Intrarenal site of action of calcium on renin secretion in dogs.
We studied the effects of intrarenal calcium infusion on renin secretion in sodium-depleted dogs in an attempt to elucidate the major site of calcium-induced inhibition of renin release. Both calcium chloride and calcium gluconate reduced renal blood flow and renin secretion while renal perfusion pressure was unchanged. These data indicate that calcium inhibition of renin secretion did not occur primarily at the renal vascular receptor; decreased renal blood flow is usually associated with increased renin secretion. Calcium chloride infusion increased urinary chloride excretion without affecting sodium excretion, and calcium gluconate failed to increase either sodium or chloride excretion. Also, the filtered loads of sodium and chloride were unchanged during the calcium infusions. These results give no indication that calcium inhibited renin secretion by increasing the sodium or chloride load at the macula densa. The effects of intrarenal calcium infusion on renin release were also assessed in dogs with a nonfiltering kidney in which renal tubular mechanisms could not influence renin secretion. The observation that calcium still suppressed renin release in these dogs provides additional evidence that the the major effect of calcium involved nontubular mechanisms. Thus, it appears likely that calcium acted directly on the juxtaglomerular cells to inhibit renin secretion. (+info
Vascular remodeling in response to altered blood flow is mediated by fibroblast growth factor-2.
Vascular structures adapt to changes in blood flow by adjusting their diameter accordingly. The factors mediating this process are only beginning to be identified. We have recently established a mouse model of arterial remodeling in which flow in the common carotid artery is interrupted by ligation of the vessel near the carotid bifurcation, resulting in a dramatic reduction in vessel diameter as a consequence of inward remodeling and intimal lesion formation. In the present study, we used this model to determine the role of fibroblast growth factor-2 (FGF-2) in the remodeling response by maintaining neutralizing serum levels of a mouse monoclonal antibody against FGF-2 for 4 weeks. Morphometric analysis revealed that intimal lesion formation was not affected by the antibody. However, lumen narrowing was significantly inhibited, resulting in a greater than 3-fold increase in lumen area in anti-FGF-2-treated animals compared with controls. Treatment with anti-FGF-2 antibody significantly inhibited the reduction in vessel diameter (inward remodeling) and shortening of the internal elastic lamina in the ligated vessel. In addition, anti-FGF-2 treatment also caused outward remodeling of the contralateral carotid artery. These findings identify FGF-2 as an important factor in vascular remodeling, and its effects are likely to be mediated by increasing vascular tone. The results are consistent with the recent observation of reduced vascular tone in the FGF-2-deficient mouse. (+info
Role of endothelin in the increased vascular tone of patients with essential hypertension.
We investigated the possible role of endothelin in the increased vasoconstrictor tone of hypertensive patients using antagonists of endothelin receptors. Forearm blood flow (FBF) responses (strain-gauge plethysmography) to intraarterial infusion of blockers of endothelin-A (ETA) (BQ-123) and endothelin-B (ETB) (BQ-788) receptors, separately and in combination, were measured in hypertensive patients and normotensive control subjects. In healthy subjects, BQ-123 alone or in combination with BQ-788 did not significantly modify FBF (P=0.78 and P=0.63, respectively). In hypertensive patients, in contrast, BQ-123 increased FBF by 33+/-7% (P<0.001 versus baseline), and the combination of BQ-123 and BQ-788 resulted in a greater vasodilator response (63+/-12%; P=0.006 versus BQ-123 alone in the same subjects). BQ-788 produced a divergent vasoactive effect in the two groups, with a decrease of FBF (17+/-5%; P=0.004 versus baseline) in control subjects and transient vasodilation (15+/-7% after 20 minutes) in hypertensive patients (P<0.001, hypertensives versus controls). The vasoconstrictor response to endothelin-1 was slightly higher (P=0.04) in hypertensive patients (46+/-4%) than in control subjects (32+/-4%). Our data indicate that patients with essential hypertension have increased vascular endothelin activity, which may be of pathophysiological relevance to their increased vascular tone. In these patients, nonselective ETA and ETB blockade seems to produce a greater vasodilator effect than selective ETA blockade. (+info
Bronchial artery perfusion scintigraphy to assess bronchial artery blood flow after lung transplantation.
The bronchial arterial system is inevitably interrupted in transplanted lungs when removing the organs from the donor, but it can be reestablished by direct bronchial artery revascularization (BAR) during implantation. The purpose of this study was to visualize and quantify the distribution of bronchial artery perfusion after en bloc double lung transplantation with BAR, by injecting radiolabeled macroaggregated albumin directly into the bronchial artery system. METHODS: BAR was performed using the internal mammary artery as conduit. Patients were imaged 1 mo (n = 13) or 2 y (n = 9) after en bloc double lung transplantation with BAR. Immediately after bronchial arteriography, 100 MBq macroaggregated albumin (45,000 particles) were injected through the arteriographic catheter. Gamma camera studies were then acquired in the anterior position. At the end of imaging, with the patient remaining in exactly the same position, 81mKr-ventilation scintigraphy or conventional intravenous pulmonary perfusion scintigraphy or both were performed. Images were evaluated by visual analysis, and a semiquantitative assessment of the bronchial arterial supply to the peripheral parts of the lungs was obtained with conventional pulmonary scintigraphy. RESULTS: The bronchial artery scintigraphic images showed that the major part of the bronchial arterial flow supplied central thoracic structures, but bronchial artery perfusion could also be demonstrated in the peripheral parts of the lungs when compared with conventional pulmonary scintigraphy. There were no differences between scintigrams obtained from patients studied 1 mo and 2 y post-transplantation. CONCLUSION: Total distribution of bronchial artery supply to the human lung has been visualized in lung transplant patients. This study demonstrates that this nutritive flow reaches even the most peripheral parts of the lungs and is present 1 mo as well as 2 y after lung transplantation. The results suggest that bronchial artery revascularization may be of significance for the long-term status of the lung transplant. (+info
Pulsed Doppler ultrasonographic evaluation of portal blood flow in dogs with experimental portal vein branch ligation.
Portal blood flow was measured using pulsed Doppler ultrasound in 6 dogs before and after left portal vein branch ligation. Mean portal vein blood flow velocity and mean portal vein blood flow were significantly reduced after ligation and the congestion index was increased (p < 0.01). Pulsed Doppler ultrasound studies provide valuable physiological information which may assist the clinician with the diagnosis of canine hepatic circulatory disorders. (+info
Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF.
Diabetes is a major risk factor for coronary and peripheral artery diseases. Although diabetic patients often present with advanced forms of these diseases, it is not known whether the compensatory mechanisms to vascular ischemia are affected in this condition. Accordingly, we sought to determine whether diabetes could: 1) impair the development of new collateral vessel formation in response to tissue ischemia and 2) inhibit cytokine-induced therapeutic neovascularization. Hindlimb ischemia was created by femoral artery ligation in nonobese diabetic mice (NOD mice, n = 20) and in control C57 mice (n = 20). Hindlimb perfusion was evaluated by serial laser Doppler studies after the surgery. In NOD mice, measurement of the Doppler flow ratio between the ischemic and the normal limb indicated that restoration of perfusion in the ischemic hindlimb was significantly impaired. At day 14 after surgery, Doppler flow ratio in the NOD mice was 0.49+/-0.04 versus 0.73+/-0.06 for the C57 mice (P< or =0.005). This impairment in blood flow recovery persisted throughout the duration of the study with Doppler flow ratio values at day 35 of 0.50+/-0.05 versus 0.90+/-0.07 in the NOD and C57 mice, respectively (P< or =0.001). CD31 immunostaining confirmed the laser Doppler data by showing a significant reduction in capillary density in the NOD mice at 35 days after surgery (302+/-4 capillaries/mm2 versus 782+/-78 in C57 mice (P< or =0.005). The reduction in neovascularization in the NOD mice was the result of a lower level of vascular endothelial growth factor (VEGF) in the ischemic tissues, as assessed by Northern blot, Western blot and immunohistochemistry. The central role of VEGF was confirmed by showing that normal levels of neovascularization (compared with C57) could be achieved in NOD mice that had been supplemented for this growth factor via intramuscular injection of an adenoviral vector encoding for VEGF. We conclude that 1) diabetes impairs endogenous neovascularization of ischemic tissues; 2) the impairment in new blood vessel formation results from reduced expression of VEGF; and 3) cytokine supplementation achieved by intramuscular adeno-VEGF gene transfer restores neovascularization in a mouse model of diabetes. (+info
Sonographic evidence for the involvement of the utero-ovarian counter-current system in the ovarian control of directed uterine sperm transport.
Sperm transport from the cervix into the tube is an important uterine function within the process of reproduction. This function is exerted by uterine peristalsis and is controlled by the dominant ovarian structure via a cascade of endocrine events. The uterine peristaltic activity involves only the stratum subvasculare of the myometrium, which exhibits a predominantly circular arrangement of muscular fibres that separate at the fundal level into the fibres of the cornua and continue into the circular muscles of the respective tubes. Since spermatozoa are transported preferentially into the tube ipsilateral to the dominant follicle, this asymmetric uterine function may be controlled by the ovary via direct effects utilizing the utero-ovarian counter-current system, in addition to the systemic circulation. To test this possibility the sonographic characteristics of the uterine vascular bed were studied during different phases of the menstrual cycle. Vaginal sonography with the measurement of Doppler flow characteristics of both uterine arteries and of the arterial anastomoses of the uterine and ovarian arteries (junctional vessels) in the cornual region of both sides of the uterus during the menstrual phase of regular-cycling women demonstrated significant lower resistance indices of the junctional vessels ipsilateral to the side of the dominant ovarian structure as compared with the corresponding arteries contralaterally. By the use of the perfusion mode technique, it could be observed that vascular perfusion of the fundal myometrium was significantly increased ipsilateral to the dominant follicle during the late follicular phase of the cycle. These results show that the endocrine control of the dominant ovarian structure over uterine function is not only exerted via the systemic circulation but also directly, most probably utilizing the utero-ovarian counter-current system. (+info
Endothelial function in Marfan syndrome: selective impairment of flow-mediated vasodilation.
BACKGROUND: The cardiovascular complications of Marfan syndrome arise due to alterations in the structural and functional properties of fibrillin, a constituent of vascular connective tissues. Fibrillin-containing microfibrils are closely associated with arterial endothelial cells, indicating a possible functional role for fibrillin in the endothelium. Plasma concentrations of endothelial cell products are elevated in Marfan subjects, which indirectly indicates endothelial dysfunction. This study directly assessed flow- and agonist-mediated endothelium-dependent brachial artery reactivity in Marfan subjects. METHODS AND RESULTS: In 20 Marfan and 20 control subjects, brachial artery diameter, blood flow, and blood pressure were measured by ultrasonic wall tracking, Doppler ultrasound, and photoplethysmography, respectively. Measurements were taken during hand hyperemia (a stimulus for endothelium-derived nitric oxide [NO] release in the upstream brachial artery) and after sublingual administration of the endothelium-independent vasodilator nitroglycerin. In 9 Marfan and 6 control subjects, the above parameters were also assessed during intra-arterial infusions of acetylcholine and bradykinin (agonists that stimulate NO production) and NG-monomethyl-L-arginine (L-NMMA, an inhibitor of NO production). Flow-mediated responses differed markedly between Marfan and control subjects (-1.6+/-3.5% versus 6. 50+/-4.1%, respectively; P<0.0001), whereas nitroglycerin produced similar vasodilation (14.2+/-5.7% versus 15.2+/-7.8%; P=NS). Agonist-induced vasodilation to incremental intra-arterial infusions of acetylcholine and bradykinin were not significantly different between Marfan and control subjects, and intra-arterial L-NMMA produced similar reductions in brachial artery diameter in both groups. CONCLUSIONS: These data demonstrate impaired flow-mediated but preserved agonist-mediated endothelium-dependent vasodilation in Marfan subjects and suggest preservation of basal NO release. Selective loss of flow-mediated dilation suggests a role for fibrillin in endothelial cell mechanotransduction. (+info