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)

The present experiments describe the endothelin-1 (ET-1) antagonist activity of BQ123 (cyclic D-Asp-L-Pro-D-Val-L-Leu-D-Trp) in conscious Sprague-Dawley (SD) rats, and we also examined the effect blockade of ETA receptors had on blood pressure in four experimental models of hypertension. Rats were anesthetized with methoxyflurane and instrumented with femoral arterial and venous catheters. In SD rats, BQ123 (0.1-10.0 mg/kg i.v.) administered 5 or 60 min prior to ET-1 inhibited both the magnitude and duration of the ET-1 (0.25 nmol/kg i.v.) pressor response. In addition, BQ123 (10.0 mg/kg) inhibited the pressor response evoked by administration of the ET-1 precursor, proendothelin-1 (1.0 nmol/kg). However, BQ123 (10.0 mg/kg) had no effect on the pressor response evoked by ET-3 (0.75 nmol/kg). In Wistar-Kyoto rats, BQ123 (10.0 mg/kg) reversed the hypertension produced by an infusion of ET-1 (0.01 nmol/kg/min). Administration of BQ123 produced a mild antihypertensive effect in normal- to low-renin models of hypertension, but no blood pressure lowering was observed in high-renin models of hypertension. These studies demonstrated the selectivity of the ETA receptor antagonist, BQ123 for ET-1, but not ET-3-induced pressor responses. Furthermore, ET-1 does not appear to be a major contributing factor to the maintenance of elevated levels of blood pressure in four experimental models of hypertension.
 ...
PMID:Pharmacologic characterization of an endothelinA (ETA) receptor antagonist in conscious rats. 128 97

Hypertension is the main side effect developing in patients suffering from renal anemia who are treated with recombinant human erythropoietin (rhEPO). We investigated the effect of rhEPO on the vascular tone of rabbit aorta. rhEPO had no direct vasoconstrictor effect, but it enhanced norepinephrine (NE)-induced contractions of rabbit aortic rings. Relaxations to acetylcholine (ACh, 1 microM) were unaltered in the presence or absence of rhEPO, indicating that the endothelium-dependent NO pathway was not affected by rhEPO. In rings of human renal artery and rabbit aorta, rhEPO (200 U/ml) increased the synthesis of constrictor prostanoids. The cyclooxygenase inhibitors indomethacin and aspirin abolished the increase in prostanoid production. However, they did not completely suppress the rhEPO-induced enhancement of NE contractions in rabbit aorta. We further investigated the effect of rhEPO on prostanoid and endothelin-1 synthesis in cultured human endothelial cells. Endothelial cells from human umbilical veins (HUVEC) were isolated and cultured. After incubation with rhEPO, the formation of prostaglandin (PG) I2 (analyzed as its stable metabolite 6-keto-PGF1 alpha), PGF2 alpha, PGE2, thromboxane (Tx) B2, and of endothelin-1 (ET-1) was measured by radioimmunoassay (RIA). rhEPO (200 U/ml) increased the formation of PGF2 alpha and TxB2 and decreased the formation of PGI2 in HUVEC. The release of ET-1 was increased by nearly 90% in the presence of rhEPO (200 U/ml). We conclude that a shift in the balance of constrictor and relaxing prostanoids as well as an increased synthesis of ET-1 may contribute to the hypertensive side effect of rhEPO therapy. ET-1 may at least in part be responsible for the unexpectedly low inhibitory effect of indomethacin on rhEPO-enhanced contractions of rabbit aorta.
 ...
PMID:Endothelin release and shift in prostaglandin balance are involved in the modulation of vascular tone by recombinant erythropoietin. 128 78

The vasoconstrictor effect, the binding, and the response of inositol phosphates to endothelin-1 (ET-1) were investigated in blood vessels of deoxycorticosterone acetate (DOCA)-salt hypertensive rats within 2 weeks of development of hypertension and in uninephrectomized control rats. In DOCA-salt and uninephrectomized rats, plasma levels of endothelin were similar (1.2 +/- 0.1 fmol/ml). Thoracic aorta and mesenteric artery rings devoid of endothelium presented significantly decreased responses to increasing concentrations of ET-1. Binding of ET-1 to mesenteric artery membranes was significantly lower in DOCA-salt rats (106 +/- 22 fmol/mg protein) than in uninephrectomized rats (172 +/- 19 fmol/mg protein, p less than 0.05), whereas affinity was similar. Phosphoinositide metabolism was examined in aorta and mesenteric arteries after incubation with [3H]myoinositol. Inositol phosphates were separated by high-performance liquid chromatography. In response to 100 nmol/l ET-1, accumulation of inositol 1,4,5-trisphosphate after 20 seconds and of inositol monophosphate, inositol bisphosphate, and inositol 1,3,4-triphosphate after 30 minutes (in the presence of 25 mmol/l LiCl) were significantly lower in DOCA-salt hypertensive than in uninephrectomized control rats, in both aorta and mesenteric arteries. In conclusion, decreased density of ET-1 receptors in DOCA-salt hypertensive rats results in decreased activation of phospholipase C and, consequently, reduced vasoconstriction induced by ET-1. Because the decrease in vasoconstrictor effects of ET-1 is found in the absence of endothelium, it is likely that receptor downregulation rather than prior receptor occupancy underlies these findings.
Hypertension 1992 Feb
PMID:Endothelin vascular receptors and responses in deoxycorticosterone acetate-salt hypertensive rats. 131 Apr 86

We examined the inhibitory effect of porcine C-type natriuretic peptide (CNP) on endothelin-1 secretion stimulated by thrombin and angiotensin II (Ang II) in cultured porcine endothelial cells. The results were compared with the effects of atrial (ANP) and brain (BNP) natriuretic peptides. Thrombin and Ang II produced a concentration-dependent stimulation of immunoreactive endothelin-1 secretion, and porcine CNP-22 potently inhibited this stimulated secretion in a concentration-dependent manner. CNP-22 had a stronger inhibitory effect than either porcine ANP(1-28) or porcine BNP-26. In addition, CNP potently increased the cellular level of cyclic guanosine 3',5'-monophosphate (GMP), with the inhibition of immunoreactive endothelin-1 secretion in response to thrombin and Ang II being paralleled by the increase in the cyclic GMP level. The increase of cyclic GMP produced by CNP was also greater than that due to porcine ANP(1-28) or porcine BNP-26. The immunoreactive endothelin-1 in the culture medium had two components on high-performance liquid chromatography; the major one corresponded to endothelin-1 (1-21) and the minor one to big endothelin-1 (porcine 1-39). Treatment with CNP did not affect this profile. Our results suggest that CNP probably inhibits the endothelin-1 secretion stimulated by thrombin and Ang II through a cyclic GMP-dependent process. The increase of cyclic GMP levels and the inhibition of immunoreactive endothelin-1 secretion produced by CNP appear to be greater than those produced by ANP or BNP.
Hypertension 1992 Apr
PMID:C-type natriuretic peptide inhibits thrombin- and angiotensin II-stimulated endothelin release via cyclic guanosine 3',5'-monophosphate. 131 93

In previous studies a decreased responsiveness to endothelin-1 (ET-1) of conduit arteries and resistance vessels of deoxycorticosterone acetate (DOCA)-salt hypertensive rats was found in comparison with uninephrectomized controls. Decreased isometric force, number of receptors, and inositol phosphate accumulation were reported in the DOCA-salt animals. In the present study effects of ET-1 on cytosolic free calcium, inositol phosphates, and 1,2-diacylglycerol were investigated in blood vessels of DOCA-salt hypertensive rats. Basal cytosolic free calcium, measured with the fluorescent dye fura-2, was 201 +/- 41 nmol/l in mesenteric arteries of DOCA-salt rats and 45 +/- 9 nmol/l in uninephrectomized controls (p less than 0.01). The maximal response of cytosolic free calcium (to 30 nmol/l ET-1) was 176 +/- 22% of the basal value for DOCA-salt and 242 +/- 6% for uninephrectomized rats (p less than 0.05). The concentration giving 50% of the maximum response was 9.0 and 6.5 nmol/l for DOCA-salt rats and controls, respectively. Inositol phosphate production after stimulation with 100 nmol/l ET-1 in the presence of LiCl was lower by at least 30% (p less than 0.01) in both aorta and mesenteric arteries of DOCA-salt hypertensive versus control rats. Basal levels of diacylglycerol in aorta were similar in DOCA-salt rats and in controls and did not respond to a 100 nmol/l ET-1 stimulation in the DOCA-salt rats, in contrast to the increase found in the control uninephrectomized rats (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1992 Jun
PMID:Calcium, phosphoinositide, and 1,2-diacylglycerol responses of blood vessels of deoxycorticosterone acetate-salt hypertensive rats to endothelin-1. 131 55

We investigated the regional balance of endothelin-1 across the renal and leg vascular bed as well as the hemodynamic effects of exogenously administered endothelin-1 in six healthy men. Net regional endothelin-1 balance was calculated from the respective arteriovenous differences in plasma concentrations and the corresponding plasma flow, the latter being determined by para-aminohippurate or indocyanine-green dye using appropriate catheter techniques. During constant intravenous (i.v.) infusion of endothelin-1 (0.4 pmol/kg/min), a slight increase in diastolic blood pressure (p less than 0.05) and a decrease in heart rate (p less than 0.01) were observed. In contrast, no significant changes in leg hemodynamics were noted. Renal plasma flow decreased by approximately 30%, and renal vascular resistance increased by 50% as compared with the control (placebo) period (p less than 0.01). Renin plasma concentrations did not change substantially during endothelin-1 infusion. During the control (placebo) period, arterial endothelin-1 plasma concentrations averaged 2.1 +/- 1.0 pM. An equilibrated peptide balance across the leg and a slight renal uptake of endothelin-1 was observed. After endothelin-1 infusion, arterial plasma concentrations of the peptide increased to 4.9 +/- 1.3 pM (p less than 0.01), and a net overall renal and limb uptake of endothelin-1 accounted for approximately 9 and 6% of the infused endothelin-1 amount, respectively. Results showed that at systemic endothelin-1 plasma concentrations, comparable to those which occur in a variety of pathologic conditions such as hypertension or cardiogenic shock, besides pulmonary clearance, renal and limb uptake of the peptide may also contribute to the short half-life (t1/2) of endothelin-1 in humans.
 ...
PMID:Regional hemodynamic effects and clearance of endothelin-1 in humans: renal and peripheral tissues may contribute to the overall disposal of the peptide. 137 85

Calcium antagonists are useful for the management of patients with ischaemic heart disease, particularly when used prophylactically. At the cellular level, these drugs act primarily by limiting calcium ion (Ca++) entry through the voltage-sensitive Ca(++)-selective channels, an effect that contributes markedly to their 'energy sparing' properties. However, the long term use of these drugs has additional advantages, particularly with respect to their ability to slow Ca(++)-dependent processes involved in the formation of atherogenic lesions, partially antagonise the effects of the raised levels of circulating endothelin-1 encountered during ischaemia-induced heart failure and hypertension, and trap and immobilise oxyradicals. Prolonged episodes of ischaemia result in an irreversible loss of homeostasis with respect to Ca++. However, the increase in myocardial cytosolic Ca++ caused by relatively short periods of ischaemia is small, reversible, and markedly attenuated by the prophylactic use of calcium antagonists. In the isolated, perfused rat heart, verapamil pretreatment produces statistically significant inhibition of the increase in cytosolic Ca++ during 20-minute global ischaemia. This stereospecific effect is associated with a decrease in the rise in total tissue Ca++ during reperfusion and amelioration of the adenosine triphosphate depletion caused by ischaemia. In general, discussion relating to the molecular basis of the use of calcium antagonists in the management of patients with ischaemic heart disease needs to take into account the duration of the ischaemic event, the workload on the myocardium, the need for prophylactic therapy, and the presence of exacerbating factors such as atherosclerosis and tobacco smoking. The early rise in cytosolic Ca++, the source of which remains uncertain, appears to be an important focus for anti-ischaemic drug therapy.
 ...
PMID:The molecular basis for the use of calcium antagonists in ischaemic heart disease. 137 84

Small arteries with a diameter of 200 microns or less play an important role in the regulation of peripheral vascular resistance. Dysregulation of vascular tone of these arteries may contribute significantly to high blood pressure. The contractile state of blood vessels is regulated by peripheral neurons, vascular smooth muscle, and the endothelium. In perfused mesenteric resistance arteries of the rat, removal of the endothelium markedly augments the sensitivity and maximal response to norepinephrine and endothelin-1. Acetylcholine causes profound endothelium-dependent relaxation of resistance arteries contracted with norepinephrine or endothelin-1. The potency of the muscarinic agonist is particularly pronounced with intraluminal application. The inhibitory effects of the endothelium against contractions induced by norepinephrine and endothelin-1 are reduced with aging and hypertension. The endothelium-dependent relaxation in response to intraluminal, but not extraluminal, acetylcholine is blunted in mesenteric resistance arteries of hypertensive rats and in the forearm circulation of hypertensive patients studied in vivo. The sensitivity of vascular smooth muscle to the effects of endothelin decreases with advancing age and in the spontaneously hypertensive rat. Thus, endothelium-derived vasoactive substances can profoundly affect vascular tone of resistance arteries studied in vitro and in vivo. The inhibitory effects of the endothelium against vasoconstrictor stimuli decreases with aging and hypertension, indicating a dysfunction of these regulatory mechanisms under these conditions.
 ...
PMID:Endothelium-dependent regulation of resistance arteries: alterations with aging and hypertension. 138 93

The enzymatic conversion of human big endothelins (1, 2, and 3) to their respective active metabolites (endothelin-1, -2, and -3) was investigated in the perfused rabbit kidney through the pressor- and eicosanoid-releasing properties of these peptides. Intra-arterial bolus injections of endothelin-1 and -2 (5-50 pmol), endothelin-3 (100-250 pmol), and big endothelin-1 and -2 (100-250 pmol) into the kidney produced dose-dependent increases of perfusion pressure, whereas big endothelin-3 was inactive at doses up to 1,000 pmol. Endothelin-1 and -2 (10 nM), endothelin-3 (100 nM), and big endothelin-1 and -2 (100 nM) are potent enhancers of prostacyclin release without inducing any release of thromboxane B2 in the perfused kidney. In contrast, big endothelin-3 did not trigger the release of eicosanoids. A metalloprotease inhibitor, phosphoramidon (100 microM, 60 minutes), reduced the prostanoid release and pressor responses induced by big endothelin-1 and -2 without affecting the response induced by endothelin-1, -2, and -3. These results suggest the presence of a phosphoramidon-sensitive endothelin converting enzyme that converts the precursors of endothelin-1 and -2, but not of endothelin-3, in the renal vasculature of the rabbit.
Hypertension 1992 Oct
PMID:Phosphoramidon-sensitive effects of big endothelins in the perfused rabbit kidney. 139 87

We have previously shown that renal vascular resistance is less in Dahl salt-sensitive rats than salt-resistant rats fed 1% NaCl diets; however, renal vascular resistance increases before nonrenal vascular resistance as salt-sensitive rats develop hypertension when fed 8% NaCl diets. When salt-resistant rats are given 8% NaCl diets, renal vascular resistance decreases. The current study reports effects of atrial natriuretic peptide, nitroprusside, norepinephrine, angiotensin II, and endothelin-1 on renal and nonrenal vascular resistance in prehypertensive salt-sensitive and salt-resistant rats given 1% NaCl diets; doses used did not affect blood pressure. Resistance of nonrenal vessels in salt-sensitive and salt-resistant rats responded similarly to dilators or constrictors. However, atrial natriuretic peptide and nitroprusside decreased renal vascular resistance of salt-resistant rats (by 65%, p less than 0.01) but not that of salt-sensitive rats. Norepinephrine, angiotensin II, and endothelin-1 increased renal vascular resistance in salt-sensitive rats by 126%, 135%, and 135%, respectively (p less than 0.01); norepinephrine and angiotensin II did not change renal vascular resistance of salt-resistant rats, but endothelin-1 decreased renal vascular resistance in salt-resistant rats by 30% (p less than 0.01). Reactivity of nonrenal blood vessels in prehypertensive salt-sensitive and salt-resistant rats was similar when infused with dilators or constrictors in doses used. By contrast, renal vessels of salt-sensitive rats did not dilate in response to atrial natriuretic peptide and nitroprusside but were hypersensitive to norepinephrine and angiotensin II. Endothelin-1 caused renal vasoconstriction in salt-sensitive rats and renal vasodilation in salt-resistant rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1992 Oct
PMID:Impaired renal vascular reactivity in prehypertensive Dahl salt-sensitive rats. 139 88


1 2 3 4 5 6 7 8 9 10 Next >>