Regulation of blood flow in the microcirculation: role of conducted vasodilation.

This review is concerned with understanding how vasodilation initiated from local sites in the tissue can spread to encompass multiple branches of the resistance vasculature. Within tissues, arteriolar networks control the distribution and magnitude of capillary perfusion. Vasodilation arising from the microcirculation can 'ascend' into feed arteries that control blood flow into arteriolar networks. Thus distal segments of the resistance network signal proximal segments to dilate and thereby increase total oxygen supply to parenchymal cells. August Krogh proposed that innervation of capillaries provided the mechanism for a spreading vasodilatory response. With greater understanding of the ultrastructural organization of resistance networks, an alternative explanation has emerged: Electrical signalling from cell to cell along the vessel wall through gap junctions. Hyperpolarization originates from ion channel activation at the site of stimulation with the endothelium serving as the predominant cellular pathway for signal conduction along the vessel wall. As hyperpolarization travels, it is transmitted into surrounding smooth muscle cells through myoendothelial coupling to promote relaxation. Conducted vasodilation (CVD) encompasses greater distances than can be explained by passive decay and understanding such behaviour is the focus of current research efforts. In the context of athletic performance, the ability of vasodilation to ascend into feed arteries is essential to achieving peak levels of muscle blood flow. CVD is tempered by sympathetic neuroeffector signalling when governing muscle blood flow at rest and during exercise. Impairment of conduction during ageing and in diseased states can limit physical work capacity by restricting muscle blood flow.

Vascular anatomy of the hamster retractor muscle with regard to its microvascular transfer.

BACKGROUND: The hamster retractor muscle (RET) is used as an in vivo model in studies of skeletal muscle ischemia-reperfusion injury. The RET is unique in that the muscle can be isolated while preserving the primary vascular supply so that its contractile function can be measured simultaneously with local microvascular responses to experimental interventions. The goal of this study was to understand the anatomical origin of the vascular supply to the RET and determine whether the RET can be used as a free flap after surgical isolation of the thoracodorsal vessels. METHODS: Microdissection was performed to determine the anatomy of the vasculature that supplies and drains the RET. RESULTS: Distinct numbers and patterns of feed arteries (2-4) and collecting veins (1-3) were identified (n = 26 animals). Dye injection (n = 8) of the thoracodorsal artery demonstrated that the RET remains perfused following its isolation on the thoracodorsal pedicle. Heterotopic allograft transplantation of the RET (n = 2) was performed by anastomosing the thoracodorsal vessels to the femoral vessels using the end-to-side technique. CONCLUSIONS: The anatomical relationships indicate that the RET can be used as a free flap model for evaluating the effect of preservation strategies and transplantation on skeletal muscle microcirculation and contractile function.

Role for endothelial cell conduction in ascending vasodilatation and exercise hyperaemia in hamster skeletal muscle.

1. Vasodilatation initiated by contracting skeletal muscle 'ascends' from the arteriolar network to encompass feed arteries. Acetylcholine delivery from a micropipette onto a feed artery evokes hyperpolarisation at the site of application; this signal can conduct through gap junctions along the endothelium to produce vasodilatation. We tested whether conduction along the endothelium contributes to the ascending vasodilatation that occurs in response to muscular exercise. 2. In anaesthetised hamsters, a feed artery (resting diameter 64 +/- 4 microm) supplying the retractor muscle was either stimulated by local microiontophoretic application of acetylcholine or the muscle was contracted rhythmically (once per 2 s, 1-2 min), before and after light-dye treatment (LDT) to disrupt the endothelial cells within a 300 microm-long segment located midway along the vessel. Endothelial cell damage with LDT was confirmed by the local loss of vasodilatation in response to acetylcholine and labelling with propidium iodide. Local vasodilatation in response to acetylcholine applied 500 microm proximal (upstream) or distal (downstream) to the central segment with LDT remained intact. 3. Before LDT, vessel diameter increased by more than 30 % along the entire feed artery (observed 1000 microm upstream from the retractor muscle) in response to distal acetylcholine or muscle contractions. Following LDT, vasodilatation in response to acetylcholine and to muscle contractions encompassed the distal segment but did not travel through the region of endothelial cell damage. At the upstream site, wall shear rate (and luminal shear stress) increased more than 3-fold, with no change in vessel diameter. Thus, flow-induced vasodilatation did not occur. 4. In response to muscle contractions, feed artery blood flow increased nearly 6-fold; this hyperaemic response was reduced by half following the loss of ascending vasodilatation. 5. These findings indicate that rhythmic contractions of skeletal muscle can initiate the conduction of a signal along the endothelium. We propose that this signalling pathway underlies ascending vasodilatation and promotes the full expression of exercise hyperaemia.

Effectiveness of a formal post-baccalaureate pre-medicine program for underrepresented minority students.

PURPOSE: To address the effectiveness of a formal postbaccalaureate (PB) experience for underrepresented minority (URM) students before medical school. The program provided an intense year-long experience of course work, research, and personal development. METHOD: There were 516 participants from one medical school: 15 URM medical students had completed the formal PB program, 58 students had done independent PB work before matriculation, and 443 students were traditional matriculants. Cognitive and academic indicators [college science and non-science grade-point averages (GPAs); biology, physics, and verbal MCAT scores; and percentage scores from first-year medical school courses] were compared for the three groups. RESULTS: Both groups of students with PB experience demonstrated competency in the first year of medical school consistent with traditional students even though the students who had completed the formal PB program had lower MCAT scores and lower college GPAs than did the traditional students. Traditional predictors of academic performance during the first year of medical school did not significantly contribute to actual academic performances of students from the formal PB program. CONCLUSION: The results support the use of a formal PB program to provide academic readiness and support for URM students prior to medical school. Such a program may also improve retention. Noncognitive variables, however, may be important to understanding the success of such students in medical school.

Electrical activation of endothelium evokes vasodilation and hyperpolarization along hamster feed arteries.

Endothelial cells are considered electrically unexcitable. However, endothelium-dependent vasodilators (e.g., acetylcholine) often evoke hyperpolarization. We hypothesized that electrical stimulation of endothelial cells could evoke hyperpolarization and vasodilation. Feed artery segments (resting diameter: 63 +/- 1 microm; length 3-4 mm) of the hamster retractor muscle were isolated and pressurized to 75 mmHg, and focal stimulation was performed via microelectrodes positioned across one end of the vessel. Stimulation at 16 Hz (30-50 V, 1-ms pulses, 5 s) evoked constriction (-20 +/- 2 microm) that spread along the entire vessel via perivascular sympathetic nerves, as shown by inhibition with tetrodotoxin, omega-conotoxin, or phentolamine. In contrast, stimulation with direct current (30 V, 5 s) evoked vasodilation (16 +/- 2 microm) and hyperpolarization (11 +/- 1 mV) of endothelial and smooth muscle cells that conducted along the entire vessel. Conducted responses were insensitive to preceding treatments, atropine, or N(omega)-nitro-L-arginine, yet were abolished by endothelial cell damage (with air). Injection of negative current (

Motor nerve topology reflects myocyte morphology in hamster retractor and epitrochlearis muscles.

Neuromuscular activation is a primary determinant of metabolic demand and oxygen transport. The m. retractor and m. epitrochlearis are model systems for studying metabolic control and oxygen transport; however, the organization of muscle fibers and motor nerves in these muscles is unknown. We tested whether the topology of motor innervation was related to the morphology of muscle fibers in m. retractor and m. epitrochlearis of male hamsters ( approximately 100 g). Respective muscles averaged 47 and 12 mm in length 100 and 35 mg in mass. Staining for acetylcholinesterase revealed neuromuscular junctions arranged in clusters throughout m. retractor and as a central band across m. epitrochlearis, suggesting differences in fiber morphology. For both muscles, complete cross-sections contained approximately 1,700 fibers. Fiber cross-sectional areas were distributed nearly normal in m. epitrochlearis (mean = 1,559 +/- 17 microm(2)) and skewed left (P < 0.05) in m. retractor (mean = 973 +/- 15 microm(2)). Single fiber length (Lf) spanned muscle length (Lm) in m. epitrochlearis, while fibers tapered to terminate within m. retractor (Lf/Lm = 0.43 +/- 0. 02). With myelin staining, a single branch of ulnar nerve projected axons across the midregion of m. epitrochlearis. For m. retractor, the spinal accessory nerve branched to give rise to proximal and distal regions of innervation, with intermingling of axons between nerve branches. Nerve bundle cross-sections stained for acetylcholinesterase indicate that each motor axon projects to an average of 65 muscle fibers in m. epitrochlearis and 100 in m. retractor. Differences in fiber morphology, innervation topology, and neuromuscular organization may contribute to the heterogeneity of metabolic demand and oxygen supply in skeletal muscle.

Electrical coupling between endothelial cells and smooth muscle cells in hamster feed arteries: role in vasomotor control.

Endothelial cells (ECs) govern smooth muscle cell (SMC) tone via the release of paracrine factors (eg, NO and metabolites of arachidonic acid). We tested the hypothesis that ECs can promote SMC relaxation or contraction via direct electrical coupling. Vessels (resting diameter, 57+/-3 microm; length, 4 mm) were isolated, cannulated, and pressurized (75 mm Hg; 37 degrees C). Two microelectrodes were used to simultaneously impale 2 cells (ECs or SMCs) in the vessel wall separated by 500 microm. Impalements of one EC and one SMC (n=26) displayed equivalent membrane potentials at rest, during spontaneous oscillations, and during hyperpolarization and vasodilation to acetylcholine. Injection of -0.8 nA into an EC caused hyperpolarization ( approximately 5 mV) and relaxation of SMCs (dilation, approximately 5 microm) along the vessel segment. In a reciprocal manner, +0.8 nA caused depolarization ( approximately 2 mV) of SMCs with constriction ( approximately 2 microm). Current injection into SMCs while recording from ECs produced similar results. We conclude that ECs and SMCs are electrically coupled to each other in these vessels, such that electrical signals conducted along the endothelium can be directly transmitted to the surrounding smooth muscle to evoke vasomotor responses.

Role of EDHF in conduction of vasodilation along hamster cheek pouch arterioles in vivo.

We tested whether local and conducted responses to ACh depend on factors released from endothelial cells (EC) in cheek pouch arterioles of anesthetized hamsters. ACh was delivered from a micropipette (1 s, 500 nA), while arteriolar diameter (rest, approximately 40 microm) was monitored at the site of application (local) and at 520 and 1,040 microm upstream (conducted). Under control conditions, ACh elicited local (22-65 microm) and conducted (14-44 microm) vasodilation. Indomethacin (10 microM) had no effect, whereas N(omega)-nitro-L-arginine (100 microM) reduced local and conducted vasodilation by 5-8% (P < 0.05). Miconazole (10 microM) or 17-octadecynoic acid (17-ODYA; 10 microM) diminished local vasodilation by 15-20% and conducted responses by 50-70% (P < 0.05), suggesting a role for cytochrome P-450 (CYP) metabolites in arteriolar responses to ACh. Membrane potential (E(m)) was recorded in smooth muscle cells (SMC) and in EC identified with dye labeling. At rest (control E(m), typically -30 mV), ACh evoked local (15-32 mV) and conducted (6-31 mV) hyperpolarizations in SMC and EC. Miconazole inhibited SMC and EC hyperpolarization, whereas 17-ODYA inhibited hyperpolarization of SMC but not of EC. Findings indicate that ACh-induced release of CYP metabolites from arteriolar EC evoke SMC hyperpolarization that contributes substantively to conducted vasodilation.

Temporal events underlying arterial remodeling after chronic flow reduction in mice: correlation of structural changes with a deficit in basal nitric oxide synthesis.

To define the cellular events of vascular remodeling in mice, we measured blood flow and analyzed the morphology of remodeled vessels at defined points after a flow-reducing remodeling stimulus for 3, 7, 14, and 35 days. Acute ligation of the left external carotid artery reduced blood flow in the left common carotid artery (LC) compared with sham and contralateral right common carotid arteries (RCs). In morphometric analyses, the decrease in diameter in LCs was reversible by vasodilator perfusion 3 days after ligation, whereas ligation for 7 days or greater resulted in a permanent diameter reduction. Coincident with structural remodeling at day 7 was an increase in cell death in remodeled LCs. Functionally, rings from remodeled LCs contracted to prostaglandin F(2alpha) and relaxed to acetylcholine in a manner identical to that of control arteries. However, remodeled LCs were hypersensitive to the nitrovasodilator sodium nitroprusside (at day 7) and exhibited a marked reduction in basal NO synthesis at 7 and 14 days after ligation. The impairment of endothelial NO synthase function was likely due to post-translational mechanisms, given that endothelial NO synthase mRNA and protein levels did not change in remodeled LCs. These data define the ontogeny of flow-triggered luminal remodeling in adult mice and suggest that endothelial dysfunction occurs during reorganization of the vessel wall.

Attenuation of vasodilatation with skeletal muscle fatigue in hamster retractor.

We tested the hypothesis that muscle fatigue would attenuate vasodilatory responsiveness throughout the resistance network. The retractor muscle of anaesthetized hamsters was contracted (once per 2 s for 1 min) at duty cycles of 2.5, 10 and 20 % before and after fatiguing contractions that diminished peak tension and muscle glycogen by >50 %. Arterioles and feed arteries (FA) dilated maximally during fatiguing contractions. Resting vasomotor tone consistently recovered following contractions. Peak blood flow was proportional to integrated tension (tension x time, expressed in mN mm-2 s); both increased with duty cycle and decreased with fatigue. Total integrated vasodilatory responses (diameter x time, expressed in microm s) increased with duty cycle and decreased with fatigue. Vasodilatation during contractions plateaued at approximately 50 % of peak integrated tension. Post-contraction vasodilatation increased with integrated tension and both were attenuated with fatigue. As integrated tension increased, distal arterioles dilated first and to the greatest extent relative to proximal arterioles and FA. Fatigue had little effect on dilatation of distal arterioles whereas dilatation of proximal arterioles and FA was suppressed. Latency of onset for vasodilatation decreased as duty cycle increased and was unaffected by fatigue. Vasodilatation and blood flow increase in proportion to integrated tension, with an ascending locus of vasomotor control and prolongation of post-contraction vasodilatation. With muscle fatigue, the locus of flow control resides in distal arterioles; both ascending and post-contraction vasodilatations are attenuated despite normal vasomotor tone.

Integration of blood flow control to skeletal muscle: key role of feed arteries.

Blood flow control reflects dynamic, integrated changes in the diameter of vessels that comprise resistance networks. Vasoconstriction and vasodilation can travel rapidly along the vessel wall via the conduction of electrical signals between endothelial and/or smooth muscle cells through gap junctions. Within the hamster cheek pouch, these conducted responses reflect complementary mechanisms for co-ordinating both increases and decreases in arteriolar diameter. In the hamster retractor muscle, vasodilation also conducts along arterioles and into feed arteries, yet vasoconstriction appears constrained to the site(s) of smooth muscle activation. Thus, mechanisms for co-ordinating vasomotor control in resistance networks can vary between tissues that differ in structure and function. The resistance vessels of the retractor (and other skeletal) muscle are richly innervated by sympathetic nerves, which are absent from the cheek pouch. Propagation along sympathetic nerves rapidly co-ordinates smooth muscle cell contraction throughout the resistance network by releasing noradrenaline along the innervation pathway. Passive extension of the retractor muscle activates periarteriolar sympathetic nerves. This activity propagates antidromically into feed arteries and may complement the central (autonomic) vasoconstrictor response to exercise. In a reciprocal manner, muscle contraction evokes arteriolar dilation that is conducted (i.e. 'ascends') into feed arteries and may thereby counteract sympathetic vasoconstriction. With feed arteries anatomically positioned to control blood flow into skeletal muscle, the integration of dilator and constrictor stimuli in these vessels is a key determinant of muscle blood flow during exercise.

Effect of motor unit recruitment on functional vasodilatation in hamster retractor muscle.

1. The effect of motor unit recruitment on functional vasodilatation was investigated in hamster retractor muscle. Recruitment (i.e. peak tension) was controlled with voltage applied to the spinal accessory nerve (high = maximum tension; intermediate = approximately 50% maximum; low = approximately 25% maximum). Vasodilatory responses (diameter times time integral, DTI) to rhythmic contractions (1 per 2s for 65s) were evaluated in first, second and third order arterioles and in feed arteries. Reciprocal changes in duty cycle (range, 2.5-25%) effectively maintained the total active tension (tension times time integral, TTI) constant across recruitment levels. 2. With constant TTI and stimulation frequency (40 Hz), DTI in all vessels increased with motor unit recruitment. DTI increased from distal arterioles up through proximal feed arteries. 3. To determine whether the effect of recruitment on DTI was due to increased peak tension, the latter was controlled with stimulation frequency (15, 20 and 40 Hz) during maximum (high) recruitment. With constant TTI, DTI then decreased as peak tension increased. 4. To explore the interaction between recruitment and duty cycle on DTI, each recruitment level was applied at 2.5, 10 and 20 % duty cycle (at 40 Hz). For a given increase in TTI, recruitment had a greater effect on DTI than did duty cycle. 5. Functional vasodilatation in response to rhythmic contractions is facilitated by motor unit recruitment. Thus, vasodilatory responses are determined not only by the total tension produced, but also by the number of active motor units.

Endothelial cell pathway for conduction of hyperpolarization and vasodilation along hamster feed artery.

Acetylcholine (ACh) evokes the conduction of vasodilation along resistance microvessels. However, it is not known which cell layer (endothelium or smooth muscle) serves as the conduction pathway. In isolated, cannulated feed arteries ( approximately 70 microm in diameter at 75 mm Hg; length approximately 4 mm) of the hamster retractor muscle, we tested the hypothesis that endothelial cells provide the pathway for conduction. Microiontophoresis of ACh (500 ms, 500 nA) onto the distal end of a feed artery evoked hyperpolarization (-13+/-2 mV) of both cell layers with vasodilation (15+/-1 microm) along the entire vessel. To selectively damage endothelial cells (confirmed by loss of vasodilation to ACh and labeling of disrupted cells with propidium iodide), an air bubble was perfused through a portion of the vessel lumen, or a 70-kDa fluorescein-conjugated dextran (FCD) was illuminated within a segment (300 microm) of the lumen. After endothelial cell damage, hyperpolarization and vasodilation conducted up to, but not through, the treated segment. To selectively damage smooth muscle cells (confirmed by loss of vasoconstriction to phenylephrine and labeling with propidium iodide), FCD was perifused around the vessel and illuminated. Vasodilation and hyperpolarization conducted past the disrupted smooth muscle cells without attenuation. We conclude that endothelial cells provide the pathway for conducting hyperpolarization and vasodilation along feed arteries in response to ACh.

Resolution of smooth muscle and endothelial pathways for conduction along hamster cheek pouch arterioles.

In the cheek pouch of anesthetized male hamsters, microiontophoresis of Ach (endothelium-dependent vasodilator) or phenylephrine (PE; smooth muscle-specific vasoconstrictor) onto an arteriole (resting diameter, 30-40 microm) evokes vasodilation or vasoconstriction (amplitude, 15-25 microm), respectively, that conducts along the arteriolar wall. In previous studies of conduction, endothelial and smooth muscle layers of the arteriolar wall have remained intact. We tested whether selective damage to endothelium or to smooth muscle would disrupt the initiation and conduction of vasodilation or vasoconstriction. Luminal (endothelial) or abluminal (smooth muscle) light-dye damage was produced within an arteriolar segment centered 500 microm upstream from the distal site of stimulation; conducted responses (amplitude, 10-15 microm) were observed at a proximal site located 1,000 microm upstream. Endothelial damage abolished local responses to ACh in the central segment without affecting those to PE. Nevertheless, ACh delivered at the distal site evoked vasodilation that conducted through the central segment and appeared unhindered at the proximal site. Smooth muscle damage inhibited responses to PE in the central segment and abolished the conduction of vasoconstriction but did not affect conducted vasodilation. We suggest that for cheek pouch arterioles in vivo, vasoconstriction to PE is initiated and conducted within the smooth muscle layer alone. In contrast, once vasodilation to ACh is initiated via intact endothelial cells, the signal is conducted along smooth muscle as well as endothelial cell layers.

Vasomotor control in arterioles of the mouse cremaster muscle.

Recent advances in transgenic mouse technology provide novel models to study cardiovascular physiology and pathophysiology. In light of these developments, there is an increasing need for understanding cardiovascular function and blood flow control in normal mice. To this end we have used intravital microscopy to investigate vasomotor control in arterioles of the superfused cremaster muscle preparation of anesthetized C57Bl6 mice. Spontaneous resting tone increased with branch order and was enhanced by oxygen. Norepinephrine and acetylcholine (ACh) caused concentration-dependent vasoconstriction and vasodilation, respectively. Microiontophoresis of ACh evoked vasodilation that conducted along arterioles; the local (direct) response was inhibited by N(omega)-nitro-L-arginine (LNA), and both local and conducted responses were inhibited by 17-octadecynoic acid (17-ODYA). Microejection of KCl evoked a biphasic response: a transient conducted vasoconstriction (inhibited by nifedipine), followed by a conducted vasodilation that was insensitive to LNA, indomethacin, and 17-ODYA. Phenylephrine evoked focal vasoconstriction that did not conduct. Perivascular sympathetic nerve stimulation evoked constriction along arterioles that was inhibited by tetrodotoxin. These findings indicate that for arterioles in the mouse cremaster muscle, nitric oxide and endothelial-derived hyperpolarizing factor (as shown by LNA and 17-ODYA interventions, respectively) mediate vasodilatory responses to ACh but not to KCl, and that vasomotor responses spread along arterioles by multiple pathways of cell-to-cell communication.

Electrophysiological basis of arteriolar vasomotion in vivo.

We tested the hypothesis that cyclic changes in membrane potential (E(m)) underlie spontaneous vasomotion in cheek pouch arterioles of anesthetized hamsters. Diameter oscillations (approximately 3 min(-1)) were preceded (approximately 3 s) by oscillations in E(m) of smooth muscle cells (SMC) and endothelial cells (EC). Oscillations in E(m) were resolved into six phases: (1) a period (6 +/- 2 s) at the most negative E(m) observed during vasomotion (-46 +/- 2 mV) correlating (r = 0.87, p < 0.01) with time (8 +/- 2 s) at the largest diameter observed during vasomotion (41 +/- 2 microm); (2) a slow depolarization (1.8 +/- 0.2 mV s(-1)) with no diameter change; (3) a fast (9.1 +/- 0.8 mV s(-1)) depolarization (to -28 +/- 2 mV) and constriction; (4) a transient partial repolarization (3-4 mV); (5) a sustained (5 +/- 1 s) depolarization (-28 +/- 2 mV) correlating (r = 0.78, p < 0.01) with time (3 +/- 1 s) at the smallest diameter (27 +/- 2 microm) during vasomotion; (6) a slow repolarization (2.5 +/- 0.2 mV s(-1)) and relaxation. The absolute change in E(m) correlated (r = 0.60, p < 0.01) with the most negative E(m). Sodium nitroprusside or nifedipine caused sustained hyperpolarization and dilation, whereas tetraethylammonium or elevated PO(2) caused sustained depolarization and constriction. We suggest that vasomotion in vivo reflects spontaneous, cyclic changes in E(m) of SMC and EC corresponding with cation fluxes across plasma membranes.

Codistribution of NOS and caveolin throughout peripheral vasculature and skeletal muscle of hamsters.

In isolated cell systems, nitric oxide synthase (NOS) activity is regulated by caveolin (CAV), a resident caveolae coat protein. Because little is known of this interaction in vivo, we tested whether NOS and caveolin are distributed together in the intact organism. Using immunohistochemistry, we investigated the localization of constitutive neuronal (nNOS) and endothelial (eNOS) enzyme isoforms along with caveolin-1 (CAV-1) and caveolin-3 (CAV-3) throughout the systemic vasculature and peripheral tissues of the hamster. The carotid artery, abdominal aorta, vena cava, femoral artery and vein, feed artery and collecting vein of the cheek pouch retractor muscle, capillaries and muscle fibers of retractor and cremaster muscles, and arterioles and venules of the cheek pouch were studied. In endothelial cells, eNOS and CAV-1 were present throughout the vasculature, whereas nNOS and CAV-3 were absent except in capillaries, which reacted for nNOS. In smooth muscle cells, nNOS and CAV-1 were also expressed systemically, whereas eNOS was absent; CAV-3 was present in the arterial but not the venous vasculature. Both nNOS and CAV-3 were located at the sarcolemma of skeletal muscle fibers, which were devoid of eNOS and CAV-1. These immunolabeling patterns suggest functional interactions between eNOS and CAV-1 throughout the endothelium, regional differences in the modulation of nNOS by caveolin isoforms in vascular smooth muscle, and modulation of nNOS by CAV-3 in skeletal muscle.

The Academic Support Program at the University of Michigan School of Medicine.

The University of Michigan has a support program aimed at early identification, remedial plans, and appropriate academic accommodations for at-risk students in under-graduate colleges and graduate and professional schools. Since 1994, the medical school has formally taken part in this program. Medical students at risk for academic failure (e.g., repeated failure in academic course work, licensure examinations, clinical examinations) are automatically referred to their academic counselors in the Student Programs Office of the medical school. Once a referral is made, the student is evaluated at the Office of Services for Students with Disabilities to identify problem areas. The office makes appropriate recommendations for interventions or accommodation. Tutoring, academic assistance, and other services are available through the medical school, specific divisions of the medical center, and the community. The Student Programs Office acts as a liaison between community and university assistance programs and between the student and the medical school. During the first four years of the program, 28 medical students were identified through it; of these, 24 (86%) were underrepresented minorities. Most (21) were referred during the first and third years of the curriculum. After a range of services for a variety of problems, 26 (93%) of the 28 students either graduated or continued to progress in their studies; the other two left the medical school for academic reasons.

Spread of vasodilatation and vasoconstriction along feed arteries and arterioles of hamster skeletal muscle.

1. In arterioles of the hamster cheek pouch, vasodilatation and vasoconstriction can spread via the conduction of electrical signals through gap junctions between cells that comprise the vessel wall. However, conduction in resistance networks supplying other tissues has received relatively little attention. In anaesthetized hamsters, we have investigated the spread of dilatation and constriction along feed arteries and arterioles of the retractor muscle, which is contiguous with the cheek pouch. 2. When released from a micropipette, acetylcholine (ACh) triggered vasodilatation that spread rapidly along feed arteries external to the muscle and arterioles within the muscle. Responses were independent of changes in wall shear rate, perivascular nerve activity, or release of nitric oxide, indicating cell-to-cell conduction. 3. Vasodilatation conducted without decrement along unbranched feed arteries, yet decayed markedly in arteriolar networks. Thus, branching of the conduction pathway dissipated the vasodilatation. 4. Noradrenaline (NA) or a depolarizing KCl stimulus evoked constriction of arterioles and feed arteries of the retractor muscle that was constrained to the vicinity of the micropipette. This behaviour contrasts sharply with the conduction of vasodilatation in these microvessels and with the conduction of vasoconstriction elicited by NA and KCl in cheek pouch arterioles. 5. Focal electrical stimulation produced constriction that spread rapidly along feed arteries and arterioles. These responses were inhibited by tetrodotoxin or prazosin, confirming the release of NA along perivascular sympathetic nerves, which are absent from arterioles studied in the cheek pouch. Thus, sympathetic nerve activity co-ordinated the contraction of smooth muscle cells as effectively as the conduction of vasodilatation co-ordinated their relaxation. 6. In the light of previous findings in the cheek pouch, the properties of vasoconstriction and vasodilatation in feed arteries and arterioles of the retractor muscle indicate that substantive differences can exist in the nature of signal transmission along microvessels of tissues that differ in structure and function.

Heterogeneity of vascular innervation in hamster cheek pouch and retractor muscle.

The hamster cheek pouch and its retractor muscle have provided valuable insights into microvascular physiology of an epithelial tissue and striated muscle, respectively. Nevertheless, the innervation of these vascular beds has not been resolved. This study has investigated the nature of autonomic and sensory innervation of these vascular beds and has tested whether it varies within or between tissues. Multiple-labelling immunohistochemistry identified autonomic and peptide-containing sensory nerve fibres. Presumptive sympathetic vasoconstrictor axons with immunoreactivity (IR) for tyrosine hydroxylase (TH) and neuropeptide Y (NPY) innervated feed arteries and arterioles (but not veins or venules) of the retractor and anterior (muscular) cheek pouch; these axons were absent from the posterior (epithelial) region of the cheek pouch, as confirmed by catecholamine fluorescence. Presumptive autonomic vasodilator axons with IR for vasoactive intestinal peptide (VIP) consistently innervated feed arteries and proximal arterioles of the cheek pouch, but generally not those of the retractor muscle nor distal arterioles of either tissue. Sparse presumptive sensory axons with IR for calcitonin gene-related peptide (CGRP) and substance P were found near arterial and venous vessels in all regions of the cheek pouch and retractor muscle; CGRP-IR was also located in motor end plates associated with striated muscle fibres. Such regional differences in vascular innervation by autonomic and sensory neurons may selectively effect local and regional control of blood flow between and within vascular beds.