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G Kaley

Publications and source records attributed to G Kaley.

At least 73 records · Page 4Linked to original sources
PubMed1992

Role of endothelium-derived prostaglandins in hypoxia-elicited arteriolar dilation in rat skeletal muscle.

The aims of the present study were to determine the response of rat cremaster muscle first-order arterioles to hypoxia and the role of endothelium-derived prostaglandins in the response. Isolated arterioles were cannulated, pressurized to 65 mm Hg, and studied in a no-flow condition in a bath containing Krebs' bicarbonate solution, pH 7.4, equilibrated with 21% O2-5% CO2-74% N2 (PO2, 150 mm Hg) or 95% N2-5% CO2 (PO2, 15 mm Hg [hypoxia]). Responses to hypoxia and vasoactive substances were studied before and after removal of the endothelium or blockade of prostaglandin synthesis by the administration of indomethacin (10(-5) M). Addition to the suffusion solution of arachidonic acid (10(-7) and 10(-6) M), prostaglandin E2 (10(-9) and 10(-8) M), acetylcholine (10(-8) and 10(-6) M), or sodium nitroprusside (10(-8) M) evoked significant arteriolar dilation. When the bath PO2 was reduced from 150 to 15 mm Hg, arteriolar diameters increased by 58.8 +/- 9.3 microns (61%). Removal of the endothelium completely inhibited responses to hypoxia, acetylcholine, and arachidonic acid, whereas responses to sodium nitroprusside and prostaglandin E2 remained unaltered. In arterioles with an intact endothelium, indomethacin completely inhibited the responses to hypoxia and arachidonic acid, whereas responses to acetylcholine and sodium nitroprusside were unaltered. These findings support the conclusion that endothelium-derived prostaglandins mediate the arteriolar dilation to hypoxia in rat skeletal muscle arterioles.

Acetylcholine↗
PubMed1991

Modified arteriolar responses to ATP after impairment of endothelium by light-dye techniques in vivo.

In this study we investigated whether endothelial cells are involved in the dilation of third-order arterioles (14 to 22 microns) in response to adenosine triphosphate (ATP) in cremaster muscle of pentobarbital-anesthetized rats. Two light/dye (L/D) techniques were employed to achieve selective, local endothelial impairment. One of these techniques utilizes a mercury lamp and sodium fluorescein, the other a Helium-Neon laser and Evans blue dye. L/D treatment (illumination with the appropriate wavelengths of light in the presence of an intravascular dye) of a 20-to 100-microns segment of an arteriole resulted in a complete loss of arteriolar dilation in response to topical administration of acetylcholine (10(-6) M) and arachidonic acid (AA, 10(-5) M). These agents were applied in 100-microl aliquots without interrupting the continuous suffusion with Ringer-gelatin solution and caused a approximately 70% increase in vascular diameter before the L/D intervention. Selectivity of the impairment was assessed by arteriolar responses to the nonendothelium-dependent dilator agents adenosine (10(-5) M) and sodium nitroprusside (2 X 10(-7) M), which elicited the same degree of dilation before and after L/D treatment. Under control conditions ATP (10(-6), 10(-5), and 10(-4) M) elicited dose-dependent increases in arteriolar diameter (from 38 to 74%). After impairment of arteriolar endothelium, dilation in response to all doses of ATP was significantly reduced. Theophylline (30 microM) significantly inhibited arteriolar dilation in response to adenosine (10(-6), 10(-5), and 10(-4) M) but did not affect the responses to various doses of ATP. Moreover, impairment of endothelium enhanced constrictor responses of arterioles to norepinephrine (0.6 X 10(-8) M). These results indicate that arteriolar endothelium of skeletal muscle can mediate or modulate arteriolar responses to various vasoactive agents, suggesting that it has an important role in the regulation of blood flow.

Acetylcholine↗
PubMed1991

Endothelial regulation of wall shear stress and blood flow in skeletal muscle microcirculation.

In the presence of intact endothelium, in control conditions, calculated wall shear rate (WSR) (means +/- SE: 2,658 +/- 123 s-1; n = 21) was independent of arteriolar diameter (16.2-27.2 microns; correlation coefficient: r = 0.12, P greater than 0.05) in cremaster muscle of pentobarbital-anesthetized rats. An increase in blood flow velocity (due to parallel arteriolar occlusion) elicited a significant increase in WSR (to 4,981 +/- 253 s-1) followed by a delayed (6-15 s) increase in diameter (from: 22.5 +/- 0.6 to 29.5 +/- 0.8 microns), which consequently resulted in a significant decrease in WSR (to 3,879 +/- 203 s-1). As a result of the increased flow velocity and dilation, calculated arteriolar blood flow increased by 230%. After impairment of the endothelium of arterioles by a light-dye technique, basal WSR became significantly higher (3,604 +/- 341 s-1), and despite a greater increase in WSR (10,360 +/- 1,471 s-1) the dilation was absent. Now an inverse linear correlation was found between arteriolar diameter and WSR both before (r = 0.58, P less than 0.05) and during increased flow velocity conditions (r = 0.85, P less than 0.05). Also, arteriolar blood flow that was already less after impairment of endothelium increased by only 66% during the period of increased flow velocity due to the absence of dilation. Results suggest that an increase in wall shear stress is the stimulus for the endothelium-dependent mechanism that elicits "flow dependent" arteriolar dilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

EDRF released from microvascular endothelial cells dilates arterioles in vivo.

Microvascular endothelial cells (MECs) from rat epididymal fat pad were isolated and cultured in vitro on Cytodex 3 microcarrier beads. In Krebs-suffused cremaster muscle of pentobarbital-anesthetized rats arteriolar diameters (mean control diam 20.9 +/- 0.9 micron) were measured using image shearing video microscopy. Two lines of suffusate (1.5 ml/min each) were established; one contained a column of microcarrier beads only (no cells in line; NC) the other contained a 1-ml column of MECs grown on beads (through cells; TC). The muscle preparation and the MECs were first treated with indomethacin (Indo; 28 microM). Indo treatment blocked arteriolar dilation to A23187 (1 microM) and arachidonic acid (AA; 0.25 microM) administered into the NC line. A 4.0 +/- 0.6 micron increase in arteriolar diameter was observed, however, when A23187 (but not AA) was infused through the TC line containing Indotreated MECs on beads. The A23187-elicited dilation was abolished by the introduction of NG-monomethyl-L-arginine (L-NMMA; 200 microM) into the TC line. Administration of atropine (2 microM) onto the cremaster muscle via the NC line inhibited the dilations in response to acetylcholine (ACh; 2.7 microM) given through the NC line. Infusion of ACh through the TC line onto the atropine-treated cremaster muscle, however, elicited a 5.8 +/- 1.3 micron increase in arteriolar diameter, a response that was blocked by prior administration of L-NMMA into the TC line. Arteriolar dilation induced by adenosine (0.5 microM) or sodium nitroprusside (0.5 microM) applied via the NC or TC line was unaffected by L-NMMA.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1991

Dilation and constriction of large coronary arteries in conscious dogs by endothelin.

This study examined the effects of endothelin on coronary circulation and the relationship between the plasma concentration of endothelin and cardiovascular function in conscious dogs. The injection of a low dose (50 ng/kg) of endothelin increased coronary artery diameter by 2.17 +/- 0.49% and then decreased coronary artery diameter by 1.13 +/- 0.17% (P less than 0.01) from 3.51 +/- 0.14 mm. This dose increased coronary blood flow by 39 +/- 8.5% and then decreased coronary blood flow by 14 +/- 3.5% (P less than 0.01) from 25 +/- 1.6 ml/min, respectively. Four doses of endothelin (1, 10, 20, and 50 ng.kg-1.min-1) were infused for 20 min each as a cumulative dose response and blood samples were taken to assay endothelin. Significant changes in systemic and coronary dynamics were observed at infusions of 10 and 20 ng.kg-1.min-1. For instance, at 10 ng.kg-1.min-1 there was a significant (P less than 0.05) increase in mean arterial pressure (10 +/- 2.7%), left ventricular (LV) end-diastolic (32 +/- 11%), and LV systolic (8 +/- 3%) pressures and late diastolic coronary resistance (12 +/- 3.0%). This was accompanied by a reduction in large coronary artery diameter (2.0 +/- 0.5%) and coronary blood flow (22 +/- 6.0%; P less than 0.05). At this infusion rate, plasma endothelin reached 70 pg/ml when compared with a control value of 4 +/- 1 pg/ml. Thus the bolus injections of endothelin evoked a biphasic response of large and small coronary arteries, whereas during infusion we observed only vasoconstriction. The levels of circulating endothelin necessary to cause significant cardiovascular effects are much higher than expected.

Animals↗
PubMed1990

Endothelium regulates skeletal muscle microcirculation by a blood flow velocity-sensing mechanism.

In rat cremaster muscle, utilizing parallel arteriolar occlusion, we found that an increase in red blood cell (RBC) velocity (3.5-26.5 mm/s) per se induced an increase in diameter (1.5-9.4 microns) of arterioles (mean control diam 21.5 +/- 0.6 microns; n = 25). The dilation of arterioles appeared only when RBC velocity increased and started always with a delay (mean 8.4 +/- 0.5 s) after the increase in flow velocity. A positive linear correlation was found between peak changes in RBC velocity and diameter (r = 0.87, P less than 0.05). The velocity sensor as well as the mechanism(s) that mediates this response is likely to be located in endothelial cells, because the dilation to increased RBC velocity was completely eliminated after impairment of arteriolar endothelium with light-dye (L-D) treatment. The in vivo demonstration of this phenomenon in arterioles suggests the existence of a new endothelium-dependent, flow velocity-sensitive mechanism for the regulation of blood flow in the microcirculation.

Animals↗
PubMed1990

Role of endothelium in reactive dilation of skeletal muscle arterioles.

In cremaster muscle of pentobarbital-anesthetized rats, the role of endothelium in the reactive dilation of an arteriole (mean control diameter: 18.2 +/- 0.5 microns) during and after short (approximately 20 s) or long (approximately 80 s) occlusion of a parent arteriole was investigated. Distal to the occluder, arteriolar diameter increased during the occlusion (mean peak increase: 6.9 +/- 0.4 and 6.7 +/- 1.1 microns, respectively) and increased even further after the release of the occlusion as blood flow was reestablished (additional mean increase: 6.5 +/- 0.7 and 5.8 +/- 0.8 microns, respectively). The duration of arteriolar dilation after the release of the occlusion was dependent on the duration of occlusion (252.2 +/- 37 vs. 411.3 +/- 57 s; P less than 0.05). After impairment of the arteriolar endothelium by light/dye treatment, a dilation was still present during both the shorter and longer occlusions (mean increase: 4.73 +/- 1.4 and 4.73 +/- 1.3 microns, respectively); however, in both cases the additional dilation after release of the occlusion was greatly diminished. The duration of reactive arteriolar responses following impairment of the endothelium was significantly reduced only on release of the shorter occlusions. The results suggest that reactive dilation (hyperemia) of arterioles is the result of multiple, endothelium-dependent and endothelium-independent vasoactive factors.

Animals↗
PubMed1990

Prostaglandins mediate arteriolar dilation to increased blood flow velocity in skeletal muscle microcirculation.

In cremaster muscle of pentobarbital-anesthetized rats, temporary occlusion of an arteriole increased red blood cell velocity (mean increase, 8.2 +/- 1.0 mm/sec from a control velocity of 7.9 +/- 0.7 mm/sec) in proximal parallel arteriolar branches (mean control diameter, 19.4 +/- 0.6 microns). Increases in flow velocity were consistently followed by proportional delayed (6-15 seconds) increases in arteriolar diameter (5.8 +/- 0.7 microns). Administration of NG-monomethyl-L-arginine (200 microM), an inhibitor of the synthesis of endothelium-derived relaxing factor that blocked the arteriolar responses to acetylcholine (1 microM) but not to arachidonic acid (10 microM), did not affect the dilation (mean increase, 8.9 +/- 1.1 microns) due to increases in red blood cell velocity (13.4 +/- 1.5 mm/sec). However, the cyclooxygenase inhibitor indomethacin (or meclofenamate), which completely blocked the dilator response to arachidonic acid but did not change the response to acetylcholine, inhibited the arteriolar dilation (mean increase, 0.3 +/- 0.2 micron) due to increases in red blood cell velocity (9.3 +/- 1.0 mm/sec). Inhibition of prostaglandin synthesis also reduced the increase in calculated blood flow by 57% during occlusion. These results suggest that the arterioles are sensitive to increases in blood flow velocity (wall shear stress), in response to which they release prostaglandins, eliciting vasodilation. The existence of this phenomenon in the skeletal muscle microcirculation suggests a new regulatory mechanism that, by modulation of vascular resistance in the microvascular network, has the role of normalizing wall shear stress and providing for substantial increases in tissue blood flow.

Acetylcholine↗
PubMed1990

Methylene blue inhibits vasodilation of skeletal muscle arterioles to acetylcholine and nitric oxide via the extracellular generation of superoxide anion.

The mechanism of modulation of cyclic GMP-associated vascular responses by methylene blue, an agent employed to inhibit the activation of soluble guanylate cyclase in tissues, was investigated in the cremaster muscle microcirculation of pentobarbital-anesthetized rats. The effect of topically applied agents on the diameter of third-order arterioles (15-20 microns diameter) was determined by in vivo television microscopy. Topical application (100 microliters) of acetylcholine (0.01 microgram) or nitric oxide (0.06-6 micrograms) caused vasodilator responses that were inhibited (P less than .05, n = 6-8) 64% and 30 to 100%, respectively, by suffusion of the preparation with 5 microM methylene blue. Agents that are thought to produce activation of guanylate cyclase via cellular metabolism to nitric oxide, nitroglycerin (0.5 ng-0.5 microgram) or nitroprusside (0.5 ng-0.5 microgram), also produced vasodilation. However, methylene blue suffusion did not inhibit these responses (n = 6-9). The inhibition of vasodilation to acetylcholine or nitric oxide by methylene blue was completely prevented by suffusion of superoxide dismutase, but not affected by suffusion of catalase. Based on the current conceptualization of the mechanism of action of these vasodilator agents in isolated larger blood vessels, methylene blue appears to inhibit responses in this skeletal muscle microcirculatory preparation through the extracellular generation of superoxide anion and not via a direct interaction with guanylate cyclase.

Acetylcholine↗
PubMed1990

Similarities in the pharmacological modulation of reactive hyperemia and vasodilation to hydrogen peroxide in rat skeletal muscle arterioles: effects of probes for endothelium-derived mediators.

Our laboratory has demonstrated previously that prostaglandins are partially responsible for the vasodilation of rat cremaster muscle arterioles in vivo to a brief occlusion or hydrogen peroxide (H2O2). In the present study, in pentobarbital-anesthetized rats, we investigated the mechanism of the prostaglandin-independent portion of the dilation to these stimuli by measurement of changes in the diameter of third order cremasteric arterioles (approximately 15 microns) by video microscopy. In the presence of indomethacin suffusion (10 micrograms/ml), arteriolar dilation to the release of a 15-sec occlusion of a single arteriole or to topical application of 0.1 to 1 mM H2O2 (100 microliters) was reduced significantly by suffusion of 20 microM quinacrine or 5 microM methylene blue, whereas vasodilation to adenosine was not affected by these probes. Furthermore, the reactive hyperemia was not altered by suffusion of 50 microM hydroquinone or 0.2 mM NG-monomethyl-L-arginine, inhibitors of the dilation to acetylcholine mediated by the endothelium-derived relaxing factor. Reactive hyperemia was also not affected by 30 microM theophylline (an adenosine antagonist) or suffusion of catalase (160 U/ml) plus superoxide dismutase (240 U/ml). Therefore, the reactive hyperemia does not appear to be mediated through endothelium-derived relaxing factor, adenosine or the extracellular formation of reactive O2 species. However, these observations suggest that the prostaglandin-independent vasodilation to H2O2 and to the release of a brief arteriolar occlusion may be mediated by a common mechanism, possibly involving cyclic GMP. Similarities in pharmacological modulation of the dilation after occlusion and to H2O2 in the cremaster microcirculation suggest consideration of the involvement of H2O2 in the hyperemic response.

Animals↗
PubMed1989

Endothelium-associated vasodilators in rat skeletal muscle microcirculation.

Pharmacological probes were used to assess the possible roles of guanosine 3',5'-cyclic monophosphate (cGMP)-associated endothelium-derived relaxing factor (EDRF) in mediating microvascular responses to endogenous and exogenous agents in vivo. Pentobarbital-anesthetized rats (Wistar, 6 wk old) were prepared for in vivo microscopic observation and quantification of changes in diameter of third-order arterioles (15-25 microns) in the cremaster muscle to topical application of all agents. In indomethacin-pretreated preparations, cremasteric arteriolar dilator responses to acetylcholine, bradykinin, or ATP, but not to adenosine, histamine, or prostaglandin E2, were inhibited by hydroquinone (50 microM). Vasodilation to acetylcholine was also inhibited by methylene blue (5 microM), a blocker of guanylate cyclase activation. Constrictor responses to norepinephrine were not affected by hydroquinone or methylene blue. The inhibition of acetylcholine-induced vasodilation by hydroquinone and methylene blue was reversed by superoxide dismutase, suggesting that superoxide anion antagonized the response. On the other hand, basal arteriolar diameters or responses to acetylcholine were not affected by oxygen metabolite scavengers. Unlike in isolated arteries, vasodilator responses to the calcium ionophore A23187 or arachidonic acid were completely antagonized by cyclooxygenase inhibition. These data suggest that EDRF could be involved in the control of microvascular tone; however, significant differences exist in the stimuli that elicit dilation through this mediator in small and large blood vessels.

Acetylcholine↗
PubMed1989

Effects of endothelial impairment on arteriolar dilator responses in vivo.

In pentobarbital-anesthetized rats we investigated the role of the endothelium in the dilation of third-order arterioles of cremaster muscle to acetylcholine, adenosine, and sodium nitroprusside in vivo. Responses to the topical administration of these agents were measured with image shearing and recorded with video microscopy before and after light-dye (L-D) treatment of a 50- to 100-microns segment of the arteriole under study. L-D treatment consisted of intravascular administration of sodium fluorescein and the illumination of a discrete area of the arteriole under study with its excitation light from a mercury lamp. Before L-D treatment, acetylcholine (10(-7) to 10(-5) M) and adenosine (10(-6) to 10(-4) M) produced dose-dependent increases in arteriolar diameter (vasodilation). After L-D treatment of the arteriolar segment, administration of 10(-7) M acetylcholine evoked a vasoconstriction (-19% from control), and the dilator responses to 10(-6) and 10(-5) M were inhibited by 91 and 77%, respectively. In contrast, the arteriolar dilator responses to all doses of adenosine and sodium nitroprusside (2 x 10(-7) M) were not altered by this treatment. In addition, the dilator responses to acetylcholine were not changed in the nonilluminated, distal, and proximal segments of the arterioles. These findings suggest that L-D treatment selectively alters the function of the endothelium resulting in the loss of vasodilation to acetylcholine, whereas arteriolar smooth muscle function does not appear to be affected.

Acetylcholine↗
PubMed1989

Endothelial impairment inhibits prostaglandin and EDRF-mediated arteriolar dilation in vivo.

The role of endothelium in the vasodilation of third order arterioles of cremaster muscle to a variety of vasoactive agents was investigated in pentobarbital-anesthetized rats. Changes in diameter to topical administration of agents were measured with image shearing, before and after mercury light/sodium fluorescein (light/dye) treatment of a 50- to 100-microns segment of the arteriole under study and were recorded with video microscopy. Before light/dye treatment, arachidonic acid (10(-5) M), prostaglandin E2 (5 x 10(-6) M), A23187 (2 x 10(-6) M), acetylcholine (10(-5) M), and adenosine (10(-4) M) elicited dilation between 75 and 106% of basal diameter. After light/dye treatment, dilations to arachidonic acid, A23187, and acetylcholine were completely eliminated; however, the responses to prostaglandin E2 and adenosine were not altered. These results indicate that light/dye treatment interferes with the production of or response to prostaglandins as well as other endothelial mediators, like endothelium-derived relaxing factor (EDRF). In a second series of experiments, bradykinin, in concentrations of 10(-9), 10(-8), and 10(-7) M elicited dose-dependent dilations, which were partially inhibited by indomethacin and completely abolished after additional light/dye treatment. Dilation of arterioles to adenosine was maintained throughout these experiments. These data suggest that vasodilation to bradykinin is mediated partly via prostaglandin production and partly via other endothelium-derived factor(s).

Acetylcholine↗
PubMed1989

Flow velocity-dependent regulation of microvascular resistance in vivo.

In skeletal (cremaster) muscle of pentobarbital anesthetized rats we tested the hypothesis that blood flow-dependent regulation of vascular resistance exists in the microcirculation. During occlusion of an arteriole we found that the consequent increase in red blood cell (RBC) velocity in a proximal parallel arteriole was followed by a mean increase in diameter of 32 percent (mean control diameter: 21.5 +/- 0.5 microns) of the arteriole under study. The increase in arteriolar diameter always appeared with a delay (mean: 8.4 +/- 0.5 s) following the onset of changes in RBC velocity. Upon release of the occlusion RBC velocity decreased followed by a decline in diameter of the arteriole under study. Since the changes in arteriolar diameter during this experimental intervention cannot be explained on the basis of previously described blood flow-regulatory mechanisms in the microcirculation we conclude that changes in blood flow velocity (wall shear stress) per se induced the changes in arteriolar diameter. The existence of this phenomenon suggests a new, flow velocity-sensitive mechanism which can regulate - via changes in diameter - the supply and distribution of blood flow in the microcirculation in vivo.

Animals↗
PubMed1989

Microvascular effects of endothelin-1.

In the present study we examined the microvascular actions of endothelin (ET-1) in rat cremaster arterioles. Pentobarbital (35 mg/kg) anesthetized, five to six week old rats were prepared for in vivo observation and measurement of microvascular control dimensions and changes in diameter, in response to the topical administration of ET-1 (1 x 10(-11) to 5 x 10(-10) M). The effects of ET-1 were determined before and after the administration, by suffusion upon the cremaster muscle, of either indomethacin (IND, 10 micrograms/ml) or methylene blue (MB, 5 microM). Third order arterioles; 13-25 microns in diameter, were selected for study. The administration of ET-1 evoked a biphasic response of cremaster arterioles, an initial small, fleeting increase in diameter (14 to 26%) followed by a dose-dependent, longer lasting decrease in diameter (20 to 77%). The administration of either MB or IND had no effect on the arteriolar dilator and constrictor responses to ET-1. These results suggest that ET-1 is more potent a constrictor than dilator agent in this vascular bed and that the dilator component of the response is not mediated by either prostaglandins or EDRF. By virtue of its actions and potency, we conclude that ET may be an important factor in the regulation of vascular tone and local blood flow.

Animals↗
PubMed1988

6-Keto-prostaglandin E1 is a potent coronary vasodilator and stimulates a vagal reflex in dogs.

These studies were performed to examine the effects of 6-keto-prostaglandin E1 (6-keto-PGE1) on coronary artery blood flow and reflex cardiovascular regulation. In seven chloralose-anesthetized dogs 6-keto-PGE1 and prostacyclin (PGI2) were injected as a bolus into the left circumflex coronary artery in doses of 250 to 4000 ng. Coronary artery blood flow significantly increased and coronary artery resistance decreased in a dose-related manner. There were no significant differences observed between 6-keto-PGE1 and PGI2 in the magnitude of the maximum increase in coronary blood flow or decrease in coronary artery resistance. In six additional anesthetized dogs in which the carotid arteries were ligated in order to minimize baroreflexes, intracoronary injection of 6-keto-PGE1 and PGI2 (in doses of 7, 14 and 23 micrograms) caused systemic hypotension and bradycardia. Bilateral vagotomy attenuated the hypotension and abolished the bradycardia induced by these substances. In five conscious dogs, 6-keto-PGE1 and PGI2 were infused (2, 10 and 20 micrograms/min i.v.) for 10 min. 6-keto-PGE1 and PGI2 caused significant decreases in mean arterial pressure; however PGI2 was significantly more potent in this respect. The tachycardia to the highest doses was compared to that induced by infusion of nitroprusside (500 micrograms/min i.v.). 6-keto-PGE1 and PGI2 caused significantly less baroreflex tachycardia per millimeter of mercury decrease in arterial pressure than did nitroprusside. Thus, in anesthetized dogs, 6-keto-PGE1 and PGI2 are equipotent coronary vasodilators. These PGs also stimulate a vagal reflex which results in hypotension, bradycardia and attenuation of baroreflex-mediated tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprostadil↗