Effect of the α(2)-adrenoceptor antagonist yohimbine on vascular regulation of the middle cerebral artery and the ophthalmic artery in healthy subjects.

There is evidence that vascular beds distal to the ophthalmic artery (OA) show vasoconstriction in response to a step decrease in systemic blood pressure (BP). The mediators of this response are mostly unidentified. The aim of the current study was to test the hypothesis that α2-adrenoreceptors may contribute to the regulatory process in response to a decrease in BP. In this randomized, double-masked, placebo-controlled study 14 healthy male volunteers received either 22mg yohimbine hydrochloride or placebo. Beat-to-beat BP was measured by analysis of arterial pressure waveform; blood flow velocities in the middle cerebral artery (MCA) and the OA were measured with Doppler ultrasound. Measurements were done before, during and after a step decrease in BP. The step decrease in BP was induced by bilateral thigh cuffs at a suprasystolic pressure followed by a rapid cuff deflation. After cuff deflation, BP returned to baseline after 7-8 pulse cycles (PC). Blood velocities in the MCA returned to baseline earlier (4 PC) than BP indicating peripheral vasodilatation. Blood velocities in the OA returned to baseline later (15-20 PC) indicating peripheral vasoconstriction. Yohimbine did not affect the blood velocity response in the MCA, but significantly shortened the time of OA blood velocities to return to baseline values (6-7 PC, p<0.05). In conclusion, our results indicate that yohimbine did not alter the regulatory response in the MCA, but modified the response of vascular beds distal to the OA. This suggests that α2-adrenoceptors play a role in the vasoconstrictor response of the vasculatures distal to the OA.

Initial counselling for cleft lip and palate: parents' evaluation, needs and expectations.

During the first counselling after the birth of a child with cleft lip and palate (CLP) information about the malformation should be delivered and a long-standing relationship between the cleft team and the affected family must be established. The present study was conducted to evaluate the parents' experiences, needs and expectations with this first consultation. A questionnaire was sent to 105 parents at the cleft clinic, which could be answered anonymously. It collected demographic data, data on the parents' pre-existing level of information and the parents' assessment of the counselling at the cleft centre. Seventy percent of the questionnaires were returned. In 16% the clefts were diagnosed prenatally, in 32% there were relatives with clefts. Seventy-one percent of the parents received detailed counselling, 89% of which occurred in the first week. The parents requested that information about surgery (80%), feeding the child (63%) and the aetiology of clefts (44%) should be given. The quality of the consultation was rated very good or good by 87% of families. This study confirms the importance of initial counselling for CLP. The exceptional psychological situation of the family has to be considered and a close collaboration between cleft centre and maternity hospitals is mandatory.

Ocular hemodynamic effects of nitrovasodilators in healthy subjects.

Nitric oxide (NO) plays a key role in the regulation of ocular blood flow and may be an interesting therapeutic target in ocular ischemic disease. In the present study, we hypothesized that NO-releasing drugs may increase blood flow to the head of the optic nerve and also in the choroid. The study employed a randomized, placebo-controlled, double blind, four-way crossover design. On separate study days, 12 healthy subjects received infusions of nitroglycerin, isosorbide dinitrate, sodium nitroprusside, or placebo. All three study drugs reduced the mean arterial pressure (MAP) and ocular perfusion pressure (OPP) (P < 0.001). None of the administered drugs increased the ocular hemodynamic variables. By contrast, vascular resistance decreased dose dependently during administration of the study drugs (P < 0.001). These results indicate that systemic administration of NO-donor drugs is associated with a decrease in vascular resistance in the ocular vasculature. However, because these drugs also reduce blood pressure, they do not improve perfusion to the posterior eye pole.

Effect of dorzolamide and timolol on ocular blood flow in patients with primary open angle glaucoma and ocular hypertension.

BACKGROUND: There is evidence that perfusion abnormalities of the optic nerve head are involved in the pathogenesis of glaucoma. There is therefore considerable interest in the effects of topical antiglaucoma drugs on ocular blood flow. A study was undertaken to compare the ocular haemodynamic effects of dorzolamide and timolol in patients with primary open angle glaucoma (POAG) or ocular hypertension (OHT). METHODS: One hundred and forty patients with POAG or OHT were included in a controlled, randomised, double blind study in two parallel groups; 70 were randomised to receive timolol and 70 to receive dorzolamide for a period of 6 months. Subjects whose intraocular pressure (IOP) did not respond to either of the two drugs were switched to the alternative treatment after 2 weeks. Scanning laser Doppler flowmetry was used to measure blood flow in the temporal neuroretinal rim and the cup of the optic nerve head. Pulsatile choroidal blood flow was assessed using laser interferometric measurement of fundus pulsation amplitude. RESULTS: Five patients did not respond to timolol and were changed to the dorzolamide group, and 18 patients changed from dorzolamide treatment to timolol. The effects of both drugs on IOP and ocular perfusion pressure were comparable. Dorzolamide, but not timolol, increased blood flow in the temporal neuroretinal rim (8.5 (1.6)%, p<0.001 versus timolol) and the cup of the optic nerve head (13.5 (2.5)%, p<0.001 versus timolol), and fundus pulsation amplitude (8.9 (1.3)%, p<0.001 versus timolol). CONCLUSIONS: This study indicates augmented blood flow in the optic nerve head and choroid after 6 months of treatment with dorzolamide, but not with timolol. It remains to be established whether this effect can help to reduce visual field loss in patients with glaucoma.

Effect of a nifedipine induced reduction in blood pressure on the association between ocular pulse amplitude and ocular fundus pulsation amplitude in systemic hypertension.

BACKGROUND: The ocular pressure/volume relation, which is described by the Friedenwald equation, forms the basis of intraocular pressure (IOP) measurement with Schiotz tonometry and measurement of pulsatile ocular blood flow (POBF) with pneumotonometry. Changes in intraocular volume during the cardiac cycle are caused by arterial inflow and venous outflow and are accompanied by changes in IOP. The relation between volume and pressure changes is dependent on the elastic properties of the eye coats as described by the ocular rigidity coefficient. Previous studies indicate that there is a vascular contribution to ocular rigidity and that the volume/pressure relationship may depend on the mean arterial pressure. METHODS: The effect of a nifedipine induced reduction in systemic blood pressure on pulse amplitude (PA) as assessed with pneumotonometry and fundus pulsation amplitude (FPA), as measured with laser interferometry was investigated in 16 untreated patients with moderate to severe systemic hypertension (mean arterial pressure 123 (SD 12) mm Hg). RESULTS: The ratio between PA and FPA was taken as a measure of the ocular rigidity coefficient. Nifedipine reduced mean arterial pressure by 17.3% and increased pulse rate by 11.0% (p<0.001 each). Whereas PA was significantly reduced after administration of nifedipine (-15.6%; p<0.001), FPA remained unchanged. Accordingly, the ratio of PA/FPA was reduced from 0.86 mm Hg/mum to 0.73 mm Hg/mum after administration of nifedipine. CONCLUSION: These data are in keeping with previous animal experiments indicating a blood pressure dependent vascular component to the rigidity of the eye coats in vivo. This needs to be taken into account for measurement of IOP with Schiotz tonometry and POBF with pneumotonometry.

Free fatty acids exert a greater effect on ocular and skin blood flow than triglycerides in healthy subjects.

BACKGROUND: Free fatty acids (FFAs) and triglycerides (TGs) can cause vascular dysfunction and arteriosclerosis. Acute elevation of plasma FFA and TG concentration strongly increase ocular and skin blood flow. This study was designed to discriminate whether FFA or TG independently induce hyperperfusion by measuring regional and systemic haemodynamics. METHODS: In a balanced, randomized, placebo-controlled, double-blind, three-way, crossover study nine healthy subjects received either Intralipid (Pharmacia and Upjohn, Vienna, Austria) with heparin, Intralipid alone or placebo control. Pulsatile choroidal blood flow was measured with laser interferometry, retinal blood flow and retinal red blood cell velocity with laser Doppler velocimetry, and skin blood flow with laser Doppler flowmetry during an euglycaemic insulin clamp. RESULTS: A sevenfold increase of FFA during Intralipid/heparin infusion was paralleled by enhanced choriodal, retinal, and skin blood flow by 17 +/- 4%, 26 +/- 5% (P < 0.001), and 47 +/- 19% (P = 0.03) from baseline, respectively. In contrast, a mere threefold increase of FFA by infusion of Intralipid alone did not affect outcome parameters, despite the presence of plasma TG levels of 250-700 mg dL(-1); similar to those obtained during combined Intralipid/heparin infusion. Systemic haemodynamics were not affected by drug infusion. CONCLUSIONS: Present findings demonstrate a concentration-dependent increase in ocular and skin blood flow by FFA independently of elevated TG plasma concentrations. As vasodilation of resistance vessels occur rapidly, FFA may play a role in the development of continued regional hyperperfusion and deteriorate microvascular function.

Twelve hour reproducibility of choroidal blood flow parameters in healthy subjects.

AIMS/BACKGROUND: To investigate the reproducibility and potential diurnal variation of choroidal blood flow parameters in healthy subjects over a period of 12 hours. METHODS: The choroidal blood flow parameters of 16 healthy non-smoking subjects were measured at five time points during the day (8:00, 11:00, 14:00, 17:00, and 20:00). Outcome parameters were pulsatile ocular blood flow as assessed by pneumotonometry, fundus pulsation amplitude as assessed by laser interferometry, blood velocities in the opthalmic and posterior ciliary arteries as assessed by colour Doppler imaging, and choroidal blood flow, volume, and velocity as assessed by fundus camera based laser Doppler flowmetry. The coefficient of variation and the maximum change from baseline in an individual were calculated for each outcome parameter. RESULTS: None of the techniques used found a diurnal variation in choroidal blood flow. Coefficients of variation were within 2.9% and 13.6% for all outcome parameters. The maximum change from baseline in an individual was much higher, ranging from 11.2% to 58.8%. CONCLUSIONS: These data indicate that in healthy subjects the selected techniques provide adequate reproducibility to be used in clinical studies. Variability may, however, be considerably higher in older subjects or subjects with ocular disease. The higher individual differences in flow parameter readings limit the use of the techniques in clinical practice. To overcome problems with measurement validity, a clinical trial should include as many choroidal blood flow outcome parameters as possible to check for consistency.

Choroidal blood flow and arterial blood pressure.

PURPOSE: Untreated hypertension is associated with ocular complications and is a risk factor for the development and progression of vascular ocular pathologies. We set out to investigate the association between systemic blood pressure and choroidal blood flow. METHODS: All subjects were male non-smokers, who did not receive any medication and had normal or slightly elevated blood pressure (systolic blood pressure < or = 160 mmHg; diastolic blood pressure < or = 100 mmHg). The association between systemic blood pressure and fundus pulsation amplitude, a measure of pulsatile choroidal blood flow, was investigated in 318 volunteers. In addition, the association between systemic blood pressure and blood flow velocities in the posterior ciliary arteries supplying the choroid was investigated in these subjects. RESULTS: Ocular fundus pulsation amplitude (r = 0.252; P < 0.001) and mean flow velocity in the posterior ciliary arteries (r = 0.346, P < 0.001) were significantly associated with mean arterial pressure. The correlation of ocular haemodynamic variables with systolic and diastolic blood pressure was in the same range. CONCLUSIONS: Our data indicate a small, but significant increase in choroidal blood flow with increasing blood pressure.

Effect of inhalation of different mixtures of O(2) and CO(2) on retinal blood flow.

AIM: To determine the effects of various mixtures of O(2) and CO(2) on retinal blood flow in healthy subjects. METHODS: A randomised, double masked, four way crossover trial was carried out in 12 healthy male non-smoking subjects. Gas mixtures (100% O(2), 97.5% O(2) + 2.5% CO(2), 95% O(2) + 5% CO(2), and 92% O(2) + 8% CO(2)) were administered for 10 minutes each. Two non-invasive methods were used: laser Doppler velocimetry (LDV) for measurement of retinal blood velocity and fundus imaging with the Zeiss retinal vessel analyser (RVA) for the assessment of retinal vessel diameters. Arterial pH, pCO(2), and pO(2) were determined with an automatic blood gas analysis system. Retinal blood flow through a major temporal vein was calculated. RESULTS: Retinal blood velocity, retinal vessel diameter, and retinal blood flow decreased during all breathing periods (p <0.001 each). Administration of 92% O(2) + 8% CO(2) significantly increased SBP, MAP, and PR (p <0.001 each, versus baseline), whereas the other gas mixtures had little effect on systemic haemodynamics. Addition of 2.5%, 5%, and 8% CO(2) to oxygen caused a marked decrease in pH and an increase in pCO(2) (p <0.001 versus pure oxygen). CONCLUSIONS: Breathing of pure oxygen and oxygen in combination with carbon dioxide significantly decreases retinal blood flow. Based on these data the authors speculate that hyperoxia induced vasoconstriction is not due to changes in intravascular pH and cannot be counteracted by an intravascular increase in pCO(2).

Endothelin ETA receptor-subtype specific antagonism does not mitigate the acute systemic or renal effects of exogenous angiotensin II in humans.

BACKGROUND: Angiotensin II (Ang II) is assumed to play a pathophysiological role in a variety of vascular diseases. Animal studies indicate that these effects are partly attributed to stimulation of endothelin-1 (ET-1) release. The aim of the present study was to investigate whether the acute effects of Ang II on systemic and renal haemodynamics in healthy subjects can be influenced by endothelin ET(A)-receptor blockade. DESIGN: The study design was balanced, randomized, placebo-controlled, double blind, two-way cross-over, in 10 healthy male subjects. METHODS: Subjects received stepwise increasing intravenous doses of Ang II (0.65, 1.25, 2.5, 5 ng kg(-1) min(-1) for 15 min per dose level) in the presence or absence of BQ-123 (60 microg min(-1)), a specific ETA-receptor antagonist. Renal plasma flow (RPF) and glomerular filtration rate (GFR) were assessed by the para-aminohippurate and inulin plasma clearance method, respectively. Renal vascular resistance (RVR) was calculated from mean arterial pressure (MAP) and renal plasma flow. RESULTS: Ang II decreased RPF by 34% and GFR by 9% and increased RVR by 94% and MAP by 27% (ANOVA, P < 0.001 vs. baseline, for all parameters). BQ-123 did not alter these renal and systemic haemodynamic responses to a significant degree. In addition, BQ-123 had no significant haemodynamic effect under baseline conditions. CONCLUSIONS: Short-term increase of circulating Ang II levels causes systemic and renal pressor effects, which are not mitigated by endothelin ETA-receptor blockade. This suggests that the pressor response to Ang II cannot be accounted for by the acute release of vasoactive ET-1.

Unilateral light-dark transitions affect choroidal blood flow in both eyes.

There is recent evidence that the perfusion of the choroid changes during dark-light transitions. We set out to investigate this response in more detail and to elucidate possible mechanisms involved in this process. For this purpose, the effect of dark-light transitions on choroidal perfusion was studied in healthy subjects. Choroidal blood flow and ocular fundus pulsation amplitude were measured as indices of choroidal perfusion during dark-light transitions using laser Doppler flowmetry and laser interferometry, respectively. In the first experiment, subjects were first kept in room light for 20 min, then light conditions were changed to darkness for 20 min, and thereafter, subjects were exposed to room light again. Both choroidal parameters decreased (-12% to -14%) during darkness but returned to baseline after the final room light period. In the second experiment, the index eye underwent the same procedure, whereas the contralateral eye was kept in light throughout the experiment. Choroidal haemodynamic parameters in the index eye reacted in a way comparable to that seen in the first experiment. The eye that was kept in light also reacted, but the effect tended to be less pronounced than that seen in the index eye (-8% to -10%). The observation that choroidal blood flow in both eyes reacts during unilateral light-dark transitions indicates that choroidal perfusion rate is adapted to retinal illumination conditions by neural control mechanisms.

Effect of endothelin and BQ123 on ocular blood flow parameters in healthy subjects.

PURPOSE: To characterize the role of the endothelin system in the blood flow control of the optic nerve head and of the choroid in humans. METHODS: Two studies were performed in healthy subjects. Study 1 was a randomized, placebo-controlled, double-masked, balanced, two-way crossover design and study 2 a three way-way crossover design. In study 1 twelve healthy male subjects received endothelin (ET)-1 in stepwise increasing doses of 1.25, 2.5, and 5 ng/kg x min (each infusion step occurred over 20 minutes) coinfused with BQ123 (60 microg/kg x min) or placebo on two different study days. In study 2 twelve healthy male subjects received two doses of BQ123 (60 or 120 microg/kg x min over 60 minutes) or placebo on three different study days. Measurements of optic nerve head blood flow (ONHBF) and choroidal blood flow (ChBF) were performed with laser Doppler flowmetry in both studies. In study 2 mean flow velocity (MFV) of the ophthalmic artery was assessed with Doppler sonography. RESULTS: In study 1, ET-1 significantly decreased ONHBF (-22.8% +/- 4.3% at 5 ng/kg x min, P = 0.003 versus baseline) and ChBF (-21.7% +/- 3.2% at 5 ng/kg x min, P = 0.0001 versus baseline). The effect of the highest administered dose of exogenous ET-1 on ONHBF was significantly attenuated (P = 0.04, ANOVA) by coinfusion of BQ123. Effects of exogenous ET-1 on blood flow (2.5 ng/kg x min ET-1 or higher) also were attenuated in the choroid by coinfusion of BQ123 (ChBF: P = 0.03, ANOVA). In study 2, both dosages of BQ123 significantly increased MFV in the ophthalmic artery (60 microg/kg x min, 12.5% +/- 7.3%; 120 microg/kg x min, 17.2% +/- 9.2%, versus baseline; P = 0.001), but did not change blood flow in the ONH or the choroid. CONCLUSIONS: BQ123 antagonizes the effects of exogenously administered ET-1 on blood flow in the ONH and the choroid. The data indicate, however, that ET-1 does not substantially contribute to the regulation of basal vascular tone in these tissues.

Retinal blood flow and systemic blood pressure in healthy young subjects.

BACKGROUND: The aim of the present study was to investigate the association between systemic blood pressure and retinal blood flow in healthy young subjects. METHODS: Three independent study cohorts were included. A cross-sectional study was performed in 420 young male subjects with systolic blood pressure < 160 mmHg and diastolic blood pressure <100 mmHg. Retinal white blood cell flux (n=210) and blood velocity in the central retinal artery (n=210) were measured. In addition, a longitudinal study was performed in 40 young male subjects in whom retinal and systemic haemodynamic parameters were measured thrice within 6 weeks. Retinal white blood cell flux was measured with the blue-field entoptic technique. Blood flow velocity in the central retinal artery was measured by means of colour Doppler imaging. RESULTS: Retinal white blood cell flux (r=0.262; P<0.001) and mean flow velocity in the central retinal artery (r=0.174, P=0.010) were significantly associated with mean arterial pressure in the cross-sectional study. In the longitudinal study retinal white blood cell flux and mean flow velocity in the central retinal artery were also correlated with systemic blood pressure. CONCLUSIONS: Our data indicate a slight but significant increase in retinal blood flow with blood pressure. Whether this is of clinical relevance in eye diseases with altered retinal perfusion, such as diabetic retinopathy, remains to be established.

RI in central retinal artery as assessed by CDI does not correspond to retinal vascular resistance.

The aim of the present study was to investigate the association between ultrasound Doppler measurements of resistive index (RI) in the central retinal artery and retinal vascular resistance (R) assessed with laser Doppler velocimetry, vessel size measurement, and calculation of ocular perfusion pressure (PP) in healthy subjects. An increase in vascular resistance was induced by inhalation of 100% O(2). During hyperoxia no significant changes in PP were observed. Mean flow velocity in main retinal veins was reduced by -27.5 +/- 2.0%. The average decrease in diameter was -11.5 +/- 1.0%. R, which was calculated as the ratio of PP to flow rate, increased by 97.6 +/- 7.7%. RI increased as well, but the effect was much smaller (6.6 +/- 2.2%). In addition, a negative correlation was found between baseline values of R and RI (r = -0.83). During hyperoxia R and RI were not associated. In conclusion, our data indicate that RI as assessed with color Doppler imaging in the central retinal artery is not an adequate measure of R.

Free fatty acids/triglycerides increase ocular and subcutaneous blood flow.

Elevated plasma free fatty acids (FFA) induce skeletal muscle insulin resistance and impair endothelial function. The aim of this study was to characterize the acute hemodynamic effects of FFA in the eye and skin. A triglyceride (Intralipid 20%, 1.5 ml/min)/heparin (bolus: 200 IU; constant infusion rate: 0.2 IU. kg(-1). min(-1)) emulsion or placebo was administered to 10 healthy subjects. Measurements of pulsatile choroidal blood flow with laser interferometry, retinal blood flow with the blue field entoptic technique, peak systolic and end diastolic blood velocity (PSV, EDV) in the ophthalmic artery with Doppler sonography, and subcutaneous blood flow with laser Doppler flowmetry were performed during an euglycemic somatostatin-insulin clamp over 405 min. Plasma FFA/triglyceride elevation induced a rise in pulsatile choroidal blood flow by 25 +/- 3% (P < 0.001) and in retinal blood flow by 60 +/- 23% (P = 0.0125). PSV increased by 27 +/- 8% (P = 0.001), whereas EDV was not affected. Skin blood flow increased by 149 +/- 38% (P = 0.001). Mean blood pressure and pulse rate remained unchanged, whereas pulse pressure amplitude increased by 17 +/- 5% (P = 0.019). Infusion of heparin alone had no hemodynamic effect in the eye or skin. In conclusion, FFA/triglyceride elevation increases subcutaneous and ocular blood flow with a more pronounced effect in the retina than in the choroid, which may play a role for early changes of ocular perfusion in the insulin resistance syndrome.

Evaluation of the Zeiss retinal vessel analyser.

AIM: To investigate the reproducibility and sensitivity of the Zeiss retinal vessel analyser, a new method for the online determination of retinal vessel diameters in healthy subjects. METHODS: Two model drugs were administered, a peripheral vasoconstrictor (the alpha receptor agonist phenylephrine) and a peripheral vasodilator (the nitric oxide donor sodium nitroprusside) in stepwise increasing doses. Nine healthy young subjects were studied in a placebo controlled double masked three way crossover design. Subjects received intravenous infusions of either placebo or stepwise increasing doses of phenylephrine (0.5, 1, or 2 microg/kg/min) or sodium nitroprusside (0.5, 1, or 2 microg/kg/min). Retinal vessel diameters were measured with the new Zeiss retinal vessel analyser. Retinal leucocyte velocity, flow, and density were measured with the blue field entoptic technique. The reproducibility of measurements was assessed with coefficients of variation and intraclass correlation coefficients. RESULTS: Placebo and phenylephrine did not influence retinal haemodynamics, although the alpha receptor antagonist significantly increased blood pressure. Sodium nitroprusside induced a significant increase in retinal venous and arterial diameters (p<0.001 each), leucocyte density (p=0.001), and leucocyte flow (p=0.024) despite lowering blood pressure to a significant degree. For venous and arterial vessel size measurements short term coefficients of variation were 1.3% and 2.6% and intraclass correlation coefficients were 0.98 and 0.96, respectively. The sensitivity was between 3% and 5% for retinal veins and 5% and 7% for retinal arteries. CONCLUSIONS: These data indicate that the Zeiss retinal vessel analyser is an accurate system for the assessment of retinal diameters in healthy subjects. In addition, nitric oxide appears to have a strong influence on retinal vascular tone.

Effects of systemic NO synthase inhibition on choroidal and optic nerve head blood flow in healthy subjects.

PURPOSE: There is evidence from animal studies that nitric oxide (NO) is a major determinant of ocular blood flow. In humans NO synthase inhibition reduces pulsatile choroidal blood flow, but no data on optic nerve head (ONH) vasculature are available yet. The goal of this study was to investigate the effects of NO synthase inhibition on human choroidal and ONH blood flow using laser Doppler flowmetry. METHODS: The study design was a randomized, placebo-controlled, double-masked, balanced three-way crossover. On separate study days 12 healthy male subjects received infusions of N:(G)-nitro-L-arginine (L-NMMA; either 3 mg/kg over 5 minutes followed by 30 microg/kg per minute over 55 minutes or 6 mg/kg over 5 minutes followed by 60 microg/kg per minute over 55 minutes) or placebo. The effects of L-NMMA or placebo on choroidal and ONH blood flow were measured with laser Doppler flowmetry. In addition, laser interferometric measurement of fundus pulsation was performed in the macula to assess pulsatile choroidal blood flow. RESULTS: L-NMMA reduced all outcome parameters in the choroid and the ONH. The higher dose of L-NMMA caused a significant decrease in blood flow in the choroid (-26% +/- 9%; P: < 0.001) and the ONH (-20% +/- 16%; P: < 0.001) as evidenced from laser Doppler flowmetry and a significant decrease in fundus pulsation amplitude (-26% +/- 5%; P: < 0.001). CONCLUSIONS: These results indicate that NO is continuously released in human choroidal and ONH vessels.

Hypercapnia-induced cerebral and ocular vasodilation is not altered by glibenclamide in humans.

Carbon dioxide is an important regulator of vascular tone. Glibenclamide, an inhibitor of ATP-sensitive potassium channel (K(ATP)) activation, significantly blunts vasodilation in response to hypercapnic acidosis in animals. We investigated whether glibenclamide also alters the cerebral and ocular vasodilator response to hypercapnia in humans. Ten healthy male subjects were studied in a controlled, randomized, double-blind two-way crossover study under normoxic and hypercapnic conditions. Glibenclamide (5 mg po) or insulin (0.3 mU. kg(-1). min(-1) iv) were administered with glucose to achieve comparable plasma insulin levels. In control experiments, five healthy volunteers received glibenclamide (5 mg) or nicorandil (40 mg) or glibenclamide and nicorandil in a randomized, three-way crossover study. Mean blood flow velocity and resistive index in the middle cerebral artery (MCA) and in the ophthalmic artery (OA) were measured with Doppler sonography. Pulsatile choroidal blood flow was assessed with laser interferometric measurement of fundus pulsation. Forearm blood flow was measured with venous occlusion plethysmography. Hypercapnia increased ocular fundus pulsation amplitude by +18.2-22.3% (P < 0. 001) and mean flow velocity in the MCA by +27.4-33.3% (P < 0.001), but not in the OA (2.1-6.5%, P = 0.2). Forearm blood flow increased by 78.2% vs. baseline (P = 0.041) after nicorandil administration. Glibenclamide did not alter hypercapnia-induced changes in cerebral or ocular hemodynamics and did not affect systemic hemodynamics or forearm blood flow but significantly increased glucose utilization and blunted the nicorandil-induced vasodilation in the forearm. This suggests that hypercapnia-induced changes in the vascular beds under study are not mediated by activation of K(ATP) channels in humans.

Effects of insulin on retinal and pulsatile choroidal blood flow in humans.

BACKGROUND: Insulin induces vasodilation in several tissues, including skeletal muscle and kidneys. OBJECTIVE: To investigate whether insulin may contribute to ocular blood flow regulation. METHODS: The study was performed in a balanced, randomized, placebo-controlled, single-masked, 3-way, crossover design in 9 healthy male subjects. Each subject received 2 doses of insulin (1.5 or 3 mU/kg per minute) or placebo on 3 different study days. Measurements of fundus pulsation amplitude with laser interferometry to assess pulsatile choroidal blood flow, of retinal blood flow with the blue-field entoptic technique, and of mean blood flow velocity in the ophthalmic artery with Doppler sonography were performed under euglycemic clamp conditions over 120 minutes. RESULTS: Hyperinsulinemia significantly increased fundus pulsation amplitude (1.5 mU/kg per minute: 8.7% +/- 1.1% vs baseline; 3 mU/kg per minute: 13.2% +/- 2.3% vs baseline; P<.001 vs placebo [analysis of variance]) and mean blood flow velocity (1.5 mU/kg per minute: 10.0% +/- 4.3% vs baseline; 3 mU/kg per minute: 6.6% +/- 3.5% vs baseline; P = .03 vs placebo). Retinal blood flow did not increase during administration of insulin (1.5 mU/kg per minute: 6.4% +/- 8.0% vs baseline; 3 mU/kg per minute: 8.0% +/- 5.1% vs baseline; P = .99 vs placebo). Neither the effect in the choroid nor that in the ophthalmic artery was dose-dependent. CONCLUSION: Hyperinsulinemia significantly increases choroidal blood flow and mean blood flow velocity in the ophthalmic artery. By contrast, retinal blood flow was not influenced by hyperinsulinemia. The maximum effective dose of insulin for ocular hemodynamics is likely to be within the physiological range.