Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine may be a physiological modulator of vascular smooth muscle tone, sympathetic neurotransmission, renin release, and renal and cardiac function. To facilitate the elucidation of the physiological role of adenosine, a microassay for adenosine was developed that allows accurate quantitation of adenosine in 75 microliters of rat plasma, thus permitting multiple determinations of plasma adenosine levels in an individual rat without inducing hemodynamic perturbations due to blood loss. The technique employs a simple and rapid extraction of plasma with a reverse-phase Sep-Pak cartridge and exploits the increased mass sensitivity of microbore high performance liquid chromatography. The assay was verified by demonstrating a linear relationship between the amount of adenosine added to plasma and the amount detected by the assay, a linear relationship between the rate of adenosine infusion into rats and plasma adenosine levels, and the absence of measurable adenosine levels in plasma incubated with adenosine deaminase. The mean arterial plasma level of adenosine in the anesthetized rat was determined to be 119 +/- 28 (SD) ng/ml (n = 10). With the use of this assay, renal venous plasma levels of adenosine were found to be elevated sixfold in two-kidney, one clip Goldblatt hypertensive rats (1 week postclipping) compared with sham-operated controls. Given the known effects of adenosine on renin release, these data support a role for endogenous adenosine as a regulator of renin release in renovascular hypertension.
Hypertension 1987 Aug
PMID:Development and application of a simple microassay for adenosine in rat plasma. 330 66

In previous studies we identified an afferent renal nerve-dependent pressor reflex elicited by acute unilateral renal artery stenosis (50% decrease in renal blood flow) in conscious, instrumented rats with reduced responsiveness of arterial baroreceptor reflexes and the renin-angiotensin system. The pressor reflex involves a neurogenic increase in peripheral resistance. The present study examined the nature of the intrarenal stimulus underlying this renal pressor reflex. Rats were subjected to sinoaortic denervation and, 7 to 10 days later, were chronically instrumented with Doppler flow probes on the right renal artery, superior mesenteric artery, and abdominal aorta and with an occluder on the right renal artery. Following surgical recovery and inhibition of the renin-angiotensin system (captopril), animals received intravenous isotonic saline, 6% of body weight over 60 minutes. Saline infusion did not alter baseline hemodynamics, vascular neurogenic tone, or responsiveness to tyramine, but it attenuated the reflex by 70%. A second series of experiments examined a possible role for intrarenal prostaglandins, kinins, or adenosine in the activation of renal sensory receptors during renal stenosis. Prostaglandin inhibition with intravenous administration of indomethacin and meclofenamate virtually abolished the reflex in the face of enhanced tyramine responsiveness, whereas kallikrein inhibition (aprotinin) attenuated the reflex pressor response by 33%. Adenosine inhibition with aminophylline or adenosine deaminase had no effect on the reflex; these agents and aprotinin did not affect vascular neuroeffector responsiveness (tyramine). The data suggest that the renal pressor reflex may be mediated by renal sensory nerves, possibly chemoreceptors, whose activation could depend on renal excretory function and synthesis of prostaglandins and kinins.
Hypertension 1987 Nov
PMID:Role of prostaglandins and kinins in the renal pressor reflex. 366 64

Adenosine-sensitive nerve endings have been found in the renal pelvis which when stimulated increase sympathetic activity producing hypertension. When urinary adenosine concentration is lowered by intrarenal infusion of adenosine deaminase in one-kidney one-clip rats, peripheral sympathetic nervous system activity and arterial pressure decrease if the renal nerves are intact. These data suggest that a stimulus for afferent renal nerve activity in one-kidney, one-clip hypertension is intrarenal adenosine. This intrarenal adenosine hypertensive reflex was examined further observing the responses to renal pelvic xylocaine infusion, selective renal deafferentation, adrenal demedullation and spinal cord transection (T6). The intrarenal adenosine hypertensive reflex was interrupted by renal pelvic xylocaine infusion, renal deafferentation and adrenal demedullation in normotensive and one-kidney, one-clip hypertensive animals. The intrarenal adenosine hypertensive reflex persisted after spinal cord transection (T6). These data support the concept that adenosine-sensitive intact afferent renal nerves located in the renal pelvis enhance sympathoadrenal activity resulting in the maintenance of one-kidney, one-clip hypertension and that this intrarenal adenosine-hypertensive response may occur as a spinal-level reflex in the rat.
 ...
PMID:Afferent renal nerves and hypertension. 367 53

The afferent renal nerves enhance sympathetic activity in the one-kidney, one-clip hypertensive rat. We have also found adenosine-sensitive nerve endings in the renal pelvis that, when stimulated, increase sympathetic activity producing hypertension. To determine whether adenosine, which is excreted when renal blood flow is reduced, activates the afferent renal nerves in one-kidney, one-clip hypertension, urinary adenosine concentration was lowered by infusing adenosine deaminase into the renal artery. Urinary adenosine concentration was threefold greater in one-kidney, one-clip hypertensive animals compared with normotensive controls. Intrarenal infusion of adenosine deaminase in one-kidney, one-clip rats lowered urinary adenosine to an undetectable level and attenuated the hypertension. Both plasma norepinephrine levels and the fall in mean arterial pressure after ganglionic blockade decreased during intrarenal adenosine deaminase infusion in one-kidney, one-clip animals. Renal denervation in one-kidney, one-clip animals prevented the changes in mean arterial pressure and plasma norepinephrine levels during intrarenal adenosine deaminase infusion. In contrast to findings in hypertensive animals, intrarenal infusion of adenosine deaminase produced no change in arterial pressure in normotensive controls. These data indicate that urinary adenosine concentration is enhanced in one-kidney, one-clip hypertension and suggest that when urinary adenosine concentration is lowered, sympathetic activity and hypertension became attenuated in this model if the renal nerves are intact.
Hypertension
PMID:Intrarenal adenosine produces hypertension via renal nerves in the one-kidney, one clip rat. 399 36

Several endogenous factors generated within the vessel wall have been implicated in contributing to the vascular remodeling process associated with hypertension and atherosclerosis. Furthermore, substances generated by smooth muscle cells (SMCs) are known to regulate SMC proliferation in an autocrine fashion. Adenosine is a vasodilator synthesized by SMCs, and exogenous adenosine inhibits SMC proliferation. However, whether adenosine produced endogenously has antimitogenic effects is not known. Hence, we evaluated the effects of SMC-derived adenosine on 2.5% fetal calf serum-induced proliferation of rat aortic SMCs. SMC proliferation was assayed by measurement of DNA synthesis ([3H]thymidine incorporation) and cell counting. To determine the effects of endogenous adenosine on SMC proliferation, we stimulated growth-arrested SMCs with 2.5% fetal calf serum in the presence and absence of modulators of adenosine levels, including (1) erythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA; inhibits adenosine deaminase), (2) dipyridamole (blocks adenosine transport and inhibits phosphodiesterase), (3) dipyridamole plus EHNA, and (4) adenosine with or without EHNA. [3H]Thymidine incorporation and cell number were measured after 24 and 96 hours, respectively. EHNA and dipyridamole inhibited both FCS-induced DNA synthesis and cell proliferation in a concentration-dependent manner. Furthermore, extracellular (in medium) adenosine levels were significantly increased when cultured cells were treated with EHNA, and the inhibitory effects of dipyridamole as well as exogenous adenosine were enhanced in the presence of EHNA. Additionally, the inhibitory effects of dipyridamole and EHNA on DNA synthesis were significantly reduced in the presence of KF17837, an A2 adenosine receptor antagonist. These results indicate that SMC-derived adenosine can inhibit SMC proliferation. Hence, it is possible that a defect in localized adenosine synthesis within the vessel wall could contribute to vascular thickening and neointima formation.
Hypertension 1996 Mar
PMID:Smooth muscle cell-derived adenosine inhibits cell growth. 861 38

In this study we determined whether cAMP is metabolized to adenosine in vascular smooth muscle cells and whether cAMP-derived adenosine modulates vascular smooth muscle cell growth. Confluent smooth muscle cells were exposed to cAMP (0.01 to 30 mumol/L) in the presence and absence of 3-isobutyl-1-methylxanthine (IBMX, 1 mmol/L; an inhibitor of both extracellular and intracellular phosphodiesterase), alpha, beta-methyleneadenosine 5'-diphosphate (AMP-CP, 100 mumol/L; an ecto-5'-nucleotidase inhibitor), and 1,3-dipropyl-8-p-sulfophenyl-xanthine (DPSPX, 100 mumol/L; a xanthine that can inhibit extracellular phosphodiesterase) for 0 to 60 minutes. Medium was then sampled and assayed for AMP, adenosine, and inosine. cAMP increased the amount of AMP, adenosine, and inosine in the medium in a time- and concentration-dependent manner. The conversion of cAMP to adenosine and inosine was inhibited by blockade of phosphodiesterase with IBMX, of ecto-phosphodiesterase with DPSPX, and of ecto-5'-nucleotidase with AMP-CP. To evaluate the physiological relevance of cAMP-derived adenosine in vascular smooth muscle cell proliferation, we studied the inhibitory effects of cAMP (10(-4) mol/L) and 8-bromo-cAMP (10(-4) mol/L) on fetal calf serum-induced DNA synthesis ([3H]thymidine incorporation) in the presence and absence of erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA, an inhibitor of adenosine deaminase), dipyridamole (a blocker of adenosine transport), KF17837 (a selective A2 adenosine receptor antagonist), and DPSPX (a nonselective adenosine receptor antagonist). cAMP inhibited DNA synthesis, and both EHNA and dipyridamole enhanced this effect. Both KF17837 and DPSPX significantly reduced the inhibitory effects of cAMP on DNA synthesis; however, they did not reduce the inhibitory effects of 8-bromo-cAMP on DNA synthesis. These results indicate that vascular smooth muscle cells metabolize cAMP to adenosine via the sequential action of ecto-phosphodiesterase and ecto-5'-nucleotidase and provide the first evidence that cAMP-derived adenosine can inhibit vascular smooth muscle cell growth. Hence, this cAMP-adenosine pathway may importantly contribute to the regulation of vascular biology.
Hypertension 1996 Nov
PMID:Cyclic AMP-adenosine pathway inhibits vascular smooth muscle cell growth. 890 21

Adenosine mechanisms are altered in brain stem nuclei associated with cardiovascular control in spontaneously hypertensive rats (SHR). Therefore, in the present study we used a number of techniques to compare the binding of the adenosine transport inhibitor [3H]nitrobenzylthioinosine ([3H]NBMPR) as well as adenosine deaminase immunoreactivity (ADA-IR) in brain stems and nodose ganglia of SHR and age-matched normotensive Donryu rats (DRY). Saturation binding revealed a single class of [3H]NBMPR binding sites in the dorsal brain stem of both strains, with Kd and Bmax values of 65 +/- 9 pmol/L and 282 +/- 31 fmol/mg protein, respectively, in SHR and 129 +/- 2 pmol/L and 217 +/- 23 fmol/mg protein in DRY. The Kd for [3H]NBMPR was significantly lower in SHR than in DRY. In competition assays, NBMPR, dilazep, dipyridamole, and adenosine displaced [3H]NBMPR binding, with Kd values of 0.21 +/- 0.04, 57.16 +/- 16.20, 1340 +/- 100, and 87000 +/- 12500 nmol/L, respectively, in DRY and 0.17 +/- 0.04, 28.24 +/- 3.60, 621 +/- 100, and 32000 +/- 6820 in SHR. Kd values for all displacers were lower in SHR; however, only values for dipyridamole and adenosine reached statistical significance. Autoradiography of adenosine transport sites with [3H]NBMPR revealed that unilateral nodose ganglionectomy reduced [3H]NBMPR binding on the denervated side of the nucleus tractus solitarius by 20.6 +/- 1.1% in DRY and 18.7 +/- 2.3% in SHR. The density of [3H]NBMPR binding in nodose ganglia was significantly lower in SHR (0.99 +/- 0.06 Bq/mm2) than in DRY (1.25 +/- 0.08). Immunohistochemical studies demonstrated ADA-IR in the dorsal vagal complex, associated with both nerve cells and fibers. Measurement of ADA-IR in the dorsal vagal complex with an 125I-labeled secondary antibody revealed a significantly higher level of ADA-IR in SHR (122%) than in DRY. In the nodose ganglia, ADA-IR was associated with a population of vagal perikarya. The present study helps provide a molecular explanation for the previously reported impaired cardiovascular responses to intra-nucleus tractus solitarius microinjection of adenosine in hypertensive rats.
Hypertension 1996 Dec
PMID:Markers of adenosine removal in normotensive and hypertensive rat nervous tissue. 895 92

The objective of this study was to characterize the effects of exogenous and endogenous (cardiac fibroblast-derived) adenosine on [3H]proline and [3H]leucine incorporation, which are reliable markers of collagen and total protein synthesis, respectively, in rat left ventricular cardiac fibroblasts. Growth-arrested confluent cardiac fibroblast monolayers were stimulated with 2.5% fetal calf serum (FCS) in the presence and absence of adenosine, 2-chloroadenosine (stable adenosine analogue), or modulators of adenosine levels including (1) erythro-9-(2-hydroxy-3-nonyl) adenine (adenosine deaminase inhibitor), (2) dipyridamole (adenosine transport blocker), and (3) iodotubericidin (adenosine kinase inhibitor). All agents inhibited in a concentration-dependent fashion FCS-induced [3H]proline and [3H]leucine incorporation. These effects were blocked by KF17837 (selective A2 antagonist) and 1,3-dipropyl-8-(p-sulfophenyl)xanthine (A1/A2 receptor antagonist) but not by 8-cyclopentyl-1,3-dipropylxanthine (selective A1 antagonist), thus excluding the participation of A1 receptors. The lack of effect of CGS21680 (selective A2A agonist) excluded involvement of A2A receptors, thus suggesting a major role for A2B receptors. Comparisons of the inhibitory potencies of N6-cyclopentyladenosine (selective A1 agonist), 5'-N-ethylcarboxamidoadenosine (A1/A2 agonist), and 5'-N-methylcarboxamidoadenosine (A1/A2 agonist) were consistent with that of an A2B receptor subtype mediating the inhibitory effects. We conclude that adenosine inhibits FCS-induced collagen and total protein synthesis in cardiac fibroblasts via activation of A2B receptors. These studies suggest, but do not prove, that endogenous adenosine may protect against cardiac fibrosis.
Hypertension 1998 Apr
PMID:Adenosine inhibits collagen and protein synthesis in cardiac fibroblasts: role of A2B receptors. 953 19

Adenosine is an ubiquitously occurring endogenous nucleoside that via cell surface receptors exerts multiple antihypertensive actions, and mediates a number of biological responses that may reduce cardiovascular disease risk. Therefore modulation of endogenous levels of adenosine may offer beneficial effects in hypertension. The objective of this study was to determine whether inhibition of adenosine deaminase lowers blood pressure in spontaneously hypertensive rats (SHR). We investigated the effects of erythro-9-(2-hydroxyl-3-nonyl) adenine (EHNA), an adenosine deaminase inhibitor, on hemodynamic and renal parameters in 16-week-old and 36-week-old SHR and normotensive Wistar Kyoto rats (WKY) and in 36-week-old SHR and WKY pretreated with 1,3-dipropyl-8-p-sulfopheznylxanthine (DPSPX, an adenosine antagonist that does not enter the brain and is restricted to the extracellular space). Adenosine deaminase inhibition with EHNA (10 mg/kg, iv.) produced a marked fall in arterial blood pressure in older (MABP 162.0+/-7.6 mmHg and 120.7+/-11.7 mmHg for baseline and EHNA period, respectively; p<0.01), but not younger, SHR, whereas no effects on blood pressure were observed in age-matched normotensive WKY rats. EHNA did not affect renal hemodynamic and excretory function in any of six groups of animals. DPSPX blocked the antihypertensive effects of EHNA, suggesting that the effects of EHNA on blood pressure are mediated via peripheral adenosine receptors. Further studies are required to elucidate why inhibition of adenosine deaminase lowers blood pressure only in older SHR. The present data suggest that inhibition of adenosine deaminase may provide beneficial effects in older hypertensives and lead us to propose that design and use of extracellular adenosine deaminase inhibitors may offer cardiovascular protection in hypertension.
 ...
PMID:Effects of adenosine deaminase inhibition on blood pressure in old spontaneously hypertensive rats. 960 86

Previous studies have shown that chronic salt loading increased renal interstitial adenosine concentrations and desensitized renal effects of adenosine, a phenomenon that could facilitate sodium excretion. However, the mechanisms responsible for the increased adenosine production and decreased adenosine response are poorly understood. This study examined the effects of the dietary high salt intake on adenosine metabolism and receptor expression in the renal cortex and medulla in Sprague Dawley rats. Fluorescent high-performance liquid chromatography analyses were performed to determine adenosine levels in snap-frozen kidney tissues. Comparing rats fed a normal (1% NaCl) versus high salt (4% NaCl) diet, renal adenosine concentrations in rats fed a high salt diet were significantly higher (cortex: 43+/-3 versus 85+/-4, P<0.05; medulla: 183+/-4 versus 302+/-8 nmol/g wet tissue, P<0.05). Increased adenosine concentrations were not associated with changes in the 5'-nucleotidase or adenosine deaminase activity, as determined by quantitative isoelectric focusing and gel electrophoresis. Western blot analyses showed that a high salt diet (4% NaCl for 3 weeks) downregulated A1 receptors (antinatriuretic type), did not alter A2A and A2B receptors (natriuretic type), and upregulated A3 receptors (function unknown) in both renal cortex and medulla. The data show that stimulation of adenosine production and downregulation of A1 receptors with salt loading may play an important role in adaptation in the kidney to promote sodium excretion.
Hypertension 1999 Jan
PMID:Effect of chronic salt loading on adenosine metabolism and receptor expression in renal cortex and medulla in rats. 1060 Nov 39


1 2 3 4 Next >>