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Biomedical subjects

J A Bevan

Publications and source records attributed to J A Bevan.

At least 73 records · Page 4Linked to original sources
PubMed1991

Evidence that neuropeptide Y and norepinephrine mediate electrical field-stimulated vasoconstriction of rabbit middle cerebral artery.

We investigated the contractile response of isolated rabbit middle cerebral artery (MCA) segments to electrical field stimulation (EFS). The dynamics of the EFS contraction were compared with a similar-sized branch of rabbit ear artery. In comparison with the ear artery, the EFS contractions of the MCA displayed a longer latency and a higher stimulus frequency threshold. Greater stimulation train lengths were required to attain equilibrium, and the time course of EFS response--including force development, plateau, and return to rest tension--was significantly slower than in the ear artery. Morphological and pharmacological studies of the MCA showed that it receives sympathetic adrenergic innervation: whole-mount preparations displayed catecholamine histofluorescence; electron micrographs of MCA sections revealed a population of varicosities containing chromaffin positive large and small vesicles; and EFS contractions were blocked by tetrodotoxin (30 nM) and guanethidine (5 microM) and by chronic surgical sympathectomy. Exposure to prazosin (10 microM) or phenoxybenzamine (1 microM) blocked norepinephrine contractions but did not significantly influence the EFS contraction. Procedures and drugs that antagonized the responses to neuropeptide Y, serotonin, or histamine were also ineffective in blocking the EFS contraction. The involvement of ATP could not be assessed, since the purinergic P2 agonist alpha,beta-methylene ATP was ineffective in blocking ATP-mediated contractions. The EFS contraction, however, could be blocked by a combination of neuropeptide Y desensitization and phenoxybenzamine (30 nM) or prazosin (0.1 microM). These results suggest that norepinephrine and neuropeptide Y are released from sympathetic nerves and mediate EFS contraction by occupation of postjunctional alpha-adrenoceptor and neuropeptide Y receptors. Since the blockade of only one of these components does not diminish the response to EFS, the adrenergic neuroeffector system in this artery may involve complex prejunctional regulatory mechanisms.

Adrenergic beta-Antagonists↗
PubMed1991

Clentiazem protects against chronic cerebral vasospasm in rabbit basilar artery.

BACKGROUND AND PURPOSE: Experiments were carried out in rabbits to determine whether clentiazem (8-chlorodiltiazem), a cerebrovascular-selective calcium channel blocker, administered 24 hours before subarachnoid hemorrhage influenced the subsequent cerebral vasospasm. METHODS: Subarachnoid hemorrhage was induced by multiple injections of blood into the prepontine cisterns of 35 male New Zealand White rabbits, and clentiazem (5 mg/kg) was administered 4 times daily until sacrifice. Cerebral artery diameter was assessed in vivo by angiography. Functional features of basilar arteries were measured using conventional in vitro methodology. RESULTS: Clentiazem reduced the angiographic narrowing seen on days 2 and 5 from 35% and 34%, respectively (sham control, 1.42 +/- 0.31 mm [n = 22]), to 8% and 11%, respectively, and prevented the narrowing (32%) that occurred on day 9. Narrowing in the untreated rabbits was only partly reversed by papaverine; all narrowing in clentiazem-treated animals was papaverine sensitive. Clentiazem prevented or reduced many of the changes in the basilar artery caused by the subarachnoid hemorrhage. Of particular relevance to arterial narrowing were the increased wall stiffness, the transient spontaneous changes in wall force, and the reduction in relaxation to acetylcholine. Reduction of the changes in wall force induced by agonists and by stimulation of intramural sympathetic nerves was observed. CONCLUSIONS: The vascular damage associated with chronic cerebral vasospasm is related to calcium entry into the smooth muscle and endothelial cells, and possibly sympathetic nerve terminals, through calcium channels sensitive to clentiazem, which suggests that clentiazem may be of value in the management of chronic cerebral vasospasm.

Acetylcholine↗
PubMed1991

Platelets augment rabbit cerebral artery constriction by activating protein kinase C.

BACKGROUND AND PURPOSE: We tested the hypothesis that activated platelets augment cerebral artery responsiveness to thrombin by activating protein kinase C, a possible intracellular modulator of Ca2+ sensitivity. METHODS: Ring segments of rabbit basilar artery were prepared for in vitro measurements of isometric force. Cumulative concentration-response curves to thrombin were made in the absence or presence of activated platelets. RESULTS: Arteries contracted to thrombin in a concentration-dependent manner; freshly obtained human platelets (8.5 x 10(8) cells/ml) activated with 10 micrograms/ml collagen increased the arteries' sensitivity to thrombin by threefold while augmenting the maximal response from 40 +/- 11% to 66 +/- 12% of the maximal response to 0.3 mM histamine. At 10 nM, staurosporine, an inhibitor of protein kinase C activity, blunted the platelet-induced augmentation of the response to thrombin but did not alter the sensitivity or the maximal contraction to 8-64 mM K+. Removal of the endothelium did not alter the characteristics of the thrombin concentration-response curve. The addition of activated platelets increased the tissue sensitivity of endothelium-denuded arteries to thrombin by a factor of 30, and the maximal response to thrombin was 101 +/- 27% of the histamine response. CONCLUSIONS: Our findings suggest that amplification of the arterial contractile response to thrombin caused by platelet-derived mediators may be due to activation of protein kinase C. There may also be a protective role for the cerebrovascular endothelium since endothelium reduced the extent of augmentation of protein kinase C-mediated tone by vasoactive agents released by activated platelets. Thus, increased vascular responsiveness caused by activated platelets may in part be due to protein kinase C-mediated changes in the intracellular sensitivity to Ca2+.

Alkaloids↗
PubMed1991

Longitudinal time course of reversible and irreversible components of chronic cerebrovasospasm of the rabbit basilar artery.

Multiple injections of autologous blood were made around the basilar artery of rabbits through a silicone catheter placed into the prepontine cistern. The total blood injected was 3 ml/kg in aliquots of 0.5 to 0.8 ml over a 4-hour period. Control angiograms were obtained 7 days before this procedure. Groups of animals were examined by angiography on each of 9 days after the injections of blood. An angiogram was obtained 15 minutes after the first injection of blood, 20 seconds after the intra-arterial injection of a maximum dilating dose of papaverine. All surviving animals showed basilar artery narrowing, which was greatest 24 hours after the hemorrhage, when the vessel diameter was reduced to 54% of the control value. The narrowing then decreased to a reduction of about 30%, which was maintained throughout the rest of the study period. A papaverine-resistant component of narrowing was not seen until the 3rd day. It increased progressively to Day 9 when it represented 63% of the total. This model has a number of features that are reminiscent of human cerebrovasospasm, including the fact that there is an initial phase of narrowing that is completely reversed by an intra-arterially administered vasodilator, and a second phase beginning on Day 3 which exhibits a progressively increasing papaverine-resistant component.

Animals↗
PubMed1991

Variation in the interaction of some phenylethylamine and imidazoline derivatives with alpha-1 adrenoceptors in rabbit arteries: further evidence for the variable receptor affinity hypothesis.

This study was undertaken to determine whether the variation in the affinity of the alpha-1 adrenoceptors previously found for norepinephrine and phenylephrine in different arteries is also seen with other alpha-1 adrenoceptor agonists, and if so, if one part of the structure is particularly responsible for the variation. The potency and dissociation constants of eight agonists, both phenylethylamines and imidazolines, were determined in five rabbit arteries. In each artery the rank order of phenylethylamine agonist potency was epinephrine greater than norepinephrine greater than phenylephrine greater than deoxyepinephrine greater than methoxamine greater than dopamine. The same rank order of dissociation constants was found. For the imidazolines, the potency order was oxymetazoline greater than clonidine. For each agonist, there was a linear correlation between artery sensitivity and receptor affinity. None of the regression line slopes differed from each other. For each artery there was a linear correlation between phenylethylamine sensitivity and affinity. With the exception of the ovarian, which was lower, slopes of the regression lines in each group do not differ from each other. There were differences in the spread of the dissociation constants of the phenylethylamine derivatives among the arteries. The range of affinities was most marked with norepinephrine (greater than 40-fold) and least with epinephrine (approximately 4-fold). They suggest that agonist affinity governs the biological activity of at least the phenylethylamines on rabbit arteries mediated by the alpha-1 adrenoceptor. Variation in agonist affinity can explain the extent of the biological response. Differences in range of amine affinities in different arteries suggest that the agonist recognition site, although similar in the different arteries, is not identical and may be related particularly to some variation of the amine attachment site of the molecule. The results provide further support for the variable receptor affinity hypothesis.

Animals↗
PubMed1991

Selective variation of agonist and neurally mediated vasoconstriction with rabbit middle cerebral artery branch order.

The in vitro contractions of four successive branches of the rabbit middle cerebral artery to norepinephrine (NE), serotonin (5HT), histamine, and electrical field stimulation (EFS) were examined. Internal lumen diameters of the four branches (designated MCA, M1, M2, M3, proximal to distal) ranged from a mean of 270 microns in the MCA to 160 microns in the M3 segments. NE produced a small alpha adrenoceptor-mediated response in the MCA (12% of tissue maximum); this was diminished in the M1 segment and there was no evidence of alpha adrenoceptor-mediated responses in the M2 and M3 branches. NE contractions, mediated through low affinity sites (extraceptors), did not change with branch order. Maximal responses to 5HT (1 microM) were small and also diminished with branch order; the MCA and M1 contracted to 24 and 18% of tissue maximum, respectively. Negligible responses were obtained in M2 and M3. EFS resulted in contractions that were tetrodotoxin- and guanethidine-sensitive. Maximum EFS responses were 21% tissue maximum in the MCA, 13% in the M1, and less than 5% in the M2 and M3. In contrast, maximal contractile responses to histamine (100 microM) were at or near tissue maximum in all segments. Removal of the endothelium did not influence the size of the contraction to NE, 5HT or histamine in the MCA and M1 segments. Neither NE, 5HT, nor histamine caused relaxation responses in agonist or KCl-contracted segments. The results indicate a differential variation in responsiveness with increasing branch order in the rabbit cerebrovascular bed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Chloroethylclonidine unmasks a non-alpha-adrenoceptor noradrenaline binding site in the rat aorta.

The effect of chloroethylclonidine on noradrenaline-induced contractions of the rat aorta was studied. Chloroethylclonidine (1-5 X 10(-5) M) shifted noradrenaline dose-response curve to the right approximately 5000-fold without depressing the maximum. The response to noradrenaline after chloroethylclonidine was not antagonized by phenoxybenzamine (10(-7) M), prazosin (10(-7) M), WB 4101 (10(-7) M) nor yohimbine (10(-5) M) and is therefore not mediated via alpha 1-adrenoceptors. These results would suggest that there is a homogenous population of chloroethylclonidine-sensitive alpha 1-adrenoceptors in the rat aorta and that chloroethylclonidine treatment reveals a non-alpha-adrenoceptor noradrenaline binding site in this tissue.

Animals↗
PubMed1990

Sequential histomorphometric changes in cancellous bone from ovariohysterectomized dogs.

To evaluate potential pharmacologic agents for the prevention or treatment of the bone loss associated with ovarian insufficiency, a predictable animal model is needed. To assess the potential utility of the ovariohysterectomized dog as a model of this condition, we characterized the sequential histomorphometric changes in canine cancellous bone in response to the loss of ovarian function. A group of 25 adult beagle dogs were ovariohysterectomized and terminated at 1, 3, 6, and 10 months following surgery. Iliac biopsies were performed following double-fluorochrome labeling at the time of surgery and at termination. Static and dynamic histomorphometry was performed on undecalcified sections. By 3 months postovariohysterectomy, there was activation of cancellous bone remodeling as indicated by significant increases in mineralizing surface and bone formation rate. Increases in osteoid surface, mineralizing surface, and bone formation rate were also apparent at 1 month postovariohysterectomy, and although not statistically significant, these trends suggest the skeletal response to acute loss of ovarian function was rapid. This increase in bone remodeling was transient. By 6 months, mineralizing surface and bone formation rate were depressed below presurgical levels. In addition to a reduction in bone formation, a reduction in osteoblast function characterized by reduced labeling of osteoid and a disproportionate increase in eroded surface also occurred. By 10 months postovariohysterectomy, cancellous bone remodeling was not significantly different from presurgical levels. At no time was a significant reduction in bone volume detected. These data suggest that the changes in cancellous bone remodeling in the ovariohysterectomized dog are a series of transient phenomena.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Flow-induced resistance artery tone: balance between constrictor and dilator mechanisms.

Infusion of physiological saline solution into the lumen of an isolated segment of a resistance artery results in constriction when the vessel is relaxed and in dilation when it is contracted. There is a level of wall tone at which infusion causes no change. In the small rabbit ear arteries used in this study (approximately 200 microns OD) this balance (null) point for infusion rates of 35 microliters/min is 69 +/- 4% of the maximum possible tone development. When tone is set at different levels by norepinephrine, infusion tends to change the level of wall force in the direction of the null point for that artery. The magnitude of flow-induced relaxation can be correlated positively (r = 0.74; P less than 0.001) and the flow-induced constriction correlated negatively (r = -0.67; P less than 0.001) with the level of wall tone. The 95% confidence prediction bands for flow relaxation and contraction against level of wall tone overlap when extrapolated to zero response. These results are consistent with the hypothesis that flow-induced change in resistance artery tone is the result of a balance between independent constrictor and dilator influences.

Animals↗
PubMed1990

Saline infusion into lumen of resistance artery and small vein causes contraction.

Infusion of saline into the lumen of a resistance artery from the rabbit ear at rates between 0.5 and 20 microliters/min causes a rate-dependent maintained contraction. This contraction is independent of the direction of saline flow and of the endothelium. The contraction is prevented by pretreatment with the vasodilator papaverine (0.1 mM), which also reversed the contraction during flow. Exclusion of calcium from the physiological saline solution plus ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (1 mM) prevents the contraction, as does pre-exposure to cobalt (1 mM) and manganese (1 mM). Both these ions depress saline flow contraction once it is established. Saline flow-dependent contraction changes in a complex manner with temperature. It is greatest in resistance arteries from the pial, ear (skin), and femoral (muscle) segments, moderate to poor in coronary, mesenteric, and renal segments, and absent in the pulmonary segments. A small ear vein adjacent to the ear resistance artery also contracts to saline infusion. Although an explanation based on the washout of a vasodilator metabolite cannot be excluded, we favor the hypothesis that saline flow-induced shear stress of the inner surface of the vessel wall mechanically activates the vascular smooth muscle cells causing an extracellular Ca2(+)-dependent contraction. This response takes place through indomethacin-insensitive calcium-dependent mechanisms in vascular smooth muscle that differ from those associated with commonly studied surface receptors and with stretch.

Animals↗
PubMed1990

Resistance artery tone is influenced independently by pressure and by flow.

The responses of rabbit resistance arteries to pressure and flow have been examined using two in vitro techniques--when mounted isometrically in a myograph and when perfused using a video system that automatically registers diameter. The latter approach allows pressure and flow to be independently controlled. Under such circumstances three responses were studied; myogenic contraction and flow-dependent constriction and dilation. All responses occurred after endothelium removal and were unaffected by indomethacin (10(-60 M). The pressure and flow effects can be elicited separately and have different ionic bases. The effective stimulus for the myogenic response is stretch and that for flow is presumably shear stress. The mechano-transducers for these effects are different and are located either in the vascular smooth muscle cells or their surrounding extracellular matrix.

Animals↗
PubMed1990

Flow-induced constriction and dilation of cerebral resistance arteries.

Rabbit pial resistance artery segments were cannulated at both ends so they could be perfused with physiological saline solution and were maintained in a tissue bath of the same solution. Both were kept at 37 degrees C and equilibrated with 95% O2 and 5% CO2. Perfusion pressure and flow were independently controlled by two servo-controlled pumps, and changes in the diameter of the segment were registered by an automated video technique. In the absence of flow, these segments maintained their diameter when intraluminal pressure was changed over the range 30-90 mm Hg. When intraluminal pressure was low (30 mm Hg), flow at 20 microliters/min caused dilation. This is half the rate of flow that causes a maximum flow-induced change under the conditions of these experiments. When pressure was high (90 mm Hg), the same flow rate caused constriction. Both responses usually continued as long as flow was maintained. Thus, flow-induced changes in the diameter of this artery can be initiated and are usually maintained despite the demonstrated capacity of the blood vessel wall to hold its diameter constant when pressure is changed in the absence of flow. The results suggest that these small arteries can independently respond to changes in pressure and flow and that the changes that occur in response to flow are not compensated for by changes in the myogenic response.

Animals↗
PubMed1990

Pharmacologic irreversible narrowing in chronic cerebrovasospasm in rabbits is associated with functional damage.

We studied isolated basilar artery segments from a rabbit model of chronic cerebrovasospasm. Autologous blood placed around the basilar artery of rabbits killed 1, 2, 3, 4, 5, 6, 7, or 9 days later caused narrowing of the segments with a biphasic time course. The first (immediate) phase was reversed by intra-arterial papaverine; the second phase exhibited an increasing component of narrowing that was papaverine-insensitive. Based on the passive force/length curves, basilar artery segments became increasingly stiff over 9 days. By contrast, the segments' contractility decreased. Responses of the basilar artery segments were greater over the first few days, but then became less than that of saline-injected controls. Contractions in response to norepinephrine and potassium were reduced. Endothelium-based acetylcholine-induced vasodilation progressively diminished, as did the response to sympathetic nerve stimulation. There was a negative correlation between artery wall stiffness and contractility. The papaverine-insensitive component of angiographic narrowing correlated directly with loss of contractility and with artery wall stiffness. These results are consistent with the conclusion that increased artery wall stiffness is a primary determining factor in the arterial narrowing of chronic cerebrovasospasm.

Acetylcholine↗
PubMed1989

Protein kinase C potentiates stretch-induced cerebral artery tone by increasing intracellular sensitivity to Ca2+.

The effects of PMA, an activator of protein kinase C, was studied on Ca2+-induced tone in the rabbit basilar artery. Contractile responses to Ca2+ occurred only in arteries pretreated with PMA; the extent of Ca2+-induced contractions were related to the level of stretch applied to the vessels. Bay K 8644, a Ca2+-channel agonist, at a concentration that was subthreshold for contraction, augmented the extent of Ca2+-induced tone occurring in PMA-treated arteries. Nifedipine, a Ca2+-entry inhibitor, and staurosporine, an inhibitor of protein kinase C attenuated the response to Ca2+ occurring either in the absence or presence of Bay K 8644. Our results suggest that PMA increases myofilament sensitivity to Ca2+, such that levels of Ca2+ previously ineffective for contraction Ca2+-influx, e.g. due to Bay K 8644, is manifest as contraction. Our results also confirm the role of extracellular Ca2+ entry via plasma membrane stretch-dependent Ca2+-channels in the maintenance of vascular tone in the basilar artery.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Staurosporine, a protein kinase C inhibitor, attenuates Ca2+-dependent stretch-induced vascular tone.

The effects of protein kinase C inhibition by staurosporine was studied on Ca-dependent tone of the rabbit facial vein. Tone was produced either by stretch or by readmission of Ca2+ in a non-depolarizing Ca2+-free salt solution. Stretch-induced tone was inhibited by staurosporine. When tissues were incubated in a Ca2+-free solution, staurosporine (50 nM) inhibited the contractile responses produced by readmission of Ca2+. These observations suggest that maintenance of stretch-induced extracellular Ca2+-dependent tone may be regulated by protein kinase C.

Alkaloids↗
PubMed1989

The selective potentiation of noradrenaline-induced tone by Bay K 8644 in the rabbit basilar artery.

A number of studies indicate that relative to the maximal tone possible, for example, to histamine, noradrenaline produces only weak contractile responses in the rabbit basilar artery. Various factors, including a limited number of alpha-adrenoceptors, have been proposed to account for the reduced response to noradrenaline. We examined the effect of the Ca2+-channel activator, Bay K 8644 (0.1 and 1.0 nM) on dose-response curves to noradrenaline, histamine, calcium (Ca2+) and potassium (K+) in ring preparations of rabbit basilar artery and central ear artery. These concentrations of Bay K 8644 (0.1 and 1.0 nM) increased the magnitude of tension developed by noradrenaline (contractility) in the basilar artery, but did not alter its sensitivity (ED50) to the adrenergic vasoconstrictor. Bay K 8644 (0.1 and 1.0 nM) did not alter the contractility or sensitivity to histamine or K+ of the rabbit basilar artery. When dose-response curves to Ca2+ were made in K+-depolarized rabbit basilar artery rings, Bay K 8644 (0.1 and 1.0 nM) dose-dependently augmented tone generated by readmission of Ca2+. Bay K 8644 (0.1 and 1.0 nM) did not alter responses to noradrenaline, histamine, or K+ in rabbit central ear artery preparations. These results are compatible with a voltage-dependent mechanism of action of Bay K 8644 in the rabbit basilar artery, which may be partially depolarized in the resting state. We propose that in addition to other factors, the contractile response of rabbit basilar arteries is limited by a weak or inefficient coupling of alpha-adrenoceptors to Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)

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