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R C Webb

Publications and source records attributed to R C Webb.

213 records · Page 12Linked to original sources
PubMedDate not supplied

Effects of serotonin antagonists on blood pressure in mineralocorticoid hypertensive sheep.

The serotonin antagonist methysergide has a partial agonistic action on isolated vascular smooth muscle from hypertensive animals, whereas ketanserin, another serotonin antagonist, does not. The goal of this study was to determine the effects of these two agents on blood pressure in the conscious, deoxycorticosterone acetate (DOCA) hypertensive sheep. Adult sheep maintained on a standard laboratory diet and 0.1% NaCl/0.25% KCl drinking water developed hypertension following DOCA implantation (mean arterial pressure: control = 83 mm Hg, DOCA = 108 mm Hg). Methysergide (40 micrograms/kg--i.v. bolus) produced a greater pressor response in hypertensive sheep than in normotensive sheep (control = 8 +/- 1 mm Hg, DOCA = 18 +/- 3 mm Hg). Ketanserin (50 micrograms/kg--i.v. bolus), on the other hand, caused a similar decrease in blood pressure (approximately -16 mm Hg) in both control and DOCA sheep. Pressor responses to infusions of serotonin were greater in DOCA sheep compared with controls. Both methysergide and ketanserin were equally effective antagonists of a serotonin-induced pressor response (75% inhibition) in control and DOCA sheep. Methysergide had no effect on a norepinephrine-induced pressor response, but ketanserin caused a 20% attenuation of this response. These results demonstrate an enhanced responsiveness to serotonin and methysergide in DOCA hypertensive sheep.

Animals↗
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Does nitric oxide regulate smooth muscle cell proliferation? A critical appraisal.

Smooth muscle proliferation is involved in the pathogenesis of atherosclerosis, restenosis after angioplasty and vein graft failure due to neointimal hyperplasia. Nitric oxide (NO) inhibits smooth muscle cell growth in vitro and experimental neointimal hyperplasia in vivo, suggesting a role for NO as a regulator of smooth muscle cell proliferation. NO is also involved in the control of numerous other vascular functions including platelet and inflammatory cell adhesion, vascular reactivity and endothelial permeability. This review critically examines the experimental and clinical evidence that supports a role for NO as a modulator of smooth muscle cell proliferation, with an emphasis on the multiple mechanisms by which NO acts on vascular lesions.

Animals↗
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Gap junctional communication and vascular smooth muscle reactivity: use of tetraethylammonium chloride.

Oscillatory contractions in uterine smooth muscle are mechanistically related to gap junction complex formation. We have tested the hypothesis that agonist-induced oscillations in vascular smooth muscle are also mediated by gap junctions and that gap junctions are important for vascular smooth muscle cell communication. Total RNA from cultured Wistar-Kyoto rat (WKY) mesenteric arterial cells hybridized strongly with a cDNA probe for the message for connexin43, a monomer of the gap junction. In these same cells, the quaternary ion tetraethylammonium (TEA) (10 mM) increased Lucifer yellow dye transfer between contiguous cells, a measure of cell-to-cell communication via gap junctions, approximately 35% above basal levels. Heptanol, an established inhibitor of gap junction communication, completely blocked both basal- and TEA-stimulated dye transfer between neighboring cells. In other experiments, helical strips of superior mesenteric and tail arteries from WKY rats were mounted in tissue baths for measurement of isometric contractile force. TEA (10(-3)-10(-1) M) induced oscillatory contractions (1-5 cycle/min) in both mesenteric and tail arteries. Removal of endothelium did not affect the pattern of TEA-stimulated oscillations. Oscillations to TEA were blocked in a concentration-dependent manner in both arteries by heptanol (10(-7)-10(-3) M). Heptanol (10(-3) M) also significantly reduced (40%) acetylcholine-induced relaxation in the mesenteric artery (contracted with phenylephrine).(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohols↗
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Serotonin stimulates protein tyrosyl phosphorylation and vascular contraction via tyrosine kinase.

Serotonin (5-HT, 5-hydroxytryptamine) is a mitogen in vascular smooth muscle and vascular reactivity to 5-HT is significantly enhanced in hypertension and atherosclerosis. We have tested the hypothesis that tyrosine kinases, enzymes important for mitogenesis, may play a role in 5-HT-induced vascular smooth muscle contractility. Helical strips of rat carotid artery and aorta denuded of endothelium were mounted in tissue baths for measurement of contractile force. The tyrosine kinase inhibitor genistein (5 x 10(-6) M) decreased the potency of 5-HT approximately 4-fold and reduced maximal contraction to 5-HT in carotid arterial strips denuded of endothelium (58% control). Genistein's inactive congener daidzein (5 x 10(-6) M) did not reduce maximal contraction to 5-HT in carotid arteries but did shift the 5-HT concentration response curve 3-fold to the right. Tyrphostin 23 (5 x 10(-5) M), another tyrosine kinase inhibitor, decreased the potency of 5-HT 4-fold and reduced the maximal contraction to 5-HT in the carotid artery (10% control). Contractions induced by phorbol-12,13-dibutyrate (10(-9) to 10(-5) M) were not reduced or shifted by either tyrosine kinase inhibitor, indicating that phorbolester-sensitive protein kinase C isoforms were not affected. KCl-induced contraction was shifted 2-fold and the maximum significantly inhibited by tyrphostin 23 (38.6% control) but not genistein or daidzein, indicating that tyrphostin 23 but not genistein may inhibit voltage-gated calcium channels to reduce contractility. Western blot analysis using antiphosphotyrosine antibody confirmed that 5-HT produced a time- and concentration-dependent increase in the phosphotyrosine immunoreactivity of a 42-kD protein in cultured aortic smooth muscle cells. Lysate immunoprecipitation with an antimitogen-activated-protein (MAP)-kinase antibody indicated that the 42-kD protein was most likely a MAP kinase. 5-HT (10(-5) M) stimulated contraction and increased antiphosphotyrosine immunoreactivity in whole aorta mounted in tissue baths. Importantly, aortic contraction to 5-HT was shifted (5-fold rightward) and reduced (69% control) by genistein but not daidzein. These findings demonstrate that (1) tyrosine kinase activation may partially mediate contractility to 5-HT in arterial smooth muscle, (2) tyrphostin 23 is somewhat nonselective and (3) 5-HT stimulates tyrosine kinase as documented by increased tyrosyl phosphorylation of proteins in cultured aortic smooth muscle cells and aortic tissue in active contraction of 5-HT. These findings have significant implications not only in understanding a novel pathway of 5-HT signal transduction but also in vascular diseases in which growth and/or contractility to 5-HT is increased (e.g. hypertension, atherosclerosis).

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Photorelaxation is not attenuated by inhibition of the nitric oxide-cGMP pathway.

Photorelaxation of arteries by ultraviolet (UV) light is hypothesized to result from nitric oxide (NO) released from photoactivable stores. Recently, a study reported enhanced photorelaxation of aortic tissue from rats administered the NO synthase (NOS) inhibitor N omega-nitro-L-arginine (L-NNA). Presumably, the potentiated photorelaxation was due to NO generated from UV-light-induced decomposition of the NO2 moiety of L-NNA. However, we hypothesized that photorelaxation is: (1) not the result of NO synthesis and subsequent activation of guanylate cyclase and (2) not due to hyperpolarization induced by NO or any other factor. Endothelium-denuded rat aortic rings were suspended in isolated baths for isometric force measurement. Rings were exposed to UV light (366 nm) before addition of phenylephrine or KCI, and then at each agonist concentration during a cumulative concentration response curve. NOS inhibition by L-NNA and L-thiocitrulline, which lacks an NO2 group, enhanced photorelaxation of basal myogenic tone and contraction to phenylephrine (EC70). Furthermore, relaxation of a maximum phenylephrine-induced contraction to the NO donor S-nitroso-N-acetyl-D,L-penicillamine during UV light exposure was not altered by incubation of rings with L-NNA or tissues from animals fed L-NNA. These data demonstrate that NO is not produced endogenously or from the breakdown of L-NNA to result in photo-relaxation. Methylene blue (MB) did not alter photorelaxation, suggesting that cGMP is not essential to the response. MB and L-NNA together potentiated photorelaxation of basal myogenic tone and phenylephrine-induced contraction. Photorelaxation of KCl-induced contraction was unaltered, indicating that hyperpolarization does not contribute to the relaxation. Photorelaxation of basal myogenic tone and KCl-induced contraction excludes the possibility that UV light is interfering with agonist-receptor binding. Collectively, these results refute the hypotheses that photorelaxation results from activation of the NO-cGMP pathway, release of a hyperpolarization factor, or inhibition of drug-receptor interaction. Interestingly, photorelaxation may be inhibited by NO-cGMP pathway activation, uncovering a novel effect of this messenger system on vascular reactivity.

Animals↗
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Inhibition of nitric oxide-induced vasodilation by gap junction inhibitors: a potential role for a cGMP-independent nitric oxide pathway.

Studies have provided evidence for the role of gap junctional intercellular communication in syncytial tissue function. This study tested the hypothesis that the vasodilating effects of nitric oxide (NO) rely on gap junctions. The effects of the gap junction inhibitors octanol (10(-4) mol/l) and heptanol (10(-3) mol/l) were examined on acetylcholine-, the NO-donor S-nitroso-N-acetyl-penicillamine (SNAP)-, and guanosine-3',5'-cyclic monophosphate (cGMP)-induced relaxation. In addition, we tested varying concentrations of the gap junction inhibitor sucrose on SNAP-induced relaxation in the presence and absence of methylene blue, an inhibitor of guanylate cyclase. Helical strips of rat thoracic aorta were placed in muscle baths for isometric force measurements. Tissues treated with SNAP and cGMP were denuded of endothelium. Tissues incubated in octanol and heptanol exhibited 4- to 7-fold rightward shifts in acetylcholine-induced and 6- to 15-fold rightward shifts in SNAP-induced relaxation. Both octanol and heptanol produced 2-fold rightward shifts in cGMP-induced relaxation, comparably less in magnitude than shifts produced in acetylcholine- and SNAP-induced relaxation. Sucrose (10(-2) to 10(-1) mol/l) produced a concentration-dependent rightward shift of up to 30-fold in relaxation to SNAP. Incubation with methylene blue (10(-6) mol/l) altered this rightward shift only slightly, indicating a possible cGMP-independent mechanism for NO. These findings support the hypothesis that NO-induced vasodilation, through both cGMP-dependent and -independent pathways, relies on gap junctional communication.

1-Octanol↗
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Nitroprusside-induced vascular relaxation in DOCA hypertensive rats.

Vascular responsiveness to nitroprusside and to norepinephrine was examined in two different preparations from DOCA hypertensive and normotensive control Sprague-Dawley rats. The blood-perfused renal vasculatures of DOCA hypertensive rats were significantly more sensitive than those of normotensive controls to the vasodilator action of low doses of nitroprusside. At high doses, responses in DOCA hypertensive and normotensive rats were similar. Since basal "structural" vascular resistances were greater in the hypertensive rats, It is possible that further vasodilation with nitroprusside was impeded more in DOCA-treated than in control rats. Nitroprusside produced a greater degree of vascular smooth muscle relaxation in tail artery strips from DOCA hypertensive rats than in those from normotensive controls. The current study is the first characterization of the effects of a vasodilator in mineralocorticoid hypertension. The two preparations gave divergent results with respect to vascular sensitivity to norepinephrine. When compared with control rats, the DOCA hypertensive rats showed a greater sensitivity to norepinephrine in tail arteries but a lesser renal vascular reactivity. It is evident that one must take a number of variables into consideration when characterizing changes in vascular responses that occur in a given model of hypertension: 1) the region of the vasculature (renal vs caudal artery);2) the level of the arterial tree (conduit vs resistance vessels);3) the technique employed for measurement of vascular changes (smooth muscle contraction vs vascular resistance changes);4) the initial vasoconstrictor tone of the preparation; and 5) the agonist used (nitroprusside vs norepinephrine).

Animals↗
PubMedDate not supplied

Potassium relaxation of vascular smooth muscle from DOCA hypertensive pigs.

This study was designed to characterize potassium-induced relaxation in vascular smooth muscle during the development of deoxycorticosterone acetate (DOCA) hypertension. Pigs were implanted subcutaneously with 100 mg/kg DOCA. Mean arterial pressure in the DOCA-treated pigs reached levels approximately 37% greater than controls. In some pigs, the left hindlimb vascular bed was "protected" from the rise in arterial pressure by ligation of the iliac artery. Arterial strips from DOCA hypertensive and normotensive pigs relaxed in response to potassium after contraction induced by norepinephrine in potassium-free solution. Arterial strips from DOCA hypertensive pigs showed greater relaxation than did those from normotensive pigs. The magnitude of relaxation in femoral arteries from "protected" hindlimbs was similar to that in arteries from the contralateral unoccluded limb. Potassium-induced relaxation in tail arteries from DOCA hypertensive pigs was more sensitive to ouabain inhibition than that from normotensive pigs. Relaxation induced by potassium varied with: 1) length of incubation in potassium-free solution; 2) concentration of added potassium; and 3) concentration of norepinephrine added during the potassium-free interval. The amplitude of potassium-induced relaxation is believed to be a functional index of the activity of the electrogenic sodium-potassium transport system. These experiments support the hypothesis that vascular smooth muscle from DOCA hypertensive animals has increased electrogenic sodium pump activity. The development of this vascular change parallels the increase in blood pressure induced by mineralocorticoid excess.

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Vascular changes in DOCA hypertension. Influence of a low protein diet.

The goal of this study was to characterize the influence of low protein diet on vascular changes induced by deoxycorticosterone acetate (DOCA) hypertension. DOCA hypertensive and control normotensive rats were placed on a low protein (5%) diet for 4 weeks. This intervention blocked the further increase in systolic blood pressure of rats treated with DOCA; systolic blood pressures of control rats were not influenced by the low protein diet. The sensitivity of isolated mesenteric arteries to norepinephrine was increased in DOCA hypertensive rats compared to that in arteries from control rats; arterial strips from rats maintained on the low protein diet were less sensitive to the catecholamine than arteries from their respective control diet group. Vascular sensitivity to calcium was identical in both normotensive and DOCA hypertensive rats, and the low protein diet had no effect on this measure of calcium activation. Calcium-induced relaxation was depressed in arteries from DOCA hypertensive rats, suggesting a decreased stabilizing influence of the cation on the excitable membrane. Arteries from rats maintained on the low protein diet showed enhanced relaxation to calcium compared to those from their respective control diet group. Membrane stores of calcium available for activation by norepinephrine were increased in arteries from DOCA hypertensive rats; the low protein diet decreased the storage capacity of these membrane sites. The total protein content of the aorta was increased in DOCA hypertensive rats and depressed to control level in DOCA rats maintained on low protein diet. No change was observed in actomyosin content nor in the actin-to-myosin ratio during the DOCA hypertension or the addition of a low protein diet. Since one action of DOCA is to increase cellular protein synthesis, the attenuation of these vascular changes in DOCA rats maintained on a protein-deficient diet is probably due to a decrease in available substrate.

Animals↗
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Increased vascular sensitivity to angiotensin ii in psychosocial hypertensive mice.

CBA mice develop hypertension when placed in complex population cages that facilitate social interactions and competition for territory. After 1 month, these mice have normal plasma renin levels, but blockade of converting enzyme lowers blood pressure to normal. To test the possibility that this normal-renin hypertension is caused by enhanced pressor responsiveness to angiotensin II (AII), we examined the effects of AII on hindquarter and renal vasculatures from 13 hypertensive and 13 normotensive mice. Both vascular beds were pump-perfused at a constant flow with plasma substitute. Optimal perfusion flows and basal pressures were similar in hindquarter (8 ml/100 g/min; 60 mm Hg) and renal vasculatures (130 ml/100 g/min; 50 mm Hg) from normotensive and hypertensive mice. Threshold constrictor responses to AII were elicited at a significantly lower dose in both vasculatures of hypertensive mice than in those of normotensive mice. Maximal pressor responses to AII were greater in the hindquarters of hypertensive mice than in those of normotensive mice, but were not different in the renal vasculatures of the two groups. Vasoconstrictor sensitivity to norepinephrine was also increased in the hindquarters of hypertensive mice; however, the changes in threshold and maximal pressor response were less than for AII. Responsiveness to norepinephrine in the renal vasculatures of hypertensive mice was not different from that in the kidneys of normotensive mice. We conclude that the hyperresponsiveness to AII in the resistance vessels plays an important role in maintaining elevated blood pressure in this psychosocial model of hypertension.

Angiotensin II↗
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Adrenergic neurotransmission in tail arteries from two-kidney, one clip, renal hypertensive rats.

The goal of this study was to determine if increased vascular smooth muscle sensitivity to norepinephrine in two-kidney, one clip (2K1C) hypertensive rats is the result of a decrease in adrenergic nerve function. Vascular sensitivity to norepinephrine was measured in isolated tail artery strips from 2K1C hypertensive and normotensive rats and in various arterial stripe preparations from normotensive rats that exhibit varying degrees of adrenergic innervation. In each case, the characteristic of the vascular smooth muscle response in the vessel with the least amount of adrenergic innervation simulated the response of the vascular smooth muscle from the 2K1C hypertensive rats. Release or displacement of endogenous norepinephrine by electrical stimulation, tyramine, potassium-free solution, and potassium excess, and measurement of tissue content of norepinephrine suggest that the blood vessels of 2K1C hypertensive animals are depleted of catecholamine stores. Based on these observations it is concluded that the increased sensitivity of vascular smooth muscle to norepinephrine in 2K1C hypertensive rats is the result of a diminished adrenergic innervation. This increased sensitivity of the vasculature may be a response of the smooth muscle cells to a decrease in innervation or the consequence of vascular wall hypertrophy leading to an increased number of smooth muscle cells that are remote from their adrenergic supply.

Adrenergic Fibers↗
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Functional evidence for increased sodium permeability in aortas from DOCA hypertensive rats.

We studied the role of increased Na+ permeability on the increased responsiveness to ouabain and to K+-free solution in aortas from DOCA hypertensive rats. Helically cut strips from DOCA hypertensive and normotensive control rats were mounted in a muscle bath for recording isometric force. In response to ouabain, aortas from DOCA hypertensive rats were significantly more sensitive and developed a greater maximal force than aortas from control rats. The rate of force development in response to K+-free solution was significantly faster in aortas from DOCA hypertensive rats as compared to those from control rats. Monensin (10(-5)M), a Na+ ionophore, increased the contractile response to ouabain and the rate of force development in response to K+-free solution in both DOCA hypertensive and control aortas. Amiloride (3 X 10(-5) M), a Na+ channel blocker, decreased the contractile response to ouabain and the rate of force development to a K+-free solution in both the DOCA hypertensive and control aortas, but the magnitude of decrease was greater in aortas from DOCA hypertensive rats. Thus, a Na+ ionophore causes the control aortas to perform like those from DOCA hypertensive rats, and a Na+ channel blocker causes aortas from DOCA hypertensive rats to perform like those from control rats. It is concluded that the difference between the two is that the smooth muscle of aortas from DOCA hypertensive rats is more permeable to Na+ than is that from control rats.

Amiloride↗
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Vascular responses to serotonin in steroid hypertensive rats.

This study investigates the mechanism responsible for increased vascular sensitivity to serotonin in deoxycorticosterone acetate (DOCA)-salt hypertension. Femoral arteries from normotensive and hypertensive rats were excised and cut into helical strips for isometric force recording. Dose-response curves to serotonin were shifted significantly to the left in arteries from DOCA-salt hypertensive rats compared to those from normotensive rats (ED50:DOCA = 7.1 X 10(-8) M; control = 27 X 10(-8) M). The partial agonistic properties of methysergide were increased in femoral arteries from DOCA-salt hypertensive rats. The competitive antagonism of serotonin by methysergide or ketanserin was similar in arteries from control and DOCA-salt hypertensive rats (pA2: methysergide, control = 10.4, DOCA = 10.5; and ketanserin, control = 10.4, DOCA = 10.4). After cellular calcium (Ca) depletion with EGTA, dose-response curves to Ca were obtained in the presence of serotonin (5.7 X 10(-5) M). The Ca sensitivity of vessels from hypertensive rats was not statistically different from that in arteries from normotensive rats. Contractile responses to serotonin in calcium-free solution following loading of a cellular store with Ca were 50% greater in arteries from DOCA hypertensive rats. These results suggest that the enhanced sensitivity to serotonin in DOCA-salt hypertensive rats is not related to a change in receptor affinity nor to an alteration in transmembrane movement of Ca following receptor activation. The increased serotonin sensitivity is related to an altered mobilization of Ca from a cellular store.

Animals↗
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Oscillatory contractions in tail arteries from genetically hypertensive rats.

This study characterizes a cellular mechanism for oscillatory contractions induced by norepinephrine in vascular smooth muscle from spontaneously hypertensive stroke prone rats (SHRSP). Helically cut strips of tail arteries from SHRSP and normotensive Wistar-Kyoto rats (WKY) were mounted in a muscle bath for measurement of isometric force generation. Norepinephrine-induced responses of arteries from SHRSP were characterized by fluctuations in contractile activity, whereas those in arteries from WKY remained constant with time. The magnitude of the oscillatory contractile activity (frequency X mean amplitude) varied directly with norepinephrine concentration (5.9 X 10(-9) to 1.8 X 10(-7) M). The oscillatory contractile activity varied inversely with the potassium concentration (3-20 mM) of the buffer solution and directly with the calcium concentration (0.1-5.0 mM) of the buffer solution. The oscillatory activity was converted to maintained contraction by barium (10(-4) M), quinidine (3 X 10(-6) M), sparteine (10(-3) M), D-600 (10(-7) M), and nifedipine (10(-8) M). Tetraethylammonium and 3,4-diaminopyridine, inhibitors of voltage-dependent potassium channels, did not alter the oscillatory contractile activity induced by norepinephrine. These observations suggest that oscillatory contractile activity in tail arteries from SHRSP is caused by an abnormal variation in potassium efflux during stimulation with norepinephrine. The altered potassium efflux appears to be related to calcium entry, which is sensitive to inhibition by channel blockers. This altered membrane property may contribute to changes in vascular sensitivity in hypertension.

Animals↗