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

We have evaluated the efficacy of SR 49059, a new orally active and specific vasopressin V1 receptor antagonist (arginine-vasopressin [AVP]), in the blockade of the vascular effects of exogenous AVP in healthy subjects. In preliminary experiments, two procedures to measure the V1 vascular effects of AVP were assessed. First, the AVP-induced changes in skin blood flow were investigated by the injection of increasing doses of AVP intradermally, with or without a previous local vasodilation with calcitonin gene-related peptide (CGRP). In a second protocol, AVP was infused intra-arterially, and the changes in radial artery diameter and blood flow were measured. The intradermal injection of AVP caused significant decreases in skin blood flow, and the use of CGRP increased the sensitivity of the method by a factor of 10(2) to 10(3). AVP infused intra-arterially caused dose-dependent decreases in the radial artery diameter and blood flow. In the main study, the potency and efficacy of SR 49059 to block the AVP-induced changes in skin blood flow were assessed in 12 healthy men with a double-blind, triple crossover study design. The subjects were randomized to receive a placebo orally and 30 mg and 300 mg of the antagonist at a 1-week interval. The subjects were then further randomized to evaluate the efficacy of the same doses of the antagonist to block the vasoconstriction of the radial artery induced by an intra-arterial infusion of AVP. SR 49059 inhibits, dose-dependently and significantly, the AVP-induced changes in skin blood flow, with a peak effect occurring between 2 and 6 hours after injection. In addition, the 300-mg dose of SR 49059 completely blocked the vasoconstriction of the radial artery induced by AVP. In conclusion, skin blood-flow measurement, after intradermal injection of AVP on a skin area vasodilated with CGRP, is an effective method to investigate the V1 vascular effect of AVP in humans. SR 49059 is a potent and specific antagonist of V1 receptors, which blocks the AVP-induced vasoconstriction.
Hypertension 1997 Nov
PMID:Effects of SR 49059, a new orally active and specific vasopressin V1 receptor antagonist, on vasopressin-induced vasoconstriction in humans. 936 65

1. We tested the hypothesis that the pattern and the intensity of autonomic mechanisms causing vasoconstriction in the resting bronchial circulation of awake dogs also exists in awake sheep. It was also postulated that sighing behaviour and the associated bronchovascular dilatation induced by non-adrenergic, non-cholinergic (NANC) mechanisms observed in the dog exist in sheep. 2. Bronchial arterial blood flow to lower airways of both lungs of awake sheep was measured continuously using pulsed Doppler flow probes mounted on the bronchial artery at prior thoracotomy. 3. Cumulative and factorial analysis of responses to randomized combinations of autonomic alpha 1-, alpha 2-, beta 1- and beta 2-adrenoceptors and cholinoceptor autonomic blockade suggests that resting vasoconstrictor activity is less in sheep than in dogs. At normal aortic pressure, the autonomic activity of these receptor groups in the sheep lowers bronchial blood flow and conductance by 30%, whereas in the awake dog, the corresponding autonomic effect is 50%. 4. Tonic autonomic control of bronchial conductance can be partitioned in sheep to show significant and separate alpha- and beta-adrenoceptor vasoconstrictor activity at a ratio of 1.8:1, an effect normally offset by a weaker vasodilator alpha-/beta-adrenoceptor interaction. In contrast to the situation in awake dogs, cholinoceptors do not play a role in awake sheep. 5. Nitric oxide (NO) synthase inhibition in sheep using NG-nitro-L-arginine following blockade of alpha- and beta-adrenoceptors and cholinoceptors causes hypertension, but minor changes, if any, in pulmonary pressures or heart rate. Bronchial flow and conductance, however, fall from a higher resting conductance by approximately 50%, suggesting that, normally, resting bronchial flow conductance is dominated by strong tonic NO vasodilator effects that interact with weaker tonic autonomic vasoconstrictor effects. 6. Superimposed (respiratory) behaviours of sighing, sneezing and coughing, which involve negative swings in intrathoracic pressure and the movement of inspired air, evoke large active bronchovascular dilator effects. These appear to be largely NANC in origin and appear to be dependent, in part, on mechanisms associated with NO release. It is postulated that the C-fibre axon reflex using substance P, calcitonin gene-related peptide and neurokinin A may be involved. Vocalization and eructation do not evoke bronchovascular effects.
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PMID:Autonomic control of bronchial circulation in awake sheep during rest and behaviour. 940 60

We previously demonstrated that the neuronal expression of calcitonin gene-related peptide (CGRP), a potent vasodilator, is increased in deoxycorticosterone-salt-induced hypertension where it acts as a compensatory vasodilator to attenuate the elevated blood pressure. To determine whether CGRP is playing a similar role in subtotal nephrectomy-salt-induced hypertension, hypertension was induced in Sprague-Dawley rats (n=6) by subtotal nephrectomy and 1.0% saline drinking water. Control rats (n=6) were sham operated and given tap water to drink. CGRP(8-37), a CGRP receptor antagonist, was used to assess the hemodynamic role of CGRP in this setting. CGRP mRNA and peptide levels in dorsal root ganglia were also determined. Three weeks after either protocol, all rats had intravenous (for drug administration) and arterial (for continuous mean arterial pressure monitoring) catheters surgically placed and were studied in the conscious, unrestrained state. CGRP(8-37) (3.2 or 6.4 x 10(4) pmol/L in 0.1 mL saline) and vehicle were administered intravenously to all rats. Baseline mean arterial pressure was higher in the subtotal nephrectomized rats compared with the controls (173+/-5 versus 113+/-5 mm Hg, P<.001). Vehicle administration did not change mean arterial pressure in either group, and CGRP(8-37) administration did not alter mean arterial pressure in the normotensive group. In contrast, CGRP(8-37) administration to the subtotal nephrectomized rats rapidly increased the already elevated mean arterial pressure at both the 3.2 x 10(4) pmol/L dose (7.8+/-1.1 mm Hg, P<.05) and the 6.4 x 10(4) pmol/L dose (9.6+/-0.8 mm Hg, P<.01). CGRP mRNA and peptide levels in the dorsal root ganglia were not significantly different between the two groups. These data suggest that in subtotal nephrectomy-salt-induced hypertension, CGRP may play a compensatory depressor role in an attempt to lower the elevated blood pressure.
Hypertension 1998 Jan
PMID:Calcitonin gene-related peptide is a depressor in subtotal nephrectomy hypertension. 945 34

Adrenomedullin (AM), a potent vasodilator peptide, exists in the cardiac ventricle; however, the role of AM in the ventricular tissue remains unknown. In the present study, we investigated the production and secretion of AM in cultured neonatal rat cardiomyocytes, and we examined the effect of AM on de novo protein synthesis in these cells by measuring [14C]phenylalanine incorporation. The cardiomyocytes cultured with serum-free media secreted AM into the media in a time-dependent manner at the rate of 12.2+/-0.5 fmol/10(5) cells/48 hours (mean+/-SEM). Angiotensin II (1 micromol/L) or 10% fetal bovine serum significantly (P<.01) increased the AM secretion by 115% and 305%, respectively. In addition, Northern blot analysis of total RNA extracted from the myocytes disclosed the expression of prepro-AM mRNA of 1.6 kb. Synthetic AM at 1 micromol/L significantly reduced the 10(-6) mol/L angiotensin II- and 10% fetal bovine serum-stimulated [14C]phenylalanine incorporation into the cells, by 16% (P<.05) and 20% (P<.01), respectively. The inhibitory effect of AM on the angiotensin II-stimulated [14C]phenylalanine incorporation was abolished dose-dependently by a calcitonin gene-related peptide receptor antagonist, CGRP(8-37). Furthermore, blockade of the action of endogenous AM by either 10(-6) mol/L CGRP(8-37) or anti-AM monoclonal antibody significantly enhanced the basal and 10(-6) mol/L angiotensin II-stimulated [14C]phenylalanine incorporation. In summary, cultured neonatal rat cardiomyocytes produce and secrete AM, and the secreted AM inhibits the protein synthesis of these cells. Thus, AM may act on cardiomyocytes as an autocrine or a paracrine factor modulating the cardiac growth.
Hypertension 1998 Jan
PMID:Adrenomedullin: a possible autocrine or paracrine inhibitor of hypertrophy of cardiomyocytes. 945 53

Adrenomedullin (ADM) is reported to be a peripherally acting hypotensive peptide, but its central actions are unclear. We investigated the effects of centrally administered ADM on blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) in conscious rats and sinoaortic-denervated (SAD) rats. We also investigated the receptors interacting with ADM using two putative antagonists. Intracerebroventricular administration of ADM in doses of 0.1 and 0.5 nmol/kg caused tachycardia and early inhibition of RSNA. Central ADM (1.0 nmol/kg) induced hypertension, tachycardia, and a decrease followed by an increase in RSNA. In SAD rats, increases in BP, HR, and RSNA at the late phase were enhanced by central ADM (1.0 nmol/kg), whereas the early decrease in RSNA remained. Thus the inhibition of RSNA via central ADM may be unrelated to the arterial baroreceptor reflex. Pretreatment with antagonists human calcitonin gene-related peptide-(8-37) and human ADM-(22-52) significantly suppressed the central actions of ADM. The findings suggest that ADM is involved as a neuropeptide in the receptor-mediated central regulation of the cardiovascular system and RSNA.
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PMID:Central actions of adrenomedullin on cardiovascular parameters and sympathetic outflow in conscious rats. 957 59

After spinal cord injury, hyper-reflexia can lead to episodic hypertension, muscle spasticity and urinary bladder dyssynergia. This condition may be caused by primary afferent fiber sprouting providing new input to partially denervated spinal interneurons, autonomic neurons and motor neurons. However, conflicting reports concerning afferent neurite sprouting after cord injury do not provide adequate information to associate sprouting with hyper-reflexia. Therefore, we studied the effect of mid-thoracic spinal cord transection on central projections of sensory neurons, quantified by area measurements. The area of myelinated afferent arbors, immunolabeled by cholera toxin B, was greater in laminae I-V in lumbar, but not thoracic cord, by one week after cord transection. Changes in small sensory neurons and their unmyelinated fibers, immunolabeled for calcitonin gene-related peptide, were assessed in the cord and in dorsal root ganglia. The area of calcitonin gene-related peptide-immunoreactive fibers in laminae III-V increased in all cord segments at two weeks after cord transection, but not at one week. Numbers of sensory neurons immunoreactive for calcitonin gene-related peptide were unchanged, suggesting that the increased area of immunoreactivity reflected sprouting rather than peptide up-regulation. Immunoreactive fibers in the lateral horn increased only above the lesion and in lumbar segments at two weeks after cord transection. They were not continuous with dorsal horn fibers, suggesting that they were not primary afferent fibers. Using the fluorescent tracer DiI to label afferent fibers, an increase in area could be seen in Clarke's nucleus caudal to the injury two weeks after transection. In conclusion, site- and time-dependent sprouting of myelinated and unmyelinated primary afferent fibers, and possibly interneurons, occurred after spinal cord transection. Afferent fiber sprouting did not reach autonomic or motor neurons directly, but may cause hyper-reflexia by increasing inputs to interneurons.
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PMID:Sprouting of primary afferent fibers after spinal cord transection in the rat. 962 43

1. A set-up for computerized acquisition and evaluation of haemodynamic data was constructed. Blood flow (BF) in the superior mesenteric and femoral artery of urethane-anaesthetized rats was measured with the ultrasonic transit time shift technique. The signals for arterial blood pressure and BF were fed into a personal computer via an analogue-digital converter. Mean arterial blood pressure, heart rate and vascular conductance (CV) were calculated on-line. For subsequent analysis of the data, algorithms were programmed to filter the data, and to determine average and peak values for each parameter. 2. Systemic hypertension induced by phenylephrine (3-300 nmol kg-1), angiotensin II (0.1-3.0 nmol kg-1) and arginine vasopressin (0.03-1.0 nmol kg-1) was accompanied by constriction of the mesenteric artery. In contrast, the femoral artery responded to phenylephrine with constriction, to angiotensin II with dilatation and to arginine vasopressin with dilation followed by constriction. The haemodynamic effects of endothelin-1 (0.03-3.0 nmol kg-1) were generally biphasic, the initial hypotension being associated with dilatation, and the delayed hypertension being accompanied by constriction of both the mesenteric and femoral arterial bed. 3. Terbutaline (3-1.0 nmol kg-1) and calcitonin gene-related peptide (0.03-1 nmol kg-1) caused systemic hypotension along with mesenteric and femoral vasodilatation. 4. Telmisartan (1 mg kg-1), an angiotensin AT1 receptor antagonist, dilated the mesenteric artery, but had no effect on femoral VC. In contrast, the alpha 1-adrenoceptor antagonist prazosin (0.1 mg kg-1), dilated the femoral artery without altering mesenteric VC. Similarly, the beta-adrenoceptor antagonist propranolol (1 mg kg-1) had no effect on mesenteric VC, but constricted the femoral arterial bed. 5. These data demonstrate that the haemodynamic effects of exogenously administered drugs can widely differ between the mesenteric and femoral arterial beds of urethane-anaesthetized rats. Furthermore, vascular tone of these two arterial beds in maintained by different vasoconstrictor systems. While the femoral artery is mainly under adrenergic control, the renin-angiotensin axis is predominant in the mesenteric arterial bed. In addition, this study also demonstrates that computerized analysis enables quick and accurate estimation of haemodynamic drug effects, and is superior to 'by hand' evaluation of peak changes in the functional diameter of the vascular bed under study.
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PMID:Differential regulation of mesenteric and femoral blood flow in the rat as revealed by computerized data acquisition and evaluation. 972 24

To test the novel hypothesis that neonatal degeneration of capsaicin-sensitive sensory nerves causes the rat to respond to a salt load with a significant and sustained rise in blood pressure, newborn Wistar rats were given 50 mg/kg capsaicin subcutaneously on the 1st and 2nd day of life. Control rats were treated with vehicle. Immediately after the weanling period, male rats were divided into 4 groups and fed different sodium diets for 2 weeks: capsaicin pretreatment plus high sodium diet (4%, CAP-HS), capsaicin plus normal sodium diet (0.5%, CAP-NS), control plus high sodium diet (CON-HS), and control plus normal sodium diet (CON-NS). Both tail-cuff systolic blood pressure and mean arterial pressure with anesthesia were significantly higher in CAP-HS than in CAP-NS, CON-HS, and CON-NS (P<0.05), but they were not different among the latter 3 groups. Radioimmunoassay revealed that levels of calcitonin gene related peptide in dorsal root ganglia were markedly decreased by capsaicin treatment (P<0.05). Twenty-four-hour urine volume and urine sodium excretion were significantly lower in CAP-HS than in CON-HS but were higher in CAP-HS and CON-HS compared with CAP-NS and CON-NS (P<0.05). Urine potassium excretion was not different among the 4 groups. Thus, this study provides the first evidence that neonatal degeneration of capsaicin-sensitive sensory nerves renders the rat salt-sensitive in terms of blood pressure regulation. Furthermore, our data suggest that neonatal capsaicin treatment may impair renal sodium and water excretion responses to high sodium intake. This model will provide a novel experimental paradigm for exploring underlying molecular mechanisms linked with salt-sensitive hypertension and sensory nerve function.
Hypertension 1998 Oct
PMID:Salt-sensitive hypertension induced by sensory denervation: introduction of a new model. 977 58

We recently reported that calcitonin gene-related peptide (CGRP) reversed the hypertension induced by nitric oxide inhibition in pregnant rats and that this effect appeared to be progesterone dependent. In the present study, we examined whether the vasodilator responses to CGRP are increased during pregnancy and whether these responses are steroid hormone dependent. Three groups of ovariectomized (Ovx) rats (n = 4-8 rats/group) were studied 3 days after daily treatment (subcutaneous injection) with progesterone (P; 2 mg/injection, twice daily for 3 days, in 0.2 ml of sesame oil), 17beta-estradiol (E; 2.5 microgram/injection, twice daily for 3 days, in 0.2 ml of sesame oil), or vehicle (sesame oil). A fourth group (n = 6 rats) of pregnant rats was studied on day 19 of gestation. A fifth group of adult, nonpregnant rats (n = 6 rats), regardless of stage of estrous cycle, was also used in this study. Mean arterial blood pressure (MAP) was continuously monitored in fully awake and free-moving instrumented rats. MAP was measured before and after administration of either saline or varying bolus doses of CGRP (9-360 pmol/kg body wt). CGRP produced a dose-dependent decrease in MAP in all rats with a significant (P < 0.05) reduction in MAP beginning with a CGRP dose of 90 pmol/kg and with maximal effects observed at 360 pmol/kg. Decreases in MAP in response to CGRP were significantly (P < 0.05) greater in pregnant compared with nonpregnant rats. Similarly to pregnant rats, Ovx rats given both E and P treatments produced greater decreases in MAP in response to CGRP at 90, 180, and 360 pmol/kg doses compared with both ovary-intact and Ovx nonpregnant rats, which were not different from each other. In summary, these data show that 1) the hypotensive effects of CGRP are dose dependent and 2) the hypotensive effects of CGRP are enhanced during pregnancy and in Ovx rats treated with either E or P. Therefore, we suggest that the decrease in vascular tone that is seen during pregnancy may be mediated, at least in part, by a sex steroid hormone-induced increase in the vascular sensitivity to the vasodilator effects of CGRP.
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PMID:Pregnancy and steroid hormones enhance the vasodilation responses to CGRP in rats. 988 42

Substance P and calcitonin gene-related peptide (CGRP) are colocalized in renal pelvic sensory nerves. Increasing renal pelvic pressure results in an increase in afferent renal nerve activity that is blocked by a substance P receptor antagonist but not by a CGRP receptor antagonist. CGRP potentiates the effects of substance P by preventing the metabolism of substance P. Therefore, we examined whether CGRP enhanced the afferent renal nerve activity responses to substance P and increased renal pelvic pressure, a stimulus known to increase substance P release. Combined administration of substance P and CGRP into the renal pelvis resulted in an increase in afferent renal nerve activity (1392+/-217%. s; area under the curve of afferent renal nerve activity versus time) that was greater (P<0.01) than that produced by substance P (620+/-156%. s) or CGRP (297+/-96%. s) alone. Likewise, CGRP enhanced the afferent renal nerve activity response to increased renal pelvic pressure. During renal pelvic administration of the neutral endopeptidase inhibitor thiorphan, the afferent renal nerve activity response to substance P plus CGRP was similar to that produced by either neuropeptide alone. Because these studies suggested that CGRP potentiated the afferent renal nerve activity responses to substance P, we examined whether the afferent renal nerve activity response to CGRP was blocked by a substance P receptor antagonist, RP67580. RP67580 blocked the afferent renal nerve activity response to CGRP by 85+/-12% (P<0.02). We conclude that CGRP activates renal pelvic sensory nerves by retarding the metabolism of substance P, thereby increasing the amount of substance P available for stimulation of substance P receptors.
Hypertension 1999 Jan
PMID:CGRP activates renal pelvic substance P receptors by retarding substance P metabolism. 993 Nov 54


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