta-adrenergic activation; this difference was significant even between rings of the two vessels immediately adjacent to the branching point and was abolished by phentolamine. In the presence of propranolol, transmural electrical stimulation, tyramine and phenylephrine, produced contractions of the left circumflex artery, but not the branch; these contractions were prevented by phentolamine. Phentolamine, but not prazosin, augmented the beta-adrenergic response of left circumflex artery to low frequency stimulation; in arteries preincubated with 3H-norepinephrine, this was accompanied by an increased overflow of tritiated neurotransmitter. The prejunctional effect of phentolamine was also evident in branch coronary arteries which exhibit no postjunctional alpha-adrenergic responses. With high frequency stimulation, both alpha-adrenergic antagonists equally augmented the relaxation of left circumflex artery; the efflux of tritiated norepinephrine was not different from untreated arteries. These experiments demonstrate, in isolated coronary arteries, that the primary adrenergic response to released endogenous norepinephrine is beta-adrenergic relaxation. The prejunctional effects of nonspecific alpha-adrenergic antagonists preclude their use in determining the importance of postjunctional coronary alpha-adrenergic receptor activation caused by sympathetic nerve stimulation.

Adrenergic alpha-Antagonists↗
PubMed1983

Contractions of canine vascular smooth muscle cells caused by ouabain are due to release of norepinephrine from adrenergic nerve endings.

Experiments were performed to determine whether the contractions of isolated canine blood vessels caused by ouabain are due solely to the release of endogenous norepinephrine. The response of segments of splenic arteries and veins and strips of splenic capsules to ouabain were compared before and after surgical sympathectomy. Successful denervation was demonstrated by absence of a contractile response to electrical stimulation, supersensitivity to exogenous norepinephrine, an extremely low content of endogenous norepinephrine, reduced accumulation of 3H-norepinephrine, and inability of electrical stimulation and tyramine to augment the overflow of 3H-norepinephrine. Ouabain augmented the overflow of 3H-norepinephrine from control but not from denervated splenic capsule. It caused contraction of control but not of denervated splenic arteries, veins, and capsules. Studies were also conducted in the same tissues and in segments of mesenteric and femoral arteries and of circular and longitudinal segments of the portal mesenteric vein before and after chemical sympathectomy with 6-hydroxydopamine. In these tissues, the contractile responses to electrical stimulation but not exogenous norepinephrine and prostaglandin F2 alpha were abolished. In the control tissues, ouabain caused strong contractions, whereas, in the denervated tissues, only a weak or no response to the glycoside occurred. The study demonstrates that, in isolated canine blood vessels, ouabain causes contraction of smooth muscle cells by virtue of its ability to release norepinephrine from the sympathetic nerves.

Adrenergic Fibers↗
PubMed1981

The effect of profound cooling on adrenergic neurotransmission in canine cutaneous veins.

1. Experiments were performed to investigate how profound cooling affects adrenergic neurotransmission and vascular smooth muscle reactivity in isolated saphenous veins of the dog. 2. Cooling from 37 to 5 degrees C caused progressive depression of the contractile responses to high K+ solutions, illustrating the direct inhibitory effect of cooling on depolarization-induced contraction of the venous smooth muscle cells. 3. During prolonged cooling to 20, 15 and 10 degrees C, the contractile response to exogenous norepinephrine (10(-8)-10(-6) M) was augmented compared to that at 37 degrees C. At 5 degrees C responses up to 10(-7) M were also augmented, but those at higher concentrations were depressed. When veins contracted with 2 x 10(-6) M-norepinephrine were cooled to 20, 15, 10 and 5 degrees C, there was a further increase in tension; this increase slowly subsided to control values at 5 degrees C but was sustained at the other temperatures. 4. Cooling to 20 and 15 degrees C augmented the contraction caused by low but not high frequencies of electrical stimulation of the adrenergic nerve endings. Further cooling to 10 degrees C depressed, and at 5 degrees C abolished the response, demonstrating that profound cooling interrupted adrenergic neurotransmission. 5. In rings stimulated electrically at a low frequency (0.5 Hz), warming from 7 to 9 degrees C or from 9 to 11 degrees C, caused marked increases in tension. This may be explained by the combination of resumption of adrenergic neurotransmission and the increased responsiveness of the cutaneous venous smooth muscle cells to adrenaline. 6. The combination of enhanced affinity for noradrenaline combined with inhibition of neurotransmitter disposition probably permits the cutaneous veins to remain constricted during exposure to severe cold.

Animals↗
PubMed1981

George E. Brown memorial lecture. Local modulation of adrenergic neurotransmission.

The cardiovascular reflexes, by regulating the traffic in the sympathetic nerves, govern the amount of norepinephrine released from the nerve endings. However, the final adjustments in the amount of neurotransmitter available to activate the beta 1 receptors in the heart and the alpha receptors in the blood vessels take place at the sympathetic neuroeffector junction. Thus, a decrease in pH, hyperosmolarity, moderate increases in the concentration of K+ ion, adenosine and adenine nucleotides depress the release of norepinephrine at any given level of sympathetic nerve activity. These metabolic changes, which occur in active tissues, and in particular in adenosine, have been proposed as mediators of the accompanying local hyperemia. In addition, they apparently facilitate this local dilatation by disconnecting the blood vessels in the active tissues from sympathetic control. Acetylcholine, histamine and 5-hydroxytryptamine are present in and around certain blood vessels and can activate specific receptors on the prejunctional fibers and cause vasodilatation by reducing the output of neutrotransmitter. Some of the norepinephrine released into the synaptic cleft may depress its continued release by activating prejunctional alpha receptors. In contrast, angiotensin II, by a local action on the nerve endings, can augment the release of transmitter. Decreases in local temperature reduce transmitter release but augment the affinity of the postjunctional alpha receptors for norepinephrine. The role of these local events at the neuroeffector junction, their physiologic significance and potential clinical importance are discussed in this review.

Acetylcholine↗
PubMed1981

Prejunctional inhibition of norepinephrine release caused by acetylcholine in the human saphenous vein.

We performed experiments to determine whether or not acetylcholine exerts a prejunctional inhibitory effect on adrenergic neurotransmission in the human blood vessel wall. Rings of human greater saphenous veins were prepared 2 to 15 hours after death and mounted for isometric tension recording in organ chambers filled with Krebs-Ringer solution. Acetylcholine depressed contractile responses to electric activation of the sympathetic nerve endings significantly more than those to exogenous norepinephrine; the relaxations caused by the cholinergic transmitter were antagonized by atropine. Helical strips were incubated with [3H]norepinephrine and mounted for superfusion. Electric stimulation augmented the fractional release of labeled norepinephrine. Acetylcholine caused a depression of the evoked 3H release which was antagonized by atropine but not by hexamethonium. These experiments demonstrate that, as in animal cutaneous veins, there are prejunctional inhibitory muscarinic receptors on the adrenergic nerve endings in the human saphenous vein. By contrast, the human vein also contains postjunctional inhibitory muscarinic receptors.

Acetylcholine↗
PubMed1981

Action of lithium on the adrenergic nerve ending.

The effect of lithium on adrenergic neurotransmission was investigated using the lateral saphenous vein of the dog as a model of the neuroeffector process. Helically cut vein strips were mounted in either an organ bath where tension was recorded or in a superfusion system where both tension and the overflow of [3H]norepinephrine and its metabolites were determined. Lithium was used at both therapeutic (0.5-1.5 mEq/l) and toxic (2.5-14.4 mEq/l) concentrations. Lithium had no effect on basal tension or overflow [3H]norepinephrine. At therapeutic concentrations, the neuronal amine uptake mechanism was augmented, whereas at toxic concentrations monoamine oxidase was inhibited. In therapeutic concentrations, lithium attenuated the response of the adrenergic nerve ending to electrical stimulation (0.5-10 Hz). This response was due in part to the augmentation of the neuronal amine uptake mechanism. At toxic concentrations, responses to low frequency (0.2-1.0 Hz) electrical stimulation were augmented, whereas those at higher frequencies (5-10 Hz) were attenuated. Inhibition of monoamine oxidase by lithium accounted for only a part of the augmented overflow of transmitter and subsequent contractile response since inhibition of monoamine oxidase did not prevent the augmentation by lithium of [3H]norepinephrine overflow. The mechanism by which lithium in both therapeutic and toxic concentrations reduces transmitter overflow and subsequently contractile responses remains to be elucidated. Thus, lithium alters the disposition and release of norepinephrine and, as a result, affects adrenergic neurotransmission.

Animals↗