These results show that nifedipine does not increase optic nerve head blood flow during baseline conditions but reverses ET-1-induced constriction in ocular vasculature at doses that do not affect systemic hemodynamics. This supports the close relation of the therapeutic effect of calcium channel blockers in patients with normal tension glaucoma to the endothelin system. Moreover, the present study provides a strong rationale for a study of low dose nifedipine as a supplementary medication in glaucoma patients.

The pathogenesis of diabetic vascular complications in the eye and kidney of humans is still not clear. There is evidence that glomerular filtration rate and renal plasma flow increase during poor metabolic control in patients with Type I (insulin-dependent) diabetes mellitus [1±3]. Several authors have also observed increased retinal and choroidal blood flow in patients with early diabetes [4±8], although there is some evidence of decreased ocular perfusion [9±10]. It has been suggested that this hyperperfusion in the kidney and the eye could predispose patients to develop vascular complications in these organs [11±14].Insulin treatment in patients with Type I diabetes induces peripheral blood hyperinsulinaemia in order to suppress interprandial hepatic glucose release. Patients treated for Type I diabetes are therefore exposed to high plasma concentrations of glucose and insulin. It has been known for a long time that a rapid increase in glucose plasma concentrations could cause vasodilation in the renal and ocular vasculature [15±16]. More recently it has been reported that insu- Diabetologia (2001) Abstract Aims/hypothesis. There is evidence that insulin and glucose cause renal and ocular vasodilation. There is, however, currently no data on the effect of combined hyperglycaemia and hyperinsulinaemia on the renal and ocular blood flow seen in diabetic patients on insulin therapy. Methods. We carried out two different 3-way crossover studies in healthy subjects (each, n = 9). In study one, hyperglycaemic clamps (5.6 mmol/l, 11.1 mmol/ l, 16.7 mmol/l) were carried out during placebo or insulin (dose 1: 1 mU/kg/min; dose 2: 2 mU/kg/min) infusion. The second study was identical but endogenous insulin secretion was blocked with somatostatin. The renal plasma flow, glomerular filtration rate and pulsatile choroidal blood flow were measured using the paraaminohippurate method, the inulin method and a laser interferometric measurement of fundus pulsation amplitude, respectively.Results. Insulin increased renal plasma flow and fundus pulsation amplitude but not the glomerular filtration rate. Hyperglycaemia increased all the renal and ocular parameters studied. Haemodynamic effects of glucose and insulin were additive when somatostatin was co-administered but not under basal conditions. Conclusions/interpretation. Glucose and insulin can exert additive vasodilator properties on renal and ocular circulation. To find out whether this observation is related to the increased regional perfusion in diabetes longitudinal studies on patients with Type I (insulin-dependent) diabetes mellitus are needed. [Diabetologia (2001) 44: 95±103]

SummaryBackground: Until now the effects of β-adrenergic agonists have largely been ascribed to their ability to induce intracellular formation of cyclic adenosine monophosphate. Recently evidence has been accumulating that at least some β1 and β2-adrenoceptor effects may be mediated by nitric oxide (NO). Based on these studies, we hypothesized that the β-adrenoceptor mediated increase of von Willebrand factor and factor VIII-activity (FVIII:C) in plasma during exercise, is caused by an NO-dependent mechanism. Methods: Thirteen young healthy subjects finished an exhaustive bicycle exercise protocol while they were infused placebo or the NO-synthase inhibitor N-monomethyl-L-arginine (L-NMMA) on two separate days in a randomized, double blind cross-over design. Findings: During exercise systemic haemo-dynamic changes were parallel in both treatment periods, but L-NMMA caused a partial inhibition of NO-synthase as evidenced by a 30% decrease in exhaled NO. The workload capacities were not different during L-NMMA or placebo infusion. However, under placebo treatment exercise increased vWF-Ag by a maximum of 61% (CI: 43-84; p = 0.002) and FVIII:C by 44% (CI: 31-59; p = 0.001), which was significantly attenuated when subjects were treated with L-NMMA (p <0.05): under L-NMMA treatment vWF-Ag increased by only 25% (CI: 5-51; p = 0.001) and FVIII:C by 12% (CI: 6-39; p = 0.001). Interpretation: Partial blockade of NO-synthase with L-NMMA blunts the exercise-induced increase in vWF-Ag and FVIII:C. Our trial points to a role of endogenous NO-generation in the β2-adrenergic increase in vWF/FVIII. Thus, we propose that physiologic processes which are induced by systemic β2-adrenoceptor stimulation may at least partly be mediated by NO.

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AimsThe introduction of specific inhibitors of AT 1 receptors, such as losartan, has enabled the investigation of the renin-angiotensin-system (RAS) in humans in vivo. We studied the role of the RAS in the cerebral and ocular circulation in healthy subjects. Haemodynamic effects of orally administered losartan were investigated with non-invasive methods. Methods In a placebo-controlled randomized, double-blind two way crossover design losartan (100 mg orally) or placebo was administered in 10 healthy subjects. The effect of losartan was studied at hourly intervals for 8 h. In addition, the effect of losartan on haemodynamic changes induced by exogenous angiotensin II (Ang II) was assessed. Blood flow velocities in the ophthalmic and the middle cerebral artery (OA, MCA) were measured with Doppler sonography. Pulsatile choroidal blood flow was estimated with laser interferometric measurement of fundus pulsation. Results Losartan significantly increased fundus pulsation amplitude (+11%, 95% CI: 5 to 16% P<0.0001), tended to increase resistive index in the ophthalmic artery (+12%, 95% CI: 0 to 23%) and tended to decrease mean arterial pressure (−15%, 95% CI: −23 to −1%). Ang II induced effects on cerebral, ocular and systemic haemodynamics were prevented by preceding administration of losartan. Conclusions The present data suggest that Ang II is not a major determinant of cerebral and ocular blood flow in vivo. The observed changes in cerebral and ocular haemodynamic parameters after losartan administration reflect effects on systemic blood pressure.Keywords: Doppler sonography, fundus pulsation, losartan, angiotensin II, cerebral blood flow, ocular blood flow that Ang II does not play an important role in the regulation Introduction of ocular blood flow [9, 10]. The involvement of the angiotensin renin system in the The renin-angiotensin system (RAS) plays a pivotal role in the regulation of vascular tone. Inhibition of the reninregulation of cerebral and ocular blood flow in vivo in humans is even less well understood. Results with ACE angiotensin system by angiotensin converting enzyme (ACE) inhibitors has been successfully used in the treatment of inhibitors are difficult to interpret, because of the lack of specificity of this class of drugs [11, 12]. We have previously hypertension and congestive heart failure [1, 2]. However, ACE is not very specific and has substrates other than Ang I investigated the effect of intravenous infusion of Ang II on cerebral and ocular haemodynamics in healthy subjects [13] including bradykinin, substance P and neurokinins, which may be responsible for some of the side effects of ACE and observed dose-dependent changes in haemodynamic parameters in the middle cerebral artery, the ophthalmic inhibitors [3]. The development of specific, selective type 1 receptor (AT 1 ) antagonists has therefore attracted much artery, and the choroid. However, careful interpretation of these results argues that these changes were mainly caused interest and its blood pressure lowering efficacy in pa...