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Biomedical subjects

J A Bevan

Publications and source records attributed to J A Bevan.

At least 109 records · Page 6Linked to original sources
PubMed1987

Some implications of the high intrasynaptic norepinephrine concentrations in resistance arteries.

Norepinephrine concentrations in excess of 10(-4) M are achieved at the post-junctional membrane of the adrenergic synaptic cleft in resistance arteries at least for short periods of time. These concentrations are greater than the threshold of low affinity non-alpha-adrenoceptors-'extraceptors', that respond to norepinephrine and would be sufficient to overcome the blockade by alpha-adrenoceptor antagonists. The relationship of such activity to the excitatory junction potential and the relevance of this to contraction in vivo remains a matter of conjecture.

Adrenergic alpha-Antagonists↗
PubMed1987

Quantitative ultrastructural measurement of innervation density, neurotransmitter vesicles and neuromuscular cleft width in the rabbit central ear artery and its main side branch.

The purpose of this study was to provide anatomical information about innervation density and the neuromuscular relationship in the rabbit central ear artery and its main side branch, so that, when combined with functional observations, a better understanding of neuroeffector mechanisms in these vessels could be established. Electron-microscopic methods were used to measure number and size of axon varicosities, their content of vesicles, the sizes of dense cores in the small vesicles and the neuromuscular cleft width. For each 100 micron of the outer circumference of the tunica media, the central ear artery contained 4 varicosities with a total cross-sectional area of 2.2 micron 2, and the main side branch about 9 varicosities with a total cross-sectional area of 4.1 micron 2. On the average, the varicosities of the central and branch arteries contained 93.6 and 95.1 small, and 2.3 and 1.9 large vesicles, respectively, per micron. The diameter of dense cores in the small vesicles was significantly smaller in the main side branch (18.3 vs. 16.7 nm). In the central ear artery, the mean cleft width was 5.27 micron, and 3% of all clefts were narrower than 1 micron. In the main side branch, the mean cleft width was 2.77 micron, and 22% were narrower than 1 micron. Thus, the innervation of the main side branch is closer to the vascular smooth muscle cells and is characterized by a larger number of smaller varicosities per unit circumference. Although vesicle density is the same as in the central artery, the dense cores are smaller in diameter. These data do not provide an explanation as to why the response of the main side branch to nerve stimulation in vitro is proportionally weaker. The reasons for this apparent contradiction are not clear, but we offer some possible explanations.

Adrenergic Fibers↗
PubMed1987

Control of peripheral vascular resistance: evidence based on the in vitro study of resistance arteries.

Resistance arteries, mainly small muscular arteries and arterioles, control the distribution of the cardiac output, capillary flow, pressure, and exchange. The active tone of these small vessels is influenced by a large variety of factors. Some less well known factors are discussed, including myogenic tone, variation in alpha 1-adrenoceptor number and affinity, and synaptic cleft width. The implications are that the adrenergic transmitter might be acting on low affinity non-alpha-adrenoceptors--extraceptors; that long-term trophic effects influence not only the function of blood vessels, but their number; and that a variety of types of vasodilator nerves exists. The adrenergic synaptic mechanism is different in small, compared with larger arteries; in particular there is an increased role of uptake. It is not known whether these influences are changed in hypertension.

Humans↗
PubMed1987

Specialization in beta-1 and beta-2 adrenoceptor distribution in veins of the rabbit face: relationship to myogenic tone and sympathetic nerve innervation.

Studies were performed on several superficial veins from the rabbit face to examine the relationship between beta adrenoceptor subtype distribution, intrinsic myogenic tone and sympathetic nerve innervation. Experiments using selective beta adrenoceptor agonists and antagonists indicate that the dorsal nasal and angularis oculi veins possess a homogeneous population of beta-2 adrenoceptors. Sympathetic nerve stimulation in these segments results only in contraction mediated through postjunctional alpha adrenoceptors. These segments are devoid of intrinsic myogenic tone. In the facial vein, of which both veins are tributaries, both beta-1 and beta-2 adrenoceptors are found. Studies with the beta-1 adrenoceptor antagonist, betaxolol, and beta-2 adrenoceptor antagonist, ICI 118,551, indicate that the prominent relaxation observed in this tissue to sympathetic nerve stimulation is mediated through postjunctional beta-1 adrenoceptors. At physiological temperatures, the facial vein possesses a marked intrinsic myogenic tone that is inhibited by this beta-1 adrenoceptor-mediated sympathetic activity. Considering the anatomical relationship between these vessels and the unique association between beta adrenoceptor subtype, intrinsic myogenic tone and sympathetic innervation, it is possible that facial blood redistribution in the rabbit can be markedly affected by sympathetic nerve stimulation. Such a process could have an important role in cranial thermoregulation.

Adrenergic beta-Agonists↗
PubMed1987

Variation in sensitivity of alpha adrenoceptor-mediated contraction of the vascular smooth muscle of rabbit elastic and muscular arteries is related to receptor affinity.

Norepinephrine sensitivity (pD2) and agonist dissociation constant (pKA) have been determined in the following 12 rabbit arteries: thoracic and abdominal aorta, basilar, ear, common, external and internal iliac, ovarian, large and medium pulmonary, renal and superior mesenteric. They were determined in the presence of beta adrenoceptor blockade and uptake 1 and uptake 2 inhibition to prevent compromising additional actions of norepinephrine and intrinsic processes that influence its concentration at the site of action. In the superior mesenteric artery, determinations were made after endothelial inactivation and in the presence of indomethacin, because in this vessel blockade by these procedures influences norepinephrine sensitivity. In 12 arteries a positive correlation was found between norepinephrine pD2 and pKA (r = 0.74, P less than .01). The slope of the regression line did not differ from unity. Norepinephrine pD2 did not correlate with receptor reserve in these arteries when assessed as antilog pD2-pKA. In three arteries, the ear and common and external iliac, a large receptor reserve was found. If these were excluded from the series, the following correlation would be found: r = 0.9; P less than .001. Here again the slope of the regression line did not differ from unity. The pD2 and pKA were determined for the more selective alpha-1 adrenoceptor agonist, phenylephrine in six of these arteries, and similar results were obtained. The KB for prazosin in this series did not correlate with norepinephrine KA (r = 0.45, P greater than .05), and the slope (0.17) was not significantly different from zero. The pD2 for histamine, determined after H2 receptor blockade, does not differ in the arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Extracellular calcium dependence of contraction and endothelium-dependent relaxation varies along the length of the aorta and its branches.

Dependence of contraction and endothelium-dependent relaxation of segments of the rabbit aorta and the celiac, superior mesenteric and renal arteries on the presence of calcium in the physiological salt solution in which they were bathed have been studied in vitro. Arteries were tested before and 60 min after removal of Ca++ from the bath solution. Norepinephrine-induced contraction and acetylcholine and A23187-induced relaxation were calcium-dependent in the thoracic and upper abdominal aorta. Contractions were resistant to the effect of calcium removal in segments from the aorta below the origin of the renal artery and from the renal artery itself. The aorta between the superior mesenteric and the renal arteries was intermediate in its dependence. Relaxation of the aorta caudal to the origin of the celiac artery and the renal artery was also resistant. The insertion of an intact everted vessel into an artery whose intima had been inactivated by rubbing restored partially the relaxation to acetylcholine and A23187 in the presence of normal calcium. Vessels that did not relax to acetylcholine after Ca++ exclusion from the bathing solution relaxed when the renal artery was the donor. Donor arteries whose relaxation was sensitive to Ca++ removal did not increase the relaxation response of the renal artery after calcium removal. Diltiazem and D600 reduced the relaxation responses of acetylcholine in the thoracic aorta and enhanced those in the renal artery. It is concluded that there is a transition in the extracellular Ca++ dependence of contraction and endothelium-derived relaxation along the length of the abdominal aorta. Changes in the dependence of contraction occurred more gradually than relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1987

Protein kinase C activation selectively augments a stretch-induced, calcium-dependent tone in vascular smooth muscle.

The interaction of the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) with vascular tone due to histamine, high K+ and stretch were studied in the rabbit facial vein. Segments were incubated in physiological salt solution (PSS) containing Ca++ (1.6 mM) and an optimal preload was applied. Myogenic or stretch-induced tone was studied in two ways. Vessels were stretched in PSS at 28 degrees C and the bath temperature was gradually increased in a standard manner. Alternatively, vessels stretched at 42 degrees C were placed in zero-Ca++ PSS at the same temperature and responses to readmission of Ca++ to the PSS recorded. TPA (0.01 or 0.1 microM for 1 hr), a protein kinase C activator, consistently enhanced myogenic responses to stretch initiated by either procedure. It had very little effect or even depressed the tone due to histamine of high K+. The selective effect of protein kinase C activation on stretch-induced, Ca++-dependent myogenic tone argues for a pathway in this vessel activated selectively by stretch that may be modulated by protein kinase C-dependent mechanisms. It is proposed that stretch of the rabbit facial vein opens specific Ca++ entry pathways; the interaction of TPA with those pathways may be such that TPA increases Ca++ sensitivity or availability.

Animals↗
PubMed1987

Diltiazem and autoregulation of canine cerebral blood flow.

Recent in vitro evidence suggests the existence of stretch-activated calcium channels in cerebrovascular smooth muscle. These channels, which may play a role in cerebral autoregulation, also appear resistant to antagonism by the benzothiazepine calcium antagonist diltiazem, an agent known to block potential-sensitive and receptor-operated calcium channels. If cerebral autoregulation involves stretch-sensitive diltiazem-resistant calcium channels, then autoregulation should remain intact during vasodilatation produced by diltiazem. The present study was conducted to test this hypothesis. Using a canine cerebral venous outflow preparation, experiments were first performed to determine the optimum dose and route of administration for diltiazem. Although continuous i.v. diltiazem (1-100 micrograms/kg/min) did not increase cerebral perfusion at any normotensive dose, i.a. (lingual artery) diltiazem at 10.0 micrograms/kg/min increased cerebral blood flow by 36% and decreased cerebrovascular resistance by 31% without significant effects on blood gas levels, cerebral oxygen uptake, cardiac output or mean arterial pressure. In autoregulation experiments, 10.0 micrograms/kg/min of diltiazem significantly attenuated but did not eliminate autoregulatory responses to increases (inflation of an aortic balloon) and decreases (hemorrhage) in cerebral perfusion pressure. Autoregulatory responses to increases and decreases in perfusion pressure were equally affected by diltiazem, but both were unaffected by i.a. saline. These data support the view that cerebral autoregulation involves both diltiazem-sensitive and diltiazem-resistant mechanisms. The diltiazem-resistant mechanisms, which may include the proposed population of stretch-sensitive calcium channels appear to account for up to one-half of the autoregulatory capacity in the cerebral circulation.

Animals↗
PubMed1987

Sources of activator calcium for extrinsic vascular tone and nimodipine inhibition of that tone in proximal vs. distal rabbit ear arteries.

The contractile responses of three artery segments of diminishing diameter in the rabbit ear (i.e., unstretched lumen diameter approximately 300 mu in central ear artery, unstretched lumen diameter approximately 150 mu in main side branch off the central ear artery and unstretched lumen diameter approximately 75 mu in terminal branch off the main side branch) to high K+, norepinephrine (NE) and 5-hydroxytryptamine (5-HT) were tested before and after their incubation in Ca++-free physiologic salt solution for times varying from 3 to 60 min. The time course of reduction of the contractile responses to K+ with Ca++-free conditions in all classes of vessels could be represented by monoexponential curves that were not significantly different from each other. The contractile response of all the ear arteries to NE and 5-HT was biphasic. The first rapid transient phase (phase I) was more resistant to change upon the removal of exogenous Ca++ than the second usually equilibrium-like component (phase II), which was dramatically and rapidly reduced (but not necessarily eliminated) by this procedure. The extent of decline upon Ca++ removal in most instances was greater for 5-HT than for NE. The rate of falloff of both phases of contraction to NE and 5-HT was faster in the smaller compared with the larger arteries. These results suggest that, as vessels in the rabbit ear arterial tree get smaller, the contribution of a tightly bound or intracellular Ca++ pool to both phases of amine-induced contraction becomes smaller, but this contribution is greater to the transient compared with the equilibrium phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Vascular bed and vasoconstrictor-dependent selectivity of the calcium channel antagonist, PN 200-110.

The potency of the dihydropyridine calcium channel blocker, PN 200-110 was assessed in vitro against contractions induced by potassium (20-55 mM) and histamine (1-300 microM) in rabbit thoracic aorta, coronary, basilar, renal and central ear arteries. PN 200-110 was particularly effective against potassium responses in the coronary and basilar arteries (IC50 30 and 50 pM) and of little effect against histamine responses in the renal artery and thoracic aorta (IC50 greater than 1 microM). These results suggest that PN 200-110 has some preferential actions dependent on both the vascular bed and also the constrictor used.

Animals↗
PubMed1986

Physiological variation in alpha-adrenoceptor-mediated arterial sensitivity: relation to agonist affinity.

Vascular smooth muscle from different arteries of the rabbit varies in sensitivity to norepinephrine, even when factors known to contribute to this variation are excluded. Sensitivity to norepinephrine mediated through the alpha-adrenoceptor is linearly related to the agonist dissociation constant, but is not significantly related to receptor reserve. These results suggest that agonist affinity is the primary determinant of sensitivity to norepinephrine, at least in these arteries, and that this is a locally regulated characteristic which may account for regional sensitivity changes.

Animals↗
PubMed1986

Dihydropyridine calcium agonists selectively enhance resistance artery myogenic tone.

Upon stretch in normal physiological salt solution (PSS), two dihydropyridine (DHP) Ca2+ agonists (Bay k 8644 and CGP 28392) enhanced the level of stretch-dependent myogenic tone in rabbit ear resistance arteries. This potentiating effect was not blocked by phenoxybenzamine (1 microM) and was Ca2+-dependent. Bay k 8644 was more potent than CGP 28392. These agonists had a smaller potentiating effect on K+ (20 mM)-induced contraction, and had little effect in the presence of high K+ (50-134 mM) PSS. Stretch-dependent myogenic tone is resistant to the inhibitory effect of nimodipine, a selective DHP Ca2+ antagonist which inhibited K+ (50 mM)-induced contraction in the nanomolar range. The potentiating effects of Bay k 8644 and CGP 28392 on myogenic tone were reversed by nimodipine. Our data suggest that DHP Ca2+ agonists selectively enhance myogenic tone by a mechanism that is antagonized by nimodipine, although physiological activation of myogenic tone is nimodipine insensitive, and the calcium related mechanisms of myogenic tone are distinct from those for high K+ depolarization-induced tone.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1986

Pharmacological characterization of histamine receptors in the rabbit renal artery.

Histamine receptors were characterized pharmacologically in the rabbit renal artery. Histamine concentration-dependent contractions were blocked by chlorpheniramine (pA2 = 8.25 +/- 0.16) and mepyramine (pA2 = 9.80 +/- 0.22). A low concentration of metiamide (0.5 microM) enhanced significantly the effect of histamine. Higher concentrations either had no effect or reduced the contractile response to histamine. Impromidine, dimaprit and, in the presence of chlorpheniramine or mepyramine, histamine (at the concentrations that produced contractions) relaxed the precontracted vessel. The relaxant effect of histamine was quantitatively greater in the presence of mepyramine than it was in the presence of chlorpheniramine. Endothelial removal did not influence the contractile response to histamine but enhanced the relaxation suggesting the presence of histamine receptors mediating contraction in the intima. Relaxation responses to histamine and dimaprit were blocked competitively by cimetidine (pA2 = 6.65 +/- 0.10 and 6.60 +/- 0.05 respectively). It is concluded that there are two types of histamine receptors in the renal artery of the rabbit; H1-receptor mediating contraction and H2-receptor mediating relaxation. Both types of receptors are present in the media: some excitatory receptors may be present in the intima.

Animals↗
PubMed1986

In vitro evidence that vasoactive intestinal peptide is a transmitter of neuro-vasodilation in the head of the cat.

Experiments have been undertaken to determine the nature of the atropine-resistant neurogenic dilation that can be demonstrated in vitro in cephalic arteries of the cat. Levels of vasoactive intestinal peptide (VIP) and substance P were measured in a number of arteries and related to the extent of the neurogenic dilation that can be elicited in vitro. There is no correlation between the tissue contents of the two peptides. A positive correlation was found between vasoactive intestinal peptide but not substance P content and neurogenic dilation. Vasoactive intestinal peptide but not substance P consistently caused a concentration-dependent dilation of cephalic arteries not subject to significant tachyphylaxis. Vasoactive intestinal peptide antiserum in concentrations that block the dilation to vasoactive intestinal peptide (10(-6) M) but not that due to papaverine, significantly reduced neurodilation of both atropinized and non-atropinized lingual arteries--the cephalic artery with the highest VIP content. These results suggest that vasoactive intestinal peptide and not substance P significantly contributes to the non-cholinergic neurogenic dilation observed in vitro in arterial segments from the head of the cat.

Animals↗
PubMed1986

Absorption of oral diphosphonate in normal subjects.

Absorption of the diphosphonate etidronate (HEDP) was measured in 20 volunteer subjects at two centres (Glasgow and Madison) using a new method based on simultaneous administration of HEDP and intravenous 99mTc-HEDP (Osteoscan). The mean absorption of HEDP in fasting subjects in Glasgow was 3.5% (range 1-8.9%) and in Madison 1.5% (0.7-2.8%) (P less than 0.035). In four subjects studies were repeated with good agreement between results (mean 3.9 cf. 3.5%). Six subjects had studies repeated when drug was ingested with food and in all cases absorption was effectively reduced to zero. We conclude that absorption of HEDP is significantly higher in normal subjects in Glasgow than in Madison. This may be of importance with regard to the finding of histological osteomalacia and fracture associated with HEDP use in Glasgow.

Administration, Oral↗
PubMed1986

Stretch-dependent (myogenic) tone in rabbit ear resistance arteries.

Rabbit ear resistance arteries are vessels with three to six layers of smooth muscle cells and an unstretched lumen diameter of 75-150 micron. Ring segments of these arteries, in response to mechanical stretch in vitro, developed a maintained tonic contraction. The stretch-dependent contraction achieved a plateau within 10-30 min. Smooth muscle relaxants, such as NaNO2 and papaverine, substitution of extracellular Ca2+ by subthreshold Ca2+ (25 microM), or exposure to the Ca2+ influx antagonist Mn2+ abolished the stretch-dependent tone. The extent of the tone was dependent on the level of the applied stretch and the extracellular Ca2+ concentration ( [Ca2+]o). The maximal tone developed at optimal stretch, and [Ca2+]o in the bath solution was 18.1 +/- 4.6% of the maximal contraction of the vessel to histamine. This level of tone is comparable to neurogenic tone developed in response to nerve stimulation within the physiological frequency range. The stretch-dependent tone is considered probably myogenic in origin, since it was present in arterial segments that had been chronically denervated by surgical sympathectomy, mechanically deprived of the endothelium, and multireceptor blocked (phenoxybenzamine, 10(-6) M). Our findings suggest first that the stretch-dependent tone is myogenic and may be similar to basal vascular tone arising from the stretch of arterial pressure and its changes in vivo. Second, the magnitude of myogenic tone is a function of the applied stretch and the [Ca2+]o. Finally, myogenic tone is important in the physiological regulation of arterial tone in the rabbit ear resistance arteries.

Animals↗
PubMed1986

A nimodipine-resistant Ca2+ pathway is involved in myogenic tone in a resistance artery.

After stretch, tone develops in ring segments of rabbit ear resistance arteries (75-150 micron unstretched lumen diam). This is myogenic tone, since it is not dependent on the presence of sympathetic nerves, endothelial cells, or the local release of any known vasoactive autacoids. It is sensitive to the extracellular Ca2+ concentration, and disappears in a low Ca2+ (25 microM) environment. Tone is restored immediately on the reintroduction of Ca2+ (0.1-1.6 mM). High K+-induced tone in these resistance arteries is also extracellular Ca2+-dependent. The Ca2+ ED50 of this tone is 2.45 X 10(-4) M, which is significantly lower than that for myogenic tone (Ca2+ ED50; 8.31 X 10(-4) M). Both tone moieties are influenced by inorganic Ca2+ antagonists (Mn2+ and Mg2+) and some organic Ca2+ antagonists (verapamil and diltiazem). Among all the Ca2+ antagonists studied, only Mn2+ completely inhibits myogenic tone. In contrast, myogenic tone is resistant to nimodipine (up to 10(-6) M), the most potent Ca2+ antagonist of K+-induced contraction (ID50; 1.0 X 10(-9) M). Other 1,4-dihydropyridine Ca2+ antagonists such as nifedipine and (-)-PN 200-110 selectively antagonize K+-induced contractions, whereas they do not affect the development and the maintenance of myogenic tone. The fact that the (+)-enantiomer of PN 200-110 does not have an inhibitory effect proves that the 1,4-DHP site is stereospecific. These results indicate that extracellular Ca2+ is essential for both stretch-dependent (myogenic) and K+-induced tone, and the Ca2+ entry pathways for the two tone moieties are differently influenced by dihydropyridines.

Analysis of Variance↗