Biomedical subjects

Steven S Segal

Publications and source records attributed to Steven S Segal.

27 records · Page 2Linked to original sources

PubMed2003

Homocellular conduction along endothelium and smooth muscle of arterioles in hamster cheek pouch: unmasking an NO wave.

We investigated roles for homocellular (endothelium or smooth muscle) and heterocellular (myoendothelial) conduction pathways along hamster cheek pouch arterioles in vivo (n=64; diameter, 33+/-1 microm). Endothelium-dependent and -independent vasoactive agents were delivered from micropipettes (0.5 or 1 second pulse) onto an arteriole while observing diameter changes at defined distances along the vessel. Acetylcholine (ACh) produced maximal diameter (63+/-1 microm) locally and vasodilation conducted rapidly ( approximately 10 microm response at 2 mm, <1 second). Responses to bradykinin (BK) were similar, whereas sodium nitroprusside produced maximal dilation locally without conduction. KCl evoked biphasic conduction of vasoconstriction and vasodilation, whereas phenylephrine (PE) produced conducted vasoconstriction. Disrupting the integrity of endothelium as a conduction pathway using focal light-dye treatment (LDT) abolished conducted vasodilation to BK and to KCl but not to ACh. Disruption of smooth muscle integrity with LDT abolished conducted vasoconstriction with no effect on conducted vasodilation. After LDT of respective cell layers at sites 1 mm apart, vasodilation to ACh conducted past disrupted smooth muscle or disrupted endothelium, but not beyond both sites in series. The loss of conduction after selective LDT indicates a lack of effective myoendothelial coupling along the arteriolar wall. During NO synthase inhibition (L-NA, 100 micromol/L), conducted vasodilation was abolished to BK and to KCl yet remained intact to ACh. However, after LDT of smooth muscle, L-NA inhibited conduction to ACh by 60%. Thus, conduction of vasodilation entails a wave of NO release along arteriolar endothelium that is masked when smooth muscle provides a parallel conduction pathway.

Acetylcholine↗

PubMed2003

Interaction between sympathetic nerve activation and muscle fibre contraction in resistance vessels of hamster retractor muscle.

The interaction between skeletal muscle contraction and sympathetic nerve activation (SNA) on blood flow during exercise has remained ambiguous due to indirect estimates of vasomotor control. In the hamster retractor muscle (n=54), interactions between three levels of SNA (approximately 3, 6 and 12 Hz) and of contractile activity (2.5, 10 and 20 % duty cycle) were studied in feed arteries (FA) and first- (1A), second- (2A), and third-order (3A) arterioles using intravital microscopy. During functional dilatation with rhythmic muscle contractions, sympathetic vasoconstriction was sustained in FA and 1A but impaired in 2A and 3A (P<0.05), where vessels 'escaped' from responding to SNA. To account for changes in baseline diameter and blood flow during contractions, vasodilatation was induced passively (2-3 levels) in resting muscles with papaverine or sodium nitroprusside. Compared to functional dilatation, the range of passive dilatation was similar in 3A and progressively greater in 2A, 1A and FA. With passive dilatation, SNA responses were sustained in 2A and increased with baseline diameter in 3A. Blood flow through FA (rest, approximately 20 nl s(-1)) increased approximately 5-fold during contractile activity and approximately 10-fold during passive dilatation. Absolute flow reductions (nl s(-1)) with SNA increased during contractile activity and during passive dilatation; relative flow reductions were impaired during functional dilatation (P<0.05) and remained constant during passive dilatation. Thus, SNA can restrict blood flow to exercising muscle by constricting FA and 1A while dilatation prevails in 2A and 3A. Such concerted interaction will promote oxygen extraction when blood flow is restricted to maintain arterial pressure.

Animals↗

PubMed2003

Abolition of arteriolar dilation but not constriction to histamine in cremaster muscle of eNOS-/- mice.

Histamine increases the permeability of capillaries and venules but little is known of its precapillary actions on the control of tissue perfusion. Using gene ablation and pharmacological interventions, we tested whether histamine could increase muscle blood flow through stimulating nitric oxide (NO) release from microvascular endothelium. Vasomotor responses to topical histamine were investigated in second-order arterioles in the superfused cremaster muscle of anesthetized C57BL6 mice and null platelet endothelial cell adhesion molecule-1 (PECAM-1-/-) and null endothelial NO synthase (eNOS-/-) mice aged 8-12 wk. Neither resting (17 +/- 1 microm) nor maximum diameters (36 +/- 2 microm) were different between groups, nor was the constrictor response (approximately 5 +/- 1 microm) to elevating superfusate oxygen from 0 to 21%. For arterioles of C57BL6 and PECAM-1-/- mice, cumulative addition of histamine to the superfusate produced vasodilation (1 nM-1 microM; peak response, 9 +/- 1 microm) and then vasoconstriction (10-100 microM; peak response, 12 +/- 2 microm). In eNOS-/- mice, histamine produced only vasoconstriction. In C57BL6 and PECAM-1-/- mice, vasodilation was abolished with Nomega-nitro-l-arginine (30 microM); in all mice, vasoconstriction was abolished with nifedipine (1 microM). Vasomotor responses were eliminated with pyrilamine (1 microM; H1 receptor antagonist) yet remained intact with cimetidine (1 microM; H2 receptor antagonist). These findings illustrate that the biphasic vasomotor response of mouse cremaster arterioles to histamine is mediated through H1 receptors on endothelium (NO-dependent vasodilation) as well as smooth muscle (Ca2+ entry and constriction). Thus histamine can increase as well as decrease muscle blood flow, according to local concentration. However, when NO production is compromised, only vasoconstriction and flow reduction occur.

Animals↗

PubMed2002

Conduction of hyperpolarization along hamster feed arteries: augmentation by acetylcholine.

The conduction of vasodilation along resistance vessels has been presumed to reflect the electrotonic spread of hyperpolarization from cell to cell along the vessel wall through gap junction channels. However, the vasomotor response to acetylcholine (ACh) encompasses greater distances than can be explained by passive decay. To investigate the underlying mechanism for this behavior, we tested the hypothesis that ACh augments the conduction of hyperpolarization. Feed arteries (n = 23; diameter, 58 +/- 4 microm; segment length, 2-8 mm) were isolated from the hamster retractor muscle, cannulated at each end, and pressurized to 75 mmHg (at 37 degrees C). Vessels were impaled with one or two dye-containing microelectrodes simultaneously (separation distance, 50 microm to 3.5 mm). Membrane potential (E(m)) (rest, approximately -30 mV) and electrical responses were similar between endothelium and smooth muscle, as predicted for robust myoendothelial coupling. Current injection (-0.8 nA, 1.5 s) evoked hyperpolarization (-10 +/- 1 mV; membrane time constant, 240 ms) that conducted along the vessel with a length constant (lambda) = 1.2 +/- 0.1 mm; spontaneous E(m) oscillations (approximately 1 Hz) decayed with lambda = 1.2 + 0.1 mm. In contrast, ACh microiontophoresis (500 nA, 500 ms, 1 microm tip) evoked hyperpolarization (-14 +/- 2 mV) that conducted with lambda = 1.9 +/- 0.1 mm, 60% further (P < 0.05) than responses evoked by purely electrical stimuli. These findings indicate that ACh augments the conduction of hyperpolarization along the vessel wall.

Acetylcholine↗

PubMedDate not supplied

Independence of connexin expression and vasomotor conduction from sympathetic innervation in hamster feed arteries.

OBJECTIVE: Vasomotor responses can travel along the wall of resistance microvessels by two distinct mechanisms: cell-to-cell conduction through gap junctions or the release of neurotransmitter along perivascular nerves. It is unknown whether vascular innervation influences the expression of connexin molecules which comprise gap junctions, or the conduction of vasomotor responses. In feed arteries of the hamster retractor muscle (RFA), the authors tested whether sympathetic denervation would alter the expression of connexin isoforms and the conduction of vasomotor responses. METHODS: Using intact vessels with sympathetic innervation and those 7-8 days following denervation surgery, mRNA expression was quantified using real-time PCR, cellular localization of Cx protein was characterized using immunohistochemistry, and vasomotor responses to dilator and constrictor stimuli were evaluated in isolated pressurized RFA. RESULTS: Connexin protein localization and mRNA expression were similar between innervated and denervated vessels. mRNA levels were Cx43 = Cx37 > Cx45 >> Cx40. Vasodilation to acetylcholine conducted >/=2000 microm along innervated and denervated vessels, as did the biphasic conduction of vasoconstriction and vasodilation in response to KCl. Vasoconstriction to phenylephrine conducted <500 microm and was attenuated (p <.05) in denervated vessels. CONCLUSIONS: The profile of connexin expression and the conduction of vasomotor responses are largely independent of sympathetic innervation in feed arteries of the hamster retractor muscle (RFA).

Acetylcholine↗

PubMedDate not supplied

Contribution of active membrane processes to conducted hyperpolarization in arterioles of hamster cheek pouch.

OBJECTIVE: Conduction of vasodilation triggered by acetylcholine (ACh) in arteriolar networks reflects hyperpolarization and its spread from cell to cell along the vessel wall. The amplitude and distance of the vasomotor response appear greater than can be explained by simple passive decay of the electrical signal. The authors tested the hypothesis that the conduction of hyperpolarization involves active membrane processes as the signal travels along the arteriolar wall. METHODS: Intracellular recordings of membrane potential were made from either the smooth muscle or endothelial cell layer of arterioles of the hamster cheek pouch in vivo. Acetylcholine was delivered onto an arteriole using microiontophoresis at defined distances from the recording site, and transient hyperpolarizations were recorded. The area enclosed by the transients (voltage x time integral below baseline) was measured and compared to the area expected if the hyperpolarization was spreading passively. RESULTS: In 11 of 15 recordings from smooth muscle and 5 of 7 from endothelium, areas of the transients were larger than expected for purely passive spread of the electrical signal. CONCLUSIONS: Conduction of hyperpolarization is enhanced by active membrane processes as the signal travels along the arteriolar wall. Signal augmentation will promote blood flow to tissue regions from which hyperpolarization of arterioles originates.

Acetylcholine↗

PubMedDate not supplied

Ischemia-reperfusion impairs ascending vasodilation in feed arteries of hamster skeletal muscle.

OBJECTIVE: Vasodilation originating within the microcirculation ascends into proximal feed arteries during muscle contraction to attain peak levels of muscle blood flow. Ascending vasodilation (AVD) requires an intact endothelium, as does conducted vasodilation in response to acetylcholine (ACh). Whereas ischemia-reperfusion (I-R) can affect endothelial cell function, the effect of I-R on AVD is unknown. The authors tested the hypothesis that I-R (1h-1h) would impair AVD. METHODS: Using the retractor muscle of anesthetized hamsters, contractions were evoked using field stimulation (200 ms at 40 Hz every 2 s for 1 min) and ACh was delivered using microiontophoresis (1 microm tip, 500-4000 ms pulse at 800 nA). Feed artery responses were monitored 500-1500 microm upstream. RESULTS: Neither resting (51 +/- 4 microm) nor maximal diameter (81 +/- 5 microm; 10 microm sodium nitroprusside) following I-R (n = 8) were different from time-matched controls (n = 10). With peak active tension of 23 +/- 4 mN x mm(-2), control AVD was 26 +/- 2 microm. Following I-R, active tension fell by 48% (p < .05) and AVD by 57% (p < .05). Stimulation at 70 Hz restored active tension but AVD remained depressed by nearly half (p < .05), as did local and conducted responses to ACh. Nevertheless, control responses to 500 ms ACh were restored by increasing stimulus duration to 4000 ms. CONCLUSIONS: Ischemia-reperfusion impairs the initiation of feed artery dilation with muscle contraction and with ACh while conduction along the vessel wall is preserved. Respective components of endothelial cell signaling events may differ in their susceptibility to I-R.

Acetylcholine↗

PubMedDate not supplied

Regulation of blood flow in the microcirculation.

The regulation of blood flow has rich history of investigation and is exemplified in exercising skeletal muscle by a concerted interaction between striated muscle fibers and their microvascular supply. This review considers blood flow control in light of the regulation of capillary perfusion by and among terminal arterioles, the distribution of blood flow in arteriolar networks according to metabolic and hemodynamic feedback from active muscle fibers, and the balance between peak muscle blood flow and arterial blood pressure governed by sympathetic nerve activity. As metabolic demand increases,the locus of regulating oxygen delivery to muscle fibers "ascends" from terminal arterioles, through intermediate distributing arterioles, and into the proximal arterioles and feed arteries, which govern total flow into a muscle. At multiple levels, venules are positioned to provide feedback to nearby arterioles regarding the metabolic state of the tissue through the convection, production and diffusion of vasodilator stimuli. Electrical signals initiated on microvascular smooth muscle and endothelial cells can travel rapidly for millimeters through cell-to-cell conduction via gap junction channels, rapidly coordinating vasodilator responses that govern the distribution and magnitude of blood flow to active muscle fibers. Sympathetic constriction of proximal arterioles and feed arteries can restrict functional hyperemia while dilation prevails in distal arterioles to promote oxygen extraction. With vasomotor tone reflecting myogenic contraction of smooth muscle cells modulated by shear stress on the endothelium, the initiation of functional vasodilation and its modulation by sympathetic innervation dictate how and where blood flow is distributed in response to metabolic demand. A remarkable ensemble of signaling pathways underlies the integration of smooth muscle and endothelial cell function in microvascular networks. These pathways are being defined with refreshing new insight as novel approaches are applied to understanding the cellular and molecular mechanisms of blood flow control.

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PubMedDate not supplied

Special edition of Microcirculation commemorating the 50th anniversary of the Microcirculatory Society, Inc.

This special edition of Microcirculation brings together the proceedings from the Symposium held in the spring of 2004 in the Natcher Auditorium on the campus of the National Institutes of Health to commemorate the 50th Anniversary of the Microcirculatory Society, Inc. Twelve brief reviews are introduced with the goals being to present a collective sense of the history of research in microcirculation, provide insight into where established topics of inquiry stand today, and to define emerging topics of investigation for future research efforts.

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