Adenosine is an endogenous nucleoside with potent vasodilatory capacities, released under ischaemic conditions in particular. Its mechanisms of action, however, remain elusive.To evaluate the role of adenosine, using a non-selective purinergic receptor antagonist, and the possible involvement of nitric oxide in this mechanism. In addition, the production of renin and catecholamines was studied during infusion of adenosine, caffeine, or both.Thirty-three hypertensive patients who underwent diagnostic renal angiography received intrarenal infusions of adenosine either alone or in combination with caffeine or the nitric oxide synthase inhibitor, N-monomethyl-L-arginine (L-NMMA). The effects on renal blood flow (RBF) were assessed by the xenon-133 washout technique and both arterial and renal venous blood samples were taken for measurement of renin and catecholamine concentrations. Intra-arterial blood pressure and heart rate were monitored continuously.Adenosine induced a dose-dependent vasodilatation. Caffeine alone did not change RBF, but shifted the dose-response curve of adenosine to the right during concomitant infusion of caffeine. RBF during combined infusion of L-NMMA and adenosine was not different from that during adenosine alone, but the decrease in renal vascular resistance was less pronounced during this combination. Renin secretion did not change during the infusion of either adenosine alone or adenosine in combination with caffeine. Catecholamine concentrations also did not change during any of the experiments.Adenosine induces vasodilatation in the human hypertensive kidney and this effect is mediated by the adenosine receptor. Nitric oxide plays, at most, a minor part in the adenosine-induced vasodilatation. Furthermore, renin secretion is not affected by adenosine and caffeine.
Abstract Background Iron deficiency (ID) is suggested to be one of the key comorbidities contributing to heart failure with preserved ejection fraction (HFpEF) and concomitant exercise intolerance, possibly by inducing systemic inflammation and microvascular dysfunction (MVD). ID is associated with poorer prognosis in HFpEF, but its exact impact on exercise capacity in HFpEF patients remains to be further investigated. Purpose To evaluate the effect of ID on exercise capacity in HFpEF patients by assessing skeletal muscle metabolism. Additionally, to assess the association between ID and MVD in HFpEF patients. Methods This prospective study included patients diagnosed with HFpEF according to the ESC Heart Failure 2016 guidelines between January 2018 and May 2021. Patients were excluded if they were of childbearing potential, had any iron supplementation 6 months or chemotherapy 1 year prior to inclusion, were known with significant peripheral artery disease, or had any contraindication for phosphorus-magnetic resonance spectroscopy (31P-MRS). Iron status was defined as absolute ID (serum ferritin <100μg/L), relative ID (serum ferritin 100–299μg/L and transferrin saturation <20%), and no ID. Skeletal muscle oxidative capacity of the upper leg was evaluated by determining phosphocreatine (PCr) recovery kinetics with 31P-MRS in the vastus lateralis muscle after isometric knee extension exercise. Microvascular function was assessed as heat-induced skin hyperemia using laser-Doppler flowmetry. Clinical data up to 6 months prior to or after inclusion was used. Results Twenty-four HFpEF patients without ID and 18 with ID were included, including 14 patients with absolute ID. Clinical characteristics of patients without ID and with ID were comparable: median age 74 [69–79] vs. 77 [69–81] years, 13 (54%) vs. 14 (78%) were females, and 20 (83%) vs. 16 (89%) had a history of hypertension (Table 1). Both groups showed similar halftime of PCr recovery after exercise (29.2 [22.8–33.2] vs. 27.0 [21.1–31.4] seconds, p=0.416), and similar skin hyperaemic flow increase (1142 [576–2247] vs. 1023 [574–1511] %, p=0.554). These measures of skeletal muscle metabolism and microvascular function were not correlated. In a subset of patients (11 without ID and 13 with ID), elevated high-sensitive C-reactive protein (hsCRP) was correlated with PCr recovery halftime in those with ID (R2 0.565, p=0.003). This correlation was not found in patients without ID (R2 0.119, p=0.300) in the original data (Figure 1), but was found after removal of a prominent outlier (R2 0.654, p=0.005). Conclusion HFpEF patients without ID showed comparable skeletal muscle oxidative capacity and microvascular skin hyperaemia compared to HFpEF patients with ID. Post-hoc analysis suggests that inflammation affects skeletal muscle metabolism in HFpEF patients, possibly regardless of ID. Future studies on the effects of ID and inflammation on cellular metabolism could suggest therapeutic targets in HFpEF. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was funded by Vifor Pharma. The funder had no influence on the study results.
Systemic infusion of brain natriuretic peptide (BNP) stimulates natriuresis and diuresis but has variable effects on the renal vasculature. In this study, we investigated whether BNP has any direct effects on the kidney in hypertensive patients. Three stepwise increasing doses of BNP (60, 120, and 180 pmol/min) or placebo were infused into the renal artery of 26 hypertensive patients. Renal blood flow was determined with the 133Xenon washout technique. Before and after infusion of BNP, arterial and venous blood samples were taken for cGMP, renin, and creatinine concentration. Intra-arterial blood pressure and heart rate were monitored continuously. Intrarenal BNP infusion did not induce significant changes in renal blood flow despite increases in circulating levels of cGMP. The latter, however, was not associated with changes in the cGMP gradient across the kidney. In addition, we did not find any BNP-related changes in the secretion of active renin and in creatinine extraction. At the highest dose, heart rate increased after BNP infusion without a change in mean intra-arterial blood pressure. In conclusion, this study suggests that at least in hypertensive subjects, BNP has no direct intrarenal hemodynamic effects and that the rise in circulating cGMP without changes in net renal extraction of this second messenger is related to a primary extrarenal target of BNP.
Background Cortisol is known to increase blood pressure. One possible mechanism is the reported increase in renal vascular resistance (RVR). It is unknown whether this is due to a direct effect of cortisol on the kidneys. Objective To study the effect of infusion of cortisol directly into the renal artery on renal blood flow (RBF) and on renal 11β-hydroxysteroid dehydrogenase (11β-HSD)-mediated conversion of cortisol to cortisone in patients with primary hypertension. Design and methods Twenty-seven patients with primary hypertension participated in this study. Fifteen received placebo and 12 received glycyrrhetinic acid (GRA; 500 mg) orally 2.5 h before the study. After a 10 min infusion of 5% glucose, cortisol was infused in stepwise increasing doses (0.625, 1.25 and 2.5 μg/kg per min), for 10 min each dose. At the end of each infusion step, RBF was measured using the xenon-133 washout technique. Plasma samples from the femoral artery and renal vein were taken for measurement of cortisol and cortisone. Urine was collected for measurement of steroid concentrations for 6 h on the day before the infusion and for 6 h after the infusion. Results After placebo or GRA, cortisol infusion did not change RVR, RBF or blood pressure. RVR values were 0.72 (0.45–0.89) mmHg/ml per min per 100 ml tissue [median (first and third quartiles)] and 0.71 (0.64–0.91) mmHg/ml per min per 100 ml tissue during infusion of 5% glucose and infusion of the highest dose of cortisol, respectively (P = NS). Cortisol infusion increased the venous–arterial difference in plasma cortisone concentration across the kidney from 76 (40–115) nmol/l to 138 (100–186) nmol/l (P< 0.05) and increased the cortisol : cortisone ratios in the renal vein and in urine (both P< 0.05). As compared with placebo, administration of GRA increased the cortisol : cortisone ratios in peripheral and renal veins and in the urine. Conclusion Acute infusion of cortisol in high doses directly into the renal artery in patients with primary hypertension did not affect RBF or RVR. Infusion of cortisol resulted in increased cortisol–cortisone conversion by renal 11β-HSD2, but the concurrent increase in renal and urinary cortisol : cortisone ratio suggests a relative insufficiency of renal 11β-HSD2 activity as a result of enzyme saturation. This may enhance mineralocorticoid receptor stimulation by cortisol.
To develop a state-of-the-art, computer-assisted intravital microscopy protocol to evaluate directly the effects of topically applied drugs on conjunctival arteriolar and venular diameters.Fifty-one normotensive volunteers were studied. Video-recordings of the bulbar conjunctival microcirculation were made before and following eye drops containing angiotensin II (AngII) (0.001% w/w, or 0.01%) or phenylephrine (0.25%). The computer-assisted analyses of arteriolar and venular diameters were performed off-line. In different protocols the microvascular reactivity to the different eye drops were compared.AngII (0.01%) eye drops, but not AngII (0.001%), induced significant constriction in both arterioles (median, 19%) and venules (13%). Phenylephrine eye drops (pharmacological control) induced similar arteriolar (18%) and venular (12%) constrictions. Repeated AngII challenges with a 30-min interval revealed reproducible vasoconstriction responses (median arteriolar constriction, 11 and 17%, respectively; NS). The vasoconstriction responses following AngII challenges on two consecutive days revealed reproducible responses (median arteriolar constriction, 13 and 11%, respectively; NS).The present results demonstrate that the proposed model for noninvasive intravital video-microscopy of the conjunctival microcirculation is sensitive for measuring direct arteriolar and venular reactivity following topically applied drugs. We consider this model a valuable tool for sophisticated research on in-vivo microvascular reactivity in humans.
It is largely unknown to what extent genetic abnormalities contribute to the development of atherosclerotic renal artery disease. Among the potential candidate genes, those of the renin-angiotensin system and the endothelial nitric oxide synthase (eNOS) rank high because of their importance in the atherosclerotic process. We investigated the association of polymorphisms in these genes (the angiotensinogen Met235Thr, the angiotensin-converting enzyme insertion/deletion, the angiotensin II type-1 receptor A1166C, and the eNOS Glu298Asp) with the presence or absence of atherosclerotic renovascular disease in 456 consecutive hypertensive patients referred for renal angiography on the suspicion of renovascular hypertension. Nondiseased normotensive (n=200) and hypertensive (n=154) patients from a family practice served as external controls. Renal artery disease was present in 30% of our angiography group. The Asp allele of the eNOS Glu298Asp polymorphism was associated with atherosclerotic renal artery stenosis with an odds ratio of 1.44 (95% confidence interval 1.00 to 2.09) versus hypertensives with angiographically proven patent arteries, of 1.89 (1.24 to 2.87) versus hypertensive family practice controls, and of 2.09 (1.29 to 3.38) versus normotensive family practice controls. However, this allele also differed significantly between patients with patent renal arteries and normotensive and hypertensive controls. No differences were found with respect to the other genetic polymorphisms. We hypothesize that the Asp allele of the Glu298Asp polymorphism may predispose to the development of atherosclerotic lesions but that renal artery involvement depends on other factors, also.
