Ursula Graselli

Role of NO in the O2 and CO2 responsiveness of cerebral and ocular circulation in humans

It is well known that changes in PCO2 or PO2 strongly influence cerebral and ocular blood flow. However, the mediators of these changes have not yet been completely identified. There is evidence from animal studies that NO may play a role in hypercapnia-induced vasodilation and that NO synthase inhibition modulates the response to hyperoxia in the choroid. Hence we have studied the effect of NO synthase inhibition by NG-monomethyl-L-arginine (L-NMMA, 3 mg/kg over 5 min as a bolus followed by a continuous infusion of 30 micrograms.kg-1.min-1) on the changes of cerebral and ocular hemodynamic parameters elicited by hypercapnia and hyperoxia in healthy young subjects. Mean flow velocities in the middle cerebral artery and the ophthalmic artery were measured with Doppler ultrasound, and ocular fundus pulsation amplitude, which estimates pulsatile choroidal blood flow, was measured with laser interferometry Administration of L-NMMA reduced ocular fundus pulsation. (-19%, P < 0.005) but only slightly reduced mean flow velocities in the larger arteries. Hypercapnia (PCO2 = 48 mmHg) significantly increased mean flow velocities in the middle cerebral artery (+26%, P < 0.01) and fundus pulsation amplitude (+16%, P < 0.005) but did not change mean flow velocity in the ophthalmic artery. The response to hypercapnia in the middle cerebral artery (P < 0.05) and in the choroid (P < 0.05) was significantly blunted by L-NMMA. On the contrary, L-NMMA did not affect hyperoxia-induced (PO2 = 530 mmHg) hemodynamic changes. The hemodynamic effects of L-NMMA (at baseline and during hypercapnia) were reversed by coadministration of L-arginine. The present study supports the concept that NO has a role in hypercapnia induced vasodilation in humans.It is well known that changes in [Formula: see text] or[Formula: see text] strongly influence cerebral and ocular blood flow. However, the mediators of these changes have not yet been completely identified. There is evidence from animal studies that NO may play a role in hypercapnia-induced vasodilation and that NO synthase inhibition modulates the response to hyperoxia in the choroid. Hence we have studied the effect of NO synthase inhibition by N G-monomethyl-l-arginine (l-NMMA, 3 mg/kg over 5 min as a bolus followed by a continuous infusion of 30 μg ⋅ kg-1 ⋅ min-1) on the changes of cerebral and ocular hemodynamic parameters elicited by hypercapnia and hyperoxia in healthy young subjects. Mean flow velocities in the middle cerebral artery and the ophthalmic artery were measured with Doppler ultrasound, and ocular fundus pulsation amplitude, which estimates pulsatile choroidal blood flow, was measured with laser interferometry. Administration ofl-NMMA reduced ocular fundus pulsations (-19%, P < 0.005) but only slightly reduced mean flow velocities in the larger arteries. Hypercapnia ([Formula: see text] = 48 mmHg) significantly increased mean flow velocities in the middle cerebral artery (+26%, P < 0.01) and fundus pulsation amplitude (+16%, P < 0.005) but did not change mean flow velocity in the ophthalmic artery. The response to hypercapnia in the middle cerebral artery ( P < 0.05) and in the choroid ( P < 0.05) was significantly blunted by l-NMMA. On the contrary,l-NMMA did not affect hyperoxia-induced ([Formula: see text] = 530 mmHg) hemodynamic changes. The hemodynamic effects ofl-NMMA (at baseline and during hypercapnia) were reversed by coadministration ofl-arginine. The present study supports the concept that NO has a role in hypercapnia-induced vasodilation in humans.

Effects of antiglaucoma drugs on ocular hemodynamics in healthy volunteers

There is evidence that ocular blood flow plays a critical role in the clinical course of glaucoma. Hence a reduction in ocular blood flow due to topical antiglaucoma treatment should be avoided. The purpose of this study was to characterize the effect of antiglaucoma drugs on ocular hemodynamics.

Large Amounts of Vascular Endothelial Growth Factor at the Site of Hemostatic Plug Formation In Vivo

Vascular endothelial growth factor (VEGF) is important for the proliferation, differentiation, and survival of microvascular endothelial cells. It is a potent angiogenic factor and a specific endothelial cell mitogen that increases fenestration and extravasation of plasma macromolecules. Recently, large quantities of VEGF were detected in human megakaryocytes. Incubation of human platelets with thrombin in vitro resulted in the release of large amounts of VEGF. To investigate whether VEGF is released from platelets during coagulation activation in vivo, we measured in human subjects VEGF at the site of plug formation, ie, in blood emerging from a standardized injury made to determine bleeding time (shed blood). VEGF was also determined in the same volunteers after treatment with the specific thrombin inhibitor recombinant hirudin (r-hirudin). In a double-blind, randomized, crossover study, 17 healthy male volunteers (aged 20 to 35 years) were investigated. VEGF concentrations were measured in venous blood and in shed blood by the use of an immunoassay 10 minutes after intravenous administration of r-hirudin (0.35 mg/kg of body weight) or physiological saline. Prothrombin fragment f1.2 (f1.2) and beta-thromboglobulin (beta-TG) were determined as indicators of coagulation and platelet activation, respectively. Concentrations of VEGF, f1.2, and beta-TG in shed blood 4 minutes after injury were significantly higher than in venous blood (VEGF, 55.8+/-9.2 versus <20 pg/mL, P<0.001; f1.2, 71.3+/-10.4 versus 0.78+/-0.03 nmol/L, P<0. 001; beta-TG, 2290+/-170 versus 53.2+/-14.0 ng/mL, P<0.001). Administration of r-hirudin caused a >50% inhibition of the beta-TG and f1.2 levels in shed blood. In a similar manner, much lower amounts of VEGF were detectable at the site of plug formation after r-hirudin treatment (69.0+/-9.5 versus 37.8+/-2.6 pg/mL per minute; P=0.0015). Our data indicate that substantial quantities of VEGF are released from platelets during the interaction with the injured vessel wall in vivo. This finding may be relevant with respect to wound healing and tissue repair, tumor vascularization, or arterial thrombus formation.

Reversal of endothelin‐1—induced ocular hemodynamic effects by low‐dose nifedipine in humans

There is evidence that calcium channel blockers may be useful in patients with normal tension glaucoma and vasospastic reactions. We therefore hypothesized that calcium channel blockers may increase ocular blood flow and that there may be a functional antagonism between endothelin‐1 (ET‐1) and calcium channel blockers in the ocular vasculature.

Comparison of the Effects of Ketamine and Memantine on Prolactin and Cortisol Release in Men: A Randomized, Double-blind, Placebo-controlled Trial

N-methyl D-aspartate (NMDA)-antagonists decrease neurotoxicity by inhibiting Ca2+ influx which is of interest for the treatment of acute cerebrovascular insults and chronic neurodegenerative disorders. Currently, there is no surrogate marker for quantification of NMDA-receptor–mediated drug effects, which hampers dose-finding clinical studies. As prolactin and cortisol liberation is in part influenced through NMDA-receptors we investigated whether the elevation of prolactin or cortisol plasma levels is a class effect of NMDA-antagonists and might be an appropriate marker for studying NMDA-antagonistic potency. Fifteen healthy male volunteers participated in this placebo-controlled, randomized, three-way crossover trial. Ketamine (0.5mg/kg), memantine (0.16 mg/kg; i.e., a well tollerated standard dose) or placebo were infused over 60 min. Ketamine increased serum prolactin and cortisol levels (p < 0.001), whereas memantine and placebo did not affect hormone levels. Further studies are needed to define whether higher doses of memantine or other NMDA antagonists can induce hormone release.

A comparison between laser interferometric measurement of fundus pulsation and pneumotonometric measurement of pulsatile ocular blood flow. 2. Effects of changes in pCO2 and pO2 and of isoproterenol.

Purpose We have shown in the companion paper that, under baseline conditions, there is a high degree of association between laser interferometrically measured fundus pulsation amplitude (FPA) and pneumotonometrically measured pulse amplitude (PA) and pulsatile ocular blood flow (POBF). The present study investigated the effect of high pCO2, of high pO2 and of isoproterenol on POBF as assessed with laser interferometry and pneumotonometry.Methods Pneumotonometry and laser interferometry were performed in young healthy subjects during breathing of 100% O2 (n = 10; hyperoxia) and of 5% CO2 + 95% air (n = 8; hypercapnia). In addition these parameters were studied during stepwise increasing doses of isoproterenol, a β-receptor agonist (n = 8).Results Inhalation of 5% CO2 + 95% air increased FPA (24 ± 12%, p < 0.001), PA (26 ± 13%, p < 0.001) and POBF (15 ± 8%, p = 0.002). Inhalation of 100% O2 decreased FPA (-5 ± 7%, p = 0.027), but did not change PA or POBF. The effect of 100% O2 inhalation on FPA in the optic disc was more pronounced (-11% to -20%) than in the macula. Isoproterenol caused a dose-dependent increase in FPA, PA and POBF (p < 0.001). The association between the induced changes in FPA and PA or POBF was highly significant.Conclusions The present study shows that FPA can be taken as a valid relative measure of pulsatile choroidal blood flow. Our results in the optic disc indicate that FPA at the neuroretinal rim and at the cup is influenced by retinal and choroidal circulation.

Cerebral and ocular hemodynamic effects of sumatriptan in the nitroglycerin headache model

Sumatriptan is a selective 5‐hydroxytryptamine1d (5‐HT1d)‐receptor agonist, highly effective in the short‐term treatment of migraine headaches. However, the mechanism underlying the action of sumatriptan is not yet completely understood. To further characterize the vascular effects of sumatriptan, we studied the effects on cerebral and ocular circulation in the well‐established nitroglycerin headache model.