Expression of multiple alpha1-adrenoceptors on vascular smooth muscle: correlation with the regulation of contraction.
(17/1299)
Previous work has shown that the genes encoding each alpha1-adrenoceptor subtype are coexpressed throughout the peripheral vascular system. We have evaluated subtype-selective antibodies as tools to determine the extent of protein expression in arteries. The alpha1A-, alpha1B-, and alpha1D-adrenoceptors were detected in the medial layer of the aorta, caudal, femoral, iliac, renal, superior mesenteric, and mesenteric resistance arteries. In Rat1 fibroblasts expressing each subtype, immunoreactivity was noted both on the cell surface and in a perinuclear orientation. Intense alpha1B-adrenoceptor immunostaining was similarly localized in cultured femoral and renal vascular smooth muscle cells. Although the cellular localization appeared to be the same, immunoreactivity obtained with alpha1A- and alpha1D-adrenoceptors was much less intense than that with the alpha1B-adrenoceptor. The alpha1A-adrenoceptor selective agonist A-61603 was 22-fold more potent in activating renal artery contraction when compared with the femoral artery. The expression of each alpha1-adrenoceptor was significantly decreased by in vivo application of antisense oligonucleotides targeted against each subtype. Inhibition of the expression of only one, the alpha1A in renal and the alpha1D in femoral arteries, reduced the contractile response to naphazoline. The results show: 1) subtype-selective antibodies can be used in tissues and cell culture to localize the alpha1-adrenoceptor subtypes, 2) in addition to expression on the cell surface, the alpha1-adrenoceptors are expressed intracellularly, and 3) despite expression of all adrenoceptors, a single subtype mediates the contractile response in the femoral and renal arteries. (+info)
Preservation of renal function by percutaneous transluminal angioplasty in ischaemic renal disease.
(18/1299)
BACKGROUND: The purpose of this study was to evaluate the effects of percutaneous transluminal renal angioplasty (PTRA) on preservation of renal function in patients with bilateral renal artery stenoses or stenosis of the artery of one functioning kidney. METHODS: A total of 227 PTRAs of 223 stenoses in 135 patients were performed from 1982 to 1993 in a single centre and retrospectively reviewed. The number of PTRAs per patient was 1.7, range 1-6. Angiographical follow-up was performed in 77%, 120+/-82 days after the first PTRA and 273+/-345 days after the last PTRA. Follow-up of serum creatinine and blood pressure was performed in 85% after 414+/-558 days. Long-term follow-up was performed for dialysis, surgical revascularization, renal transplantation and death, mean follow-up 8.8 years, range 5.5-14.8. RESULTS: The immediate technical success was 90%, and another 5% were improved. The primary patency rate per patient was 43% and the secondary patency rate 64%. Improved renal function was achieved in 23% of the patients, stabilized in 56% and failed in 21%. Stabilized or improved function was higher when baseline serum creatinine was < or =250 micromol/l (85%) than >250 micromol/l (60%). Three of 99 (3%) patients with creatinine < or =250 micromol/l started dialysis during follow-up (41 days, 7.4 and 8 years), as did 13 of 36 (36%) patients with creatinine >250 micromol/l. Blood pressure and the number of antihypertensive drugs decreased in patients with creatinine < or =250 micromol/l, but was unchanged in those with creatinine >250 micromol/l. The 5-year survival rates were 84, 66 and 17% for patients with creatinine <125 micromol/l, 125-250 micromol/l and >250 micromol/l, respectively. Twelve patients (9%) experienced complications, including two deaths. CONCLUSIONS: Our study shows that PTRA improved or preserved the renal function in most patients with normal to moderately impaired renal function. Close follow-up and possibly re-intervention are necessary to obtain satisfactory clinical and angiographical result. (+info)
Noninvasive evaluation of a novel swine model of renal artery stenosis.
(19/1299)
Intrarenal hemodynamics and excretory function distal to renal artery stenosis are difficult to quantify noninvasively. In this study, a swine model of chronic unilateral renal artery stenosis, achieved by implantation of an intravascular device that leads to a gradual and progressive luminal area narrowing, was developed and evaluated. Bilateral cortical and medullary volumes, blood flows, and segmental tubular dynamics were assessed in the intact kidneys of seven pigs using electron-beam computerized tomography before and 1 mo after implantation of the device. Within 1 mo, a 66% angiographic stenosis was significantly correlated with a 25% increase in BP. The volume and blood flow were markedly lower in the stenotic compared with the contralateral kidney and cortex, while the medulla exhibited minimal changes. In the stenotic kidney, intratubular contrast content has decreased in all nephron segments, especially in the distal tubule, where it correlated with an increase in serum creatinine and stenosis severity. In the contralateral kidney, dilution of proximal tubular fluid correlated with the increase in BP, likely due to pressure-natriuresis. In conclusion, the swine model closely resembles human renovascular hypertension. In the stenotic kidney, the hemodynamic impairment of the cortex is dissociated from the relatively preserved renal medulla, and the earliest effect on excretory function is observed in the distal nephron, where the fall in the amount of fluid reaching that segment is directly proportional to the renal arterial compromise. Electron-beam computerized tomography shows promise to noninvasively quantify, follow-up, and study changes in concurrent, in vivo intrarenal hemodynamics and segmental tubular function in renovascular hypertension. (+info)
In vivo and in vitro evidence of blood-brain barrier transport of a novel cationic arginine-vasopressin fragment 4-9 analog.
(20/1299)
The blood-brain barrier (BBB) transport and metabolism of a novel arginine-vasopressin fragment 4-9 [AVP(4-9), isoelectric point; (pI) = 9.2] analog, that is, cationic AVP(4-9) (C-AVP(4-9), PI = 9.8), were examined in vivo and in vitro. At 45 min after an i.v. administration to mice, the cerebrum-to-plasma concentration ratios of (35)S-labeled AVP(4-9) and (125)I-labeled C-AVP(4-9) were 0.103 and 0.330 ml/g cerebrum, respectively, and the BBB permeation clearances were 1.47 x 10(-4) and 3.10 x 10(-4) ml/min/g cerebrum, respectively. In the in vitro study using mouse brain capillary endothelial cells immortalized by SV40 infection (MBEC4), the acid-resistant binding values of (35)S-labeled AVP(4-9) and (125)I-labeled C-AVP(4-9) to MBEC4 at 120 min were 0.93 and 1.95 microliter/mg protein (as the cell/medium ratios), respectively. (35)S-labeled AVP(4-9) showed two-phase saturable acid-resistant binding, and its half-saturation constants (K(D)) were 3.8 nM (high affinity) and 45.7 microM (low affinity). (125)I-labeled C-AVP(4-9) showed single-phase saturable acid-resistant binding, with a K(D) value of 16.4 microM. The acid-resistant binding of (125)I-labeled C-AVP(4-9) was significantly dependent on temperature and medium osmolarity. The acid-resistant binding of (125)I-labeled C-AVP(4-9) was inhibited by dancylcadaverine, phenylarsine oxide (endocytosis inhibitors), 2,4-dinitrophenol (a metabolic inhibitor), and AVP(4-9), poly(L-lysine), and protamine (cationic substances), but not by poly(L-glutamic acid) (an anionic peptide) and the V(1) and V(2) vasopressin receptor antagonists. In addition, the conversion of C-AVP(4-9) to AVP(4-9) in the cerebral homogenate was confirmed by HPLC and mass spectrometry. The present results demonstrate that C-AVP(4-9) is transported through the BBB more effectively than AVP(4-9), via absorptive-mediated endocytosis, and that C-AVP(4-9) is converted to the neuroactive parent peptide, AVP(4-9), in the cerebrum. (+info)
The course of the remnant kidney model in mice.
(21/1299)
The remnant kidney model was produced in mice by unilateral nephrectomy and partial infarction of the remaining kidney. Control mice underwent laparotomy only. The mice were studied for up to 44 weeks. No quantitative differences were noted in systolic arterial pressure, proteinuria, or histopathology between control mice and those with a remnant kidney. Glomerular enlargement occurred in the remnant kidney. (+info)
Potent antihypertrophic effect of the bradykinin B2 receptor system on the renal vasculature.
(22/1299)
BACKGROUND: Angiotensin type 1 (AT1) receptor-deficient mice (Agtr1-/-), which selectively lack both AT1A and AT1B receptor genes, are characterized by marked intrarenal vascular thickening. In the present study, we explored the possible involvement of the kinin-kallikrein system in the development of this renal vascular hypertrophy. METHODS: Wild-type and Agtr1-/- mice were examined for the developmental regulation pattern of the kinin-kallikrein system and treated with aprotinin (a kallikrein inhibitor), AcLys [D-b Nal7, Ile8] des-Arg9-bradykinin (a bradykinin B1 receptor antagonist), or Hoe-140 (a bradykinin B2 receptor antagonist) from 3 to 14 days of age. RESULTS: The normal postnatal up-regulation of kininase II was organ-specifically suppressed in Agtr1-/- kidneys at 2 and 3 weeks of age. Immunohistochemical staining in Agtr1-/- mice revealed tissue kallikrein staining along the nephron from connecting tubules to cortical collecting tubules in proximity to the hypertrophic vasculature, whereas tissue kallikrein staining was confined to connecting tubules in wild-type mice. Aprotinin and Hoe-140 accelerated the vascular hypertrophy significantly as determined by wall thickness ratio, whereas B1 receptor antagonism had no effect. CONCLUSION: The kinin-kallikrein system in the Agtr1-/- mouse kidney is functionally activated by local suppression of kininase II and extensive redistribution of kallikrein to perivascular areas. This activation, specific to the kidney, serves to dampen a development of the marked vascular hypertrophy. These results demonstrate, to our knowledge for the first time, the antihypertrophic effect of the bradykinin B2 receptor system on the renal vasculature in vivo. (+info)
The heterogeneity of vascular findings in the kidneys of patients with benign essential hypertension.
(23/1299)
As the interlobular arteries of the ageing kidney progressively accumulate intimal fibroplasia, these fibroplastic changes appear to introduce strictures upon the interlobular arteries. These strictures are expected to generate nephron heterogeneity, which is a uniquely disturbed setting peculiarly suited to sustaining both high and low renin forms of hypertension. Fibroplastic renovasculopathy accumulates with age at varying rates in different human populations, and these rates closely parallel the rise of blood pressure with age, as documented by community surveys. Here, I introduce the expression type 1 for hypertension in subjects with mild or minimal renovasculopathy, and type 2 for those with severe vasculopathy. Data reviewed here imply that variations in prevailing blood pressure levels between populations can be attributed entirely, or almost entirely, to type 2 hypertension. No practical test is available to detect nephron heterogeneity clinically. Tests for this purpose have not been and are not now in development. The reason for this deficiency is probably the general lack of suspicion regarding the existence of this pathological entity. Once the entity becomes the target of attention, a variety of tests for measuring its severity in clinical patients should follow readily. (+info)
Quantification of conversion and degradation of circulating angiotensin in rats.
(24/1299)
The aim of the present study was to quantify with a uniform technique the rates of conversion of ANG I to ANG II in the lung and kidney and the degradation of both peptides to biologically inactive products in the pulmonary, renal, and systemic circulation. We infused the peptides intravenously, into the left ventricle, and into the left renal artery of rats and compared their effects on renal blood flow. The measured change in renal blood flow was used as a bioassay parameter to estimate the concentration of circulating ANG II. Mathematical analysis of our data allowed us to calculate conversion and degradation rates. Furthermore, the role of aminopeptidases A (EC 3.4.11.7) and N (EC 3.4.11.2) in the degradation of the peptides in the kidney was investigated by intrarenal infusion of the inhibitor amastatin. Our results show that the conversion rate of ANG I is 75% in the pulmonary and 21% in the renal circulation. Both peptides are degraded by 5% in the pulmonary, by 67% in the systemic, and by 93% in the renal circulation. Amastatin prevented 60% of the renal degradation of the peptides to inactive products, and this effect could be attributed to inhibition of aminopeptidase N. The results indicate that the converting capacity of the kidney is of minor importance for endocrine generation of ANG II but could be useful for the paracrine production. (+info)