ETa-receptor blockade, but not ACE inhibition, blunts retinal vessel response during isometric exercise

Angiotensin II and endothelin-1 are potent vasoconstrictors that appear to play a role in retinal blood flow regulation. In the present study, we investigated the possible role of the angiotensin and the endothelin system in the regulation of retinal vessel diameters during isometric exercise in healthy humans. The study design was randomized, double-masked, placebo-controlled, and three-way cross over. Twelve healthy subjects performed squatting exercises for 6 min during infusion of either an angiotensin-converting enzyme inhibitor (enalapril), an ET(A)-receptor antagonist (BQ-123), or placebo. Retinal vessel diameters were measured continuously with the Zeiss retinal vessel analyzer. Systemic hemodynamics were assessed noninvasively, and intraocular pressure was measured with applanation tonometry. Squatting induced a significant increase in blood pressure and pulse rate, which was paralleled by a vasoconstriction in retinal arteries and veins. Intraocular pressure was only slightly increased during the squatting periods. BQ-123 significantly blunted the exercise-induced decrease in venous (P < 0.01) and arterial (P < 0.02, ANOVA) vessel diameters but had no effect on basal retinal diameters. By contrast, enalapril did neither influence vessel diameter at baseline conditions nor in response to isometric exercise. The data of the present study indicate that retinal vasoconstriction during isometric exercise is modified by ET(A)-receptor blockade, whereas it is not altered by angiotensin-converting enzyme inhibition. Hence, the present data indicate that endothelin-1, but not angiotensin II, is involved in retinal blood flow regulation during isometric exercise.     

Nitric oxide regulates retinal vascular tone in humans

The purpose of the present study was to investigate the contribution of basal nitric oxide (NO) on retinal vascular tone in humans. In addition, we set out to elucidate the role of NO in flicker-induced retinal vasodilation in humans. Twelve healthy young subjects were studied in a three-way crossover design. Subjects received an intravenous infusion of either placebo or NG-monomethyl-L-arginine (L-NMMA; 3 or 6 mg/kg over 5 min), an inhibitor of NO synthase. Thereafter, diffuse luminance flicker was consecutively performed for 16, 32, and 64 s at a frequency of 8 Hz. The effect of L-NMMA on retinal arterial and venous diameter was assessed under resting conditions and during the hyperemic flicker response. Retinal vessel diameter was measured with a Zeiss retinal vessel analyzer. L-NMMA significantly reduced arterial diameter (3 mg/kg: -2%; 6 mg/kg: -4%, P < 0.001) and venous diameter (3 mg/kg: -5%; 6 mg/kg: -8%, P < 0.001). After placebo infusion, flicker induced a significant increase in retinal vessel diameter (P < 0.001). At a flicker duration of 64 s, arterial diameter increased by 4% and venous diameter increased by 3%. L-NMMA did not abolish these hyperemic responses but blunted venous vasodilation (P = 0.017) and arterial vasodilation (P = 0.02) in response to flicker stimulation. Our data indicate that NO contributes to basal retinal vascular tone in humans. In addition, NO appears to play a role in flicker-induced vasodilation of the human retinal vasculature.     

Effect of histamine and cimetidine on retinal and choroidal blood flow in humans

Intravenous administration of histamine causes an increase in choroidal blood flow and retinal vessel diameter in healthy subjects. The mechanism underlying this effect remains to be elucidated. In the present study, we hypothesized that H2 receptor blockade alters hemodynamic effects of histamine in the choroid and retina. Eighteen healthy male nonsmoking volunteers were included in this randomized, double-masked, placebo-controlled two-way crossover study. Histamine (0.32 microg.kg(-1).min(-1) over 30 min) was infused intravenously in the absence (NaCl as placebo) or presence of the H2 blocker cimetidine (2.3 mg/min over 50 min). Ocular hemodynamic parameters, blood pressure, and intraocular pressure were measured before drug administration, after infusion of cimetidine or placebo, and after coinfusion of histamine. Subfoveal choroidal blood flow and fundus pulsation amplitude were measured with laser-Doppler flowmetry and laser interferometry, respectively. Retinal arterial and venous diameters were measured with a retinal vessel analyzer. Retinal blood velocity was assessed with bidirectional laser-Doppler velocimetry. Histamine increased subfoveal choroidal blood flow (+14 +/- 15%, P < 0.001), fundus pulsation amplitude (+11 +/- 5%, P < 0.001), retinal venous diameter (+3.0 +/- 3.6%, P = 0.002), and retinal arterial diameter (+2.8 +/- 4.2%, P < 0.01) but did not change retinal blood velocity. The H2 antagonist cimetidine had no significant effect on ocular hemodynamic parameters. In addition, cimetidine did not modify effects of histamine on choroidal blood flow, fundus pulsation amplitude, retinal venous diameter, and retinal arterial diameter compared with placebo. The present data confirm that histamine increases choroidal blood flow and retinal vessel diameters in healthy subjects. This ocular vasodilator effect of histamine is, however, not altered by administration of an H2 blocker. Whether the increase in blood flow is mediated via H1 receptors or other hitherto unidentified mechanisms remains to be elucidated.     

Distribution and function of muscarinic receptor subtypes in the ovine submandibular gland.

The effects of muscarinic receptor antagonists on responses to electrical stimulation of the chorda-lingual nerve were determined in pentobarbitone-anesthetized sheep and correlated to the morphology of tissue specimens. Stimulation at 2 Hz continuously, or in bursts of 1 s at 20 Hz every 10 s, for 10 min induced similar submandibular fluid responses (19 +/- 3 vs. 21 +/- 3 microl x min(-1) x g gland(-1)), whereas vasodilatation was greater during stimulation in bursts (-52 +/- 4 vs. -43 +/- 5%; P < 0.01). Continuous stimulation at 8 Hz induced substantially greater responses (66 +/- 9 microl x min(-1) x g gland(-1) and -77 +/- 3%). While atropine (0.5 mg/kg iv) abolished the secretory response at 2 and 20 Hz (1:10 s), a small response persisted at 8 Hz (<5%). The "M1-selective" antagonist pirenzepine (40 microg/kg iv) reduced the fluid response at all frequencies tested (P < 0.05-0.01), most conspicuously at 2 Hz (reduced by 69%). Methoctramine ("M2/M4-selective"; 100 microg/kg iv; n = 5) had no effect on fluid or the vascular responses but increased the protein output at 2 (+90%, P < 0.05) and 8 Hz (+45%, P < 0.05). The immunoblotting showed distinct bands for muscarinic M1, M3, M4, and M5 receptors, and immunohistochemistry showed muscarinic M1 and M3 receptors to occur in the parenchyma. Thus muscarinic M1 receptors contribute to the secretory response to parasympathetic stimulation but have little effect on the vasodilatation in the ovine submandibular gland. Increased transmitter release caused by blockade of neuronal inhibitory receptors of the M4 subtype would explain the increase in protein output.     

Endothelin-mediated constriction of prenodal lymphatic vessels in the canine forelimb

Endothelin is a 21 amino acid peptide which is produced by the vascular endothelium and is believed to be the mediator of endothelium-dependent vasoconstriction. In the current study we assessed the ability of synthetic human endothelin-1 to affect prenodal lymphatic vessel contractility in the canine forelimb. Intralymphatic infusion of endothelin at 1.09 x 10(-9), 1.09 x 10(-8) and 1.09 x 10(-7) M significantly constricted lymphatic vessels as evidenced by dose-dependent increases in lymphatic perfusion pressure. The increase in lymphatic perfusion pressure seen during intralymphatic infusion of endothelin at 1.09 x 10(-8) M during the intra-arterial infusion of phentolamine was not significantly different from that seen prior to phentolamine, indicating that endothelin-mediated lymphatic constriction is not alpha-receptor mediated. Intra-arterial infusion of endothelin at three infusion rates significantly increased forelimb arterial, systemic and lymphatic perfusion pressures. The constriction seen when endothelin (1.09 x 10(-8) M) was infused intralymphatically in the intact lymphatic system was not significantly different from that observed when only the prenodal lymph vessel was perfused. This indicated that the lymph nodes and efferent lymph vessels do not contribute significantly to the lymphatic constriction produced by endothelin. These data are consistent with the hypothesis that endothelin may modulate lymphatic function under either normal or pathophysiological conditions.     

Rapid dilation of arterioles with single contraction of hamster skeletal muscle

Skeletal muscle blood flow increases rapidly with exercise onset, but little is known of where or how the rapid onset of vasodilation (ROV) is governed within the microcirculation. In the retractor muscle of anesthetized hamsters (n = 26), we tested the following: 1) where in the resistance network ROV occurred, 2) how microvascular responses were affected by the duration of contraction, and 3) whether ROV involved muscarinic receptor activation. Single tetanic contractions were evoked using supramaximal field stimulation (100 Hz) to depolarize motor end plates. In response to a 200-ms contraction, red blood cell (rbc) velocity (V(rbc)) in feed arteries (FA; rest: 17.8 +/- 2 mm/s) increased within 1 s; a transient first peak (P1; 50 +/- 7% increase) occurred at approximately 5 s; and a second peak (P2; 50 +/- 15% increase) occurred at approximately 15-20 s. For vasodilation, P1 increased in frequency from proximal FA (2/7) and 1A arterioles (2/7) to distal 2A (4/7) and 3A (7/8) arterioles (P < 0.05). Relative to resting (and maximal, 10 microM sodium nitroprusside) diameters, P1 increased from proximal (FA, 3 +/- 2% from 57 +/- 5 microm) to distal (3A, 27 +/- 6% from 14 +/- 1 microm) vessel branches (P < 0.05). P2 was manifest in all vessels and increased relative to resting diameters from FA (11 +/- 3%) to 3A (36 +/- 6%) branches (P < 0.01). Extending a contraction from 200 to 1,000 ms (tension x time integral from 17 +/- 2 to 73 +/- 4 mN/mm2 x s) increased P1 and P2 for V(rbc) and for diameter (P < 0.05) while reducing the time of onset for P2 (P < 0.05). Superfusion with atropine (10 microM) attenuated P1 of vasodilation (200 ms contraction) from 26 +/- 8% to 6 +/- 2% (n = 7 across branches; P < 0.05) and reduced the diameter x time integral by 46 +/- 13% (P < 0.05) without changing P2. We conclude that ROV in the hamster retractor muscle is initiated in distal arterioles, increases with the duration of muscle contraction, and involves muscarinic receptor activation.     

Time- and order-dependent changes in functional and NO-mediated dilation during exercise training

Lash, Julia M., and H. Glenn Bohlen. Time- andorder-dependent changes in functional and NO-mediated dilation during exercise training. J. Appl. Physiol.82(2): 460-468, 1997.Arterial vessel responses to sodiumnitroprusside (SNP) and acetylcholine (ACh) were measured in thespinotrapezius muscle of sedentary (Sed) and treadmill-trained (Tr)rats to determine whether these endothelium-dependent (ACh) and-independent (SNP) mechanisms contribute to thetraining-induced increase in functional vasodilation previouslyobserved. Control and maximal vessel diameters were similar between Sedand Tr. After 8 wk of training, functional dilation (2-, 4-, and 8-Hzcontractions) was enhanced in all orders of vessels studied[terminal feed artery (FA), largest arterioles (1A), andintermediate-sized arterioles (2A)], but responses to SNP wereincreased only in FA. Responses to ACh were not significantly increasedin any vessel order. After 16 wk of training, functional dilation hadregressed in Tr such that only the FA response to 4 Hz wassignificantly elevated relative to Sed. However, the FA and 1Aresponses to SNP were significantly greater in Tr than in Sed, as werethe 1A and 2A responses to ACh. These results show a dissociation offunctional dilation and SNP- or ACh-mediated responses, as well asage-dependent interactions, a time-dependent progression, and vesselorder specificity in the adaptations to training.

     

Poststenotic dilatation: arterial wall mechanics in response to vibration.

A study of the relationship between the mechanical response of human iliac arteries subjected to sinusoidally varying dynamic pressures superimposed on a static pressure of 100 mm Hg (1mm Hg = 133 N/m2) and the development of arterial dilatation, with particular reference to poststenotic dilatation has been conducted. In 13 experiments, optical measurements of the amplitude of vessel wall movements in response to dynamic pressures of amplitude 5 mm Hg peak to peak indicated the presence of at least one, and at most four resonance peaks for frequencies in the mean range 0-100 Hz. Four specimens were vibrated at resonance and four at frequencies 15 Hz higher than resonance, in response to a dynamic pressure of 5 mm Hg peak to peak for 3 h. All specimens exhibited some dilatation, the average percentage increase in diameter being in the range 0.22 to 0.42% per hour. In four additional experiments, the dynamic pressure was doubled at constant frequency. This resulted in an increased amplitude of vibration and additional dilatation at an increased rate. It is concluded that the dynamic stresses present in the vessel influence the rate of dilatation.     

Vitamin C lowers blood pressure and alters vascular responsiveness in salt-induced hypertension

The present study was undertaken to investigate the effect of vitamin C treatment on blood pressure and vascular reactivity in salt-induced hypertension. Male Sprague-Dawley rats were fed a normal rat diet, a high-sodium (8% NaCl) diet, a normal rat diet plus vitamin C treament (100 mg x kg(-1) x day(-1)), or a high-sodium diet plus vitamin C treatment for 6 weeks. Salt loading significantly increased blood pressure, which was attenuated by vitamin C treatment. Aortic rings from the different groups were suspended for isometric-tension recording. The contractile response to noradrenaline was significantly increased in the salt-loaded rats. Vitamin C reduced the sensitivity of aortic rings to noradrenaline in rats on normal and high-sodium diets. In noradrenaline-precontracted rings, the relaxation response to acetylcholine, which was attenuated in the salt-loaded rats, was restored by vitamin C treatment. Pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME) abolished the enhanced response to acetylcholine caused by vitamin C. The results suggest that the antihypertensive effect of vitamin C is associated with a reduction in vascular sensitivity to noradrenaline and enhancement of endothelium-dependent relaxation due to increased nitric oxide bioavailability.     

Effect of procaine hydrochloride on the aggregation behavior and suspension viscoelasticity of human red blood cells

The present study examined the effects of procaine hydrochloride (PRHCL), a cationic local anesthetic, on the aggregation behavior of human red blood cells (RBC); the effects of PRHCL on RBC suspension viscoelasticity, cell shape, volume and density were also investigated. Four indices of RBC aggregation, induced by autologous plasma or 3 g% dextran T70, were evaluated by a computerized light transmission method, and the viscous and elastic components of the complex viscosity were determined by oscillatory viscometry. Low concentrations of PRHCL (8 x 10(-5) to 8 x 10(-4) M) significantly (p less than 0.05 or better) reduced the extent of aggregation (maximal decrease of 22% at 8 x 10(-4) M), but did not alter the viscoelastic components, cell shape, volume or density. The anti-aggregating effect of PRHCL (8 x 10(-4) M) in plasma significantly (p less than 0.005) decreased with time; this temporal effect was abolished by addition of eserine (1 x 10(-4) M). High concentrations of PRHCL (8 x 10(-2) M) caused: 1) increased extent of aggregation and decreased strength of the aggregates (p less than 0.01 or better); 2) elevation of both viscoelastic components for cells in plasma or buffer; 3) a discocyte-stomatocyte shape change; 4) decreased cell density (p less than 0.001) without alteration of cell volume. Our results at low concentrations of PRHCL suggest a mechanism based on an increase of RBC negative surface potential; at the highest concentration, the effects are most likely due to altered cell shape and deformability, and to decreased RBC negative surface potential.     

Hydraulic conductance of pulmonary microvascular and macrovascular endothelial cell monolayers

Endothelial cells isolated from pulmonary arteries (RPAEC) and microcirculation (RPMVEC) of rat lungs were grown to confluence on porous filters and mounted on an Ussing-type chamber. Transmembrane pressure (deltaP) was controlled by the reservoir height, and the filtration rate corrected for surface area (J(v)/A) was measured by timing fluid movement in a calibrated micropipette. These parameters were used to calculate hydraulic conductance (Lp) by using linear regression of J(v)/A on deltaP. Mean Lp values for newly confluent RPAEC monolayers were 22 times higher than those for RPMVEC monolayers (28.6 +/- 5.6 vs. 1.30 +/- 0.50 x 10(-7) cm x s(-1) x cmH2O(-1); P < or = 0.01). After confluence was reached, electrical resistance and Lp remained stable in RPAEC but continued to change in RPMVEC with days in culture. Both phenotypes exhibited an initial time-dependent sealing response, but Lp also had an inverse relationship to deltaP in RPMVEC monolayers > or = 4 days postconfluence that was attributed to cell overgrowth rather than junctional length. In a comparison of the cadherin contents, E-cadherin was predominant in RPMVEC, but VE-cadherin was predominant in RPAEC. At a constant deltaP of 40-45 cmH2O for 2 h, J(v)/A increased 225% in RPAEC monolayers but did not change significantly in RPMVEC monolayers. Significant decreases in Lp were obtained after treatment with 5% albumin, GdCl3, or isoproterenol plus rolipram in both phenotypes. Thus lung microvascular endothelial cells exhibited a significantly lower Lp than conduit vessel endothelium, which would limit alveolar flooding relative to perivascular edema cuff formation during increased pulmonary vascular pressures.     

Effect of dopamine, bombesin and cysteamine hydrochloride on plasma growth hormone response to synthetic growth hormone-releasing factor in rats

In urethane anesthetized rats, an intracerebroventricular (icv) injection of 2 micrograms bombesin 5 min prior to the administration of synthetic human growth hormone-releasing factor (GRF) (1 microgram/kg, iv) inhibited plasma growth hormone (GH) response, while cysteamine hydrochloride (90 mg/kg, sc) administered 150 min beforehand depleted immunoreactive somatostatin content in the pituitary-stalk median eminence and consequently potentiated the response to GRF. Under the same experimental conditions, central injection of 1.89 micrograms (10(-8)M) dopamine hydrochloride or iv administration of L-DOPA (10 mg/kg) did not influence the subsequent plasma GH response to GRF. Results suggest indirectly that bombesin and cysteamine, but not dopamine, predominantly modulate somatostatin release from the hypothalamus.     

Gastric acid secretion in streptozotocin-diabetic rats--different responses to various secretagogues.

We compared gastric acid secretion in response to various stimuli in normal and streptozotocin (STZ)-induced diabetic rats, in an attempt to characterize the alteration of acid secretory response in diabetic conditions. Animals were injected STZ (70 mg x kg(-1), i.p.) and used after 5 weeks of diabetes with blood glucose > 350 mg x dL(-1). Under urethane anesthesia, a rat stomach was mounted on an ex vivo chamber, perfused with saline and acid secretion was measured at pH 7.0 using a pH-stat method and by adding 100 mM NaOH. The acid secretion was stimulated by i.v. infusion of either histamine (4 mg x kg(-1) x h(-1)), pentagastrin (60 microg x kg(-1) x h(-1)) or carbachol (20 microg x kg(-1) x h(-1)) or i.v. injection of YM-14673 (0.3 mg x kg(-1)), an analog of thyrotropin-releasing hormone, or vagal electrical stimulation (2 ms, 3 Hz, 0.5 mA). In normal rats, gastric acid secretion was increased in response to either histamine, pentagastrin, carbachol, YM-14673 or electrical vagal stimulation. In STZ diabetic rats, however, changes in acid secretion varied depending on the stimuli; the acid secretory responses to histamine remained unchanged, those to YM-14673 and vagal electrical stimulation significantly decreased, but the responses to both pentagastrin and carbachol were significantly enhanced as compared to normal rats. Luminal release of histamine in response to both pentagastrin and carbachol was increased in STZ-diabetic rats as compared to normal animals. The altered acid secretory responses in STZ diabetic rats were partially reversed by daily injection of insulin with amelioration of high blood glucose levels. These results suggest that STZ-diabetic rats showed different changes in gastric acid secretory responses to various stimuli; no change in response to histamine, a decrease to both YM-14673 and vagal electrical stimulation and an increase to both pentagastrin and carbachol. The increased acid secretory response may be associated with an enhanced release of mucosal histamine, while the decreased response may be due to vagal neuropathy.     

Effect of aerobic and resistance exercise training on vascular function in heart failure

Exercise training of a muscle group improves local vascular function in subjects with chronic heart failure (CHF). We studied forearm resistance vessel function in 12 patients with CHF in response to an 8-wk exercise program, which specifically excluded forearm exercise, using a crossover design. Forearm blood flow (FBF) was measured using strain-gauge plethysmography. Responses to three dose levels of intra-arterial acetylcholine were significantly augmented after exercise training when analyzed in terms of absolute flows (7.0 +/- 1.8 to 10.9 +/- 2.1 ml x 100 ml(-1) x min(-1) for the highest dose, P < 0.05 by ANOVA), forearm vascular resistance (21.5 +/- 5.0 to 15.3 +/- 3.9 ml x 100 ml forearm(-1) x min(-1), P < 0.01), or FBF ratios (P < 0.01, ANOVA). FBF ratio responses to sodium nitroprusside were also significantly increased after training (P < 0.05, ANOVA). Reactive hyperemic flow significantly increased in both upper limbs after training (27.9 +/- 2.7 to 33.5 +/- 3.1 ml x 100 ml(-1) x min(-1), infused limb; P < 0.05 by paired t-test). Exercise training improves endothelium-dependent and -independent vascular function and peak vasodilator capacity in patients with CHF. These effects on the vasculature are generalized, as they were evident in a vascular bed not directly involved in the exercise stimulus.     

Effects of endothelin on the renal microcirculation of the split hydronephrotic rat kidney.

We have examined the effects of endothelin (ET) on the renal microcirculation by in vivo microscopy using the model of the split hydronephrotic rat kidney. ET, a potent vasoconstrictor peptide synthesized by vascular endothelial cells, showed marked and long-lasting effects on glomerular blood flow and vessel diameters in various segments of the renal vascular bed. Intravenously applied ET (100 ng/min/kg) increased systemic blood pressure from 123 +/- 7 to 156 +/- 4 mm Hg, decreased glomerular blood flow by 70%, and preferentially constricted larger preglomerular vessels, e.g. the arcuate artery. The competitive leukotriene antagonist FPL55712 significantly attenuated the vasoconstrictor response of the larger vessels. Local ET administration decreased glomerular blood flow in a dose-dependent manner (50% reduction at a concentration of 2.6 +/- 0.7 x 10(-9) M) and constricted smaller vessel segments, e.g. the afferent and efferent arterioles near the glomerulus. The constriction induced by ET was not significantly affected by the Ca2+ channel blocker nitrendipine (2.8 x 10(-6) to 1.1 x 10(-5) M). We conclude that intravenous ET effects are probably mediated by leukotrienes, inducing constriction of larger renal vessels. Locally administered ET acts directly on the renal vasculature, especially on smaller vessels.     

L-NAME enhances pulmonary vasoconstriction without inhibiting EDRF-dependent vasodilation.

The purpose of the present study was to determine the influence of NG-nitro-L-arginine methyl ester (L-NAME) on pulmonary vascular responses to endothelium-dependent relaxing factor- (EDRF) dependent and EDRF-independent substances in the pulmonary vascular bed of the anesthetized cat. Because pulmonary blood flow and left atrial pressure were kept constant, changes in lobar arterial pressure directly reflect changes in pulmonary vascular resistance. When pulmonary vasomotor tone was actively increased by intralobar infusion of U-46619, intralobar bolus injections of acetylcholine, bradykinin, serotonin, and 5-carboxyamidotryptamine (a serotonin1A receptor agonist) decreased lobar arterial pressure in a dose-related manner. The pulmonary vasodilator response to serotonin, but not to 5-carboxyamidotryptamine, acetylcholine, and bradykinin, was significantly decreased by L-NAME (100 mg/kg i.v.). Administration of ritanserin (0.5 mg/kg i.v.), but not L-arginine (1 g/kg i.v. with 60 mg.kg-1 x min-1 i.v. infusion), reversed the inhibitory effects of L-NAME on the pulmonary vasodilator response to serotonin and abolished the enhanced pulmonary vasoconstrictor response to (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminoproprane hydrochloride (a serotonin2 receptor agonist) after L-NAME administration. In conclusion, the present experiments suggest that L-NAME inhibits the pulmonary vasodilator response to serotonin by increasing the sensitivity of serotonin2 receptor-mediated vasoconstriction and not by inhibiting EDRF formation. Because the pulmonary vasodilator responses to bolus administration of acetylcholine and bradykinin were not inhibited by L-NAME, these data suggest that L-NAME does not appear to be an adequate probe to study the role of endogenous EDRF in the adult feline pulmonary vascular bed in vivo.     

Retinal Arterioles Narrow with Increasing Duration of Anti-Retroviral Therapy in HIV Infection: A Novel Estimator of Vascular Risk in HIV?

Objectives

HIV infection is associated with an increased risk of age-related morbidity mediated by immune dysfunction, atherosclerosis and inflammation. Changes in retinal vessel calibre may reflect cumulative structural damage arising from these mechanisms. The relationship of retinal vessel calibre with clinical and demographic characteristics was investigated in a population of HIV-infected individuals in South Africa.

Methods

Case-control study of 491 adults ≥30 years, composed of 242 HIV-infected adults and 249 age- and gender-matched HIV-negative controls. Retinal vessel calibre was measured using computer-assisted techniques to determine mean arteriolar and venular diameters of each eye.

Results

The median age was 40 years (IQR: 35–48 years). Among HIV-infected adults, 87.1% were receiving highly active antiretroviral therapy (HAART) (median duration, 58 months), their median CD4 count was 468 cells/µL, and 84.3% had undetectable plasma viral load. Unadjusted mean retinal arteriolar diameters were 163.67±17.69 µm in cases and 161.34±17.38 µm in controls (p = 0.15). Unadjusted mean venular diameters were 267.77±18.21 µm in cases and 270.81±18.98 µm in controls (p = 0.07). Age modified the effect of retinal arteriolar and venular diameters in relation to HIV status, with a tendency towards narrower retinal diameters in HIV cases but not in controls. Among cases, retinal arteriolar diameters narrowed with increasing duration of HAART, independently of age (167.83 µm <3 years of HAART vs. 158.89 µm >6 years, p-trend = 0.02), and with a HIV viral load >10,000 copies/mL while on HAART (p = 0.05). HIV-related venular changes were not detected.

Conclusions

Narrowing of retinal arteriolar diameters is associated with HAART duration and viral load, and may reflect heightened inflammatory and pro-atherogenic states of the systemic vasculature. Measurement of retinal vascular calibre could be an innovative non-invasive method of estimating vascular risk in HIV-infected individuals.     

Effect of rhythmic tetanic skeletal muscle contractions on peak muscle perfusion.

The purpose of this investigation was to examine the effect of rhythmic tetanic skeletal muscle contractions on peak muscle perfusion by using spontaneously perfused canine gastrocnemii in situ. Simultaneous pulsatile blood pressures were measured by means of transducers placed in the popliteal artery and vein, and pulsatile flow was measured with a flow-through-type transit-time ultrasound probe placed in the venous return line. Two series of experiments were performed. In series 1, maximal vasodilation of the muscles' vascular beds was elicited by infusing a normal saline solution containing adenosine (29.3 mg/min) and sodium nitroprusside (180 microg/min) for 15 s and then simultaneously occluding both the popliteal artery and vein for 5 min. The release of occlusion initiated a maximal hyperemic response, during which time four tetanic contractions were induced with supramaximal voltage (6-8 V, 0.2-ms stimuli for 200-ms duration at 50 Hz, 1/s). In series 2, the muscles were stimulated for 3 min before the muscle contractions were stopped for a period of 3 s; stimulation was then resumed. The results of series 1 indicate that, although contractions lowered venous pressure, muscle blood flow was significantly reduced from 2,056 +/- 246 to 1,738 +/- 225 ml x kg(-1) x min(-1) when contractions were initiated and then increased significantly to 1,925 +/- 225 ml x kg(-1) x min(-1) during the first 5 s after contractions were stopped. In series 2, blood flow after 3 min of contractions averaged 1,454 +/- 149 ml x kg(-1) x min(-1). Stopping the contractions for 3 s caused blood flow to increase significantly to 1,874 +/- 172 ml x kg(-1) x min(-1); blood flow declined significantly to 1,458 +/- 139 ml x kg(-1) x min(-1) when contractions were resumed. We conclude that the mechanical action of rhythmic, synchronous, maximal isometric tetanic skeletal muscle contractions inhibits peak muscle perfusion during maximal and near-maximal vasodilation of the muscle's vascular bed. This argues against a primary role for the muscle pump in achieving peak skeletal muscle blood flow.     

Cerebrovascular effects of intravenous dopamine infusions in fetal sheep.

Preterm infants are often treated with intravenous dopamine to increase mean arterial blood pressure (MAP). However, there are few data regarding cerebrovascular responses of developing animals to dopamine infusions. We studied eight near-term and eight preterm chronically catheterized unanesthetized fetal sheep. We measured cerebral blood flow and calculated cerebral vascular resistance (CVR) at baseline and during dopamine infusion at 2.5, 7.5, 25, and 75 microg x kg(-1) x min(-1). In preterm fetuses, MAP increased only at 75 microg x kg(-1) x min(-1) (25 +/- 5%), whereas in near-term fetuses MAP increased at 25 microg x kg(-1) x min(-1) (28 +/- 4%) and further at 75 microg x kg(-1) x min(-1) (51 +/- 3%). Dopamine infusion was associated with cerebral vasoconstriction in both groups. At 25 microg x kg(-1) x min(-1), CVR increased 77 +/- 51% in preterm fetuses and 41 +/- 11% in near-term fetuses, and at 75 microg x kg(-1) x min(-1), CVR increased 80 +/- 33% in preterm fetuses and 83 +/- 21% in near-term fetuses. We tested these responses to dopamine in 11 additional near-term fetuses under alpha-adrenergic blockade (phenoxybenzamine, n = 5) and under dopaminergic D(1)-receptor blockade (SCH-23390, n = 6). Phenoxybenzamine completely blocked dopamine's pressor and cerebral vasoconstrictive effects, while D(1)-receptor blockade had no effect. Therefore, in unanesthetized developing fetuses, dopamine infusion is associated with cerebral vasoconstriction, which is likely an autoregulatory, alpha-adrenergic response to an increase in blood pressure.     

Brimonidine evokes heterogeneous vasomotor response of retinal arterioles: diminished nitric oxide-mediated vasodilation when size goes small

Brimonidine, an alpha2-adrenergic receptor (AR) agonist, has been employed in the treatment of glaucoma due to its beneficial effects on intraocular pressure reduction and neuroprotection. In addition, some studies have implicated that brimonidine might influence ocular blood flow; however, its effect on the retinal microcirculation has not been documented. Herein, we examined the vasomotor action of brimonidine on different branching orders of retinal arterioles in vitro and determined the contribution of the alpha2-AR subtype and the role of endothelium-derived nitric oxide (NO) in this vasomotor response. First- and second-order retinal arterioles of pigs were isolated, cannulated, and pressurized for functional studies. Videomicroscopic techniques were employed to record diameter changes in response to brimonidine. RT-PCR was performed for detection of alpha-AR and endothelial NO synthase (eNOS) mRNA in retinal arterioles. All first-order arterioles (82 +/- 2 microm ID) dilated dose dependently to brimonidine (0.1 nM to 10 microM) with 10% dilation at the highest concentration. Second-order arterioles (50 +/- 1 microm ID) responded heterogeneously with either dilation or constriction. The incidence and magnitude of vasoconstriction were increased with increasing brimonidine concentration. Administration of the NO synthase inhibitor NG-nitro-L-arginine methyl ester abolished the brimonidine-induced vasodilation in first- and second-order arterioles. Regardless of vessel size, vasomotor responses (i.e., vasodilation and vasoconstriction) of retinal arterioles were sensitive to the alpha2-AR antagonist rauwolscine. Consistent with the functional data, alpha2A-AR and eNOS mRNAs were detected in retinal arterioles. Collectively, our data demonstrate that brimonidine at clinical doses evokes a consistent NO-dependent vasodilation in first-order retinal arterioles but a heterogeneous response in second-order arterioles. These vasomotor responses are mediated by the activation of alpha2-AR. It appears that brimonidine, depending on the concentration and vessel size, may alter local retinal blood flow.