Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hyperpolarization of most blood vessels occurs by the opening of K(Ca) channels. 1-Ethyl-2-benzimidazolinone (1-EBIO) is a direct activator of K(Ca) channels in epithelial cells and is potentially valuable for studying cellular hyperpolarization. This study reports the effects of 1-EBIO on isolated rat mesenteric beds perfused with normal (4.7 mM), or high (20 or 80 mM) K+ physiological salt solution (PSS) and constricted with an alpha1-adrenoceptor agonist, cirazoline (0.3-1 microM). Arterial perfusion pressures were decreased by 1-EBIO (0.1-30 nmol) in a dose- and endothelium-dependent manner. Infusion of penitrem A (100 nM), a maxi-K+ channel blocker, or apamin (0.5 microM), a small-conductance (SK(Ca)) K+ channel blocker, produced significant increases in cirazoline-mediated tone (mm Hg): 103.3 +/- 8.7 (control) vs. 156.3 +/- 14.3 (penitrem A); or 93.0 +/- 15.8 (control) vs. 114.0 +/- 15.4 (apamin). 1-EBIO relaxations were attenuated by penitrem A, while apamin, dendrotoxin (50 nM; a Kv channel antagonist), or ouabain (100 microM; a sodium pump blocker) failed to alter the responses. I-EBIO-mediated relaxations decreased significantly with increasing extracellular [K+]: relaxations to 30 nmol were 89.3% +/- 3.2% (4.7 mM K+, normal PSS) vs. 59.5% +/- 3.4% and 19.0% +/- 3.9% for 20 and 80 mM K+ PSS, respectively. Nomega-nitro-L-arginine-methyl ester (L-NAME; 100 microM), and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 microM), selective inhibitors of nitric oxide synthase, and nitric oxide-sensitive guanylate cyclase, respectively, abolished 1-EBIO relaxations in vessels perfused with 20 or 80 mM K+ PSS. We conclude that: (1) maxi-K+ and SK(Ca) channels are present in rat mesenteric arterial vessels and actively contribute to vascular tone, (2) vasodilator action of 1-EBIO involves the opening of endothelial maxi-K+ channels and nitric oxide synthesis.
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PMID:1-Ethyl-2-benzimidazolinone stimulates endothelial K(Ca) channels and nitric oxide formation in rat mesenteric vessels. 1049 1

We investigated the vasorelaxation in renal arteries isolated from spontaneously hypertensive rats (SHRs) fed a basal, a high-salt, or a high-cholesterol diet for 8 weeks. In renal arterial rings from the control group, acetylcholine (ACh)-induced endothelium-dependent relaxations were markedly increased by indomethacin (IND) and ONO-3708, a prostaglandin H2/thromboxane A2-receptor antagonist, but not affected by OKY-046, a thromboxane A2 synthetase inhibitor. These increased relaxations were partially inhibited by either NG-nitro-L-arginine methyl ester (L-NAME) or charybdotoxin (CTX), and almost completely abolished by the combination of L-NAME plus CTX. The ACh-induced endothelium-dependent relaxations in the absence of IND were significantly attenuated by the high-salt intake but not affected by the high-cholesterol intake. The degrees of relaxations in the presence of IND were approximately equal among the three diet groups. On the other hand, the relaxations in the presence of IND plus L-NAME were significantly augmented by a high-cholesterol intake and abolished by a high-salt intake, and the relaxations in the presence of IND plus CTX were slightly reduced by a high-cholesterol intake and significantly augmented by a high-salt intake. The production of cyclic guanosine monophosphate (cGMP) in response to ACh was significantly decreased by a high-cholesterol intake and tended to be increased by a high-salt intake. These findings indicate that in the renal artery of SHRs, ACh causes production of a sufficient amount of nitric oxide (NO), together with a relaxing factor resembling endothelium-derived hyperpolarizing factors (EDHFs) and also endothelium-derived contracting factors (EDCFs), probably prostaglandin H2. Our results also suggest that excessive salt intake increases the release of EDCF and NO and decreases that of an EDHF-like factor, whereas excessive cholesterol intake increases release of an EDHF-like factor and decreases that of NO.
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PMID:Excessive salt or cholesterol intake alters the balance among endothelium-derived factors released from renal arteries in spontaneously hypertensive rats. 1051 Nov 28

In spontaneously hypertensive rats, ouabain exerts an excitatory effect on baroreceptor nerve activity (BNA). The aim of this study was to determine the effects of ouabain on BNA in other experimental models of hypertension and its interaction with nitric oxide. Rats were made hypertensive using the procedures for N(omega)-nitro-L-arginine methyl ester (L-NAME), deoxycorticosterone acetate (DOCA) salt, and 2-kidney, 1 clip (2K1C) hypertension models. In these groups, systolic arterial pressure was 195+/-7, 149+/-6, and 148+/-4 mm Hg, respectively, compared with 110+/-4 mm Hg in normotensive rats. Acute ouabain administration had an excitatory effect on BNA in normotensive rats (37+/-4%), an inhibitory effect in L-NAME hypertensive rats (-60+/-7%), and no effect in DOCA-salt and 2K1C hypertensive rats. The effects of ouabain were not related to arterial pressure levels, and no excitatory effect on BNA was observed in prehypertensive DOCA-salt rats. Long-term administration of L-arginine (3 g x kg(-1) x day(-1)) prevented DOCA-salt (121+/-8 mm Hg) and 2K1C (104+/-4 mm Hg) hypertension, markedly attenuated L-NAME (130+/-9 mm Hg) hypertension, and restored the excitatory effect of ouabain on BNA in these groups to levels similar to the normotensive rats and their respective control groups. We conclude that ouabain has a diverse effect on BNA in experimental models of hypertension, and it can be normalized by L-arginine. The data also indicate that nitric oxide may play a pivotal role in mediating the excitatory effect of ouabain on BNA, and we speculate that a therapeutic combination of ouabain and L-arginine may be beneficial in secondary hypertension.
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PMID:L-arginine restores the effect of ouabain on baroreceptor activity and prevents hypertension. 1052 50

Endothelin-1 (ET-1) is overexpressed in the vascular wall in certain models of experimental hypertension: deoxycorticosterone acetate salt-treated rats, deoxycorticosterone acetate salt-treated spontaneously hypertensive rats (SHR), stroke-prone SHR, Dahl salt-sensitive rats, angiotensin II-infused rats, and 1-kidney 1 clip Goldblatt rats; it is not overexpressed in SHR, 2-kidney 1-clip hypertensive rats, or L-NAME-treated rats. In hypertensive rats without generalized vascular overexpression, however, expression of ET-1 was often enhanced in intramyocardial coronary arteries, suggesting a role of endothelin in myocardial ischemia in hypertension. In rats overexpressing ET-1, ET(A/B) and ET(A)-selective receptor antagonists lowered blood pressure and reduced vascular growth, particularly in small arteries, beyond what could be attributed to blood pressure lowering, suggesting a direct effect of ET-1 on growth. Hypertensive rats treated with endothelin antagonists are protected from stroke and renal injury. The ET(A/B) antagonist bosentan induced blood-pressure reductions in mildly hypertensive patients similar to those achieved with an angiotensin-converting enzyme inhibitor. Moderately to severely hypertensive patients presented with enhanced expression of prepro-ET-1 mRNA in the endothelium of subcutaneous resistance arteries, suggesting that these stages of hypertension may respond particularly well to endothelin antagonism. Hypertensive patients with coronary artery disease have increased arterial expression of ET-1, and increased plasma levels of immunoreactive endothelin have been described in black patients. ET-1 plays an important role in atherosclerosis, for which hypertension is an important risk factor. Thus, ET-1 may be involved in experimental and human hypertension. Endothelin antagonists may prove effective as disease-modifying agents if they are shown clinically, as they are experimentally, to offer target organ protection and reduce long-term complications of hypertension. This remains to be demonstrated in humans.
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PMID:State-of-the-Art lecture. Role of endothelin-1 in hypertension. 1052 77

1. To explore the role of nitric oxide (NO) in the regulation of the renin-angiotensin system (RAS) in Dahl salt-sensitive (DS) rats, the effects of NG-nitro-L-arginine methyl ester (L-NAME) on plasma renin activity (PRA), and concentrations of angiotensin (Ang)I and AngII in the plasma, aorta and kidney were investigated in DS and Dahl salt-resistant (DR) rats. 2. NG-Nitro-L-arginine methyl ester (12-18 mg/kg per day) administration for 1 week increased mean arterial pressure (MAP) in DS and DR rats fed a 0.3% NaCl diet and in DR rats fed an 8% NaCl diet compared with corresponding vehicle (water)-treated groups. However, L-NAME administration did not change MAP in DS rats fed an 8% NaCl diet. 3. NG-Nitro-L-arginine methyl ester administration increased PRA in DS rats fed an 8% NaCl diet, but not in DR rats fed an 8% NaCl diet. NG-Nitro-L-arginine methyl ester administration increased AngI and AngII concentrations in plasma, aorta and kidney only in DS rats fed an 8% NaCl diet. The ratio of AngI to AngII did not change following L-NAME administration in any rats. 4. These results suggest that NO has an inhibitory role on renin release in DS rats fed a high-salt diet.
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PMID:Inhibitory effect of nitric oxide on the renin-angiotensin system in Dahl salt-sensitive rats. 1056 14

The kidney function plays a crucial role in the salt-induced hypertension of genetically salt-sensitive, hypertension-prone rats. We have previously reported that renal xanthine oxidoreductase (XOR) activity is increased in hypertension-prone rats, and even more markedly in salt-induced experimental hypertension. XOR is an enzyme involved in purine metabolism, converting ATP metabolites hypoxanthine and xanthine to uric acid. Because the possible involvement of XOR in nitric oxide metabolism has gained recent interest, we determined renal XOR activity after treating spontaneously hypertensive rats (SHRs), kept on different salt intake levels (0.2, 1.1 and 6.0% of NaCl in the chow), for three weeks with a nitric oxide synthase (NOS) inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME, 20mg/kg/d). L-NAME treatment induced renal XOR activity by 14 to 37 % (P<0.001), depending on the intake level of salt. Increased salt intake was no more able to aggravate L-NAME induced hypertension, but it did further increase the renal XOR activity (p<0.05). Treatment of SHRs with a nitric oxide donor, isosorbide-5-mononitrate (60-70 mg/kg/d for 8 weeks), markedly attenuated the salt-enhanced hypertension without a clear effect on renal XOR activity. Thus, the results indicate that the NO concentration needed to inhibit XOR is supra-physiological, and suggest that renal NO production is not impaired in the SHR model of hypertension.
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PMID:Inhibition of nitric oxide synthase induces renal xanthine oxidoreductase activity in spontaneously hypertensive rats. 1062 77

Work in our laboratory has focused on the role of nitric oxide synthase (NOS) in the regulation of renal medullary function. Biochemical studies demonstrated that the renal medulla is enriched in immunoreactive NOS protein and NOS enzymatic activity when compared with the renal cortex. Further experiments showed large amounts of NOS activity in the inner medullary collecting ducts, while moderate NOS activity was found in glomeruli and vasa recta and minimal NOS activity was detected in other nephron segments examined. In subsequent functional studies, selective renal medullary infusion of NOS stimulators (bradykinin or acetylcholine) or inhibitors (L-NAME) preferentially altered medullary blood flow. The alterations in medullary flow were associated with parallel changes in sodium and water excretion. Similar to the effects observed in anaesthetized rats, chronic infusion of L-NAME directly into the renal medullary interstitial space of conscious, uninephrectomized SD rats selectively decreased renal medullary blood flow throughout a 5-day L-NAME infusion period. The decrease in medullary blood flow was associated with retention of sodium and the development of hypertension, and the effects were reversible. In contrast to the effects of chronic NOS inhibition, renal medullary infusion of NOS substrate L-arginine prevented the development of sodium-sensitive hypertension in the Dahl salt-sensitive rat placed on a high sodium diet. The data reviewed in this paper indicate that NOS isoforms expressed in the renal medulla have a potent influence on renal medullary tubular and vascular function with consequential effects on fluid and electrolyte homeostasis and arterial blood pressure.
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PMID:Control of arterial blood pressure and renal sodium excretion by nitric oxide synthase in the renal medulla. 1069 93

We analyzed the effects of a possible interaction between nitric oxide deficiency and mineralocorticoids on the long-term control of blood pressure and renal and endocrine variables. Six groups of uninephrectomized male Wistar rats were used: control animals and rats that received (1) N(G)-nitro-L-arginine methyl ester (L-NAME) subpressor (0.5 mg/100 mL drinking fluid), (2) L-NAME pressor (35 mg/100 mL drinking fluid), (3) deoxycorticosterone acetate (DOCA; 12. 5 mg/wk per rat), (4) DOCA plus L-NAME subpressor, or (5) L-NAME pressor plus DOCA. For all groups, the drinking fluid was tap water or 1% NaCl solution. We measured the time course of tail systolic blood pressure (SBP) and body weight for 3 weeks in all rats. At the end of the experimental period, we measured mean arterial pressure (direct recording) and endocrine and renal variables. Tail SBP rose significantly in the DOCA plus L-NAME subpressor-treated group but remained at normotensive levels in the DOCA-treated group. The addition of L-NAME to the subpressor dose accelerated the blood pressure increase in DOCA-salt hypertensive rats. The simultaneous administration of DOCA and L-NAME increased blood pressure and mortality rates in rats that drank water or saline compared with the rats treated with L-NAME alone. The subpressor dose of L-NAME did not increase blood pressure in saline-drinking rats. We conclude that impaired NO synthesis results in increased sensitivity to the pressor effect of mineralocorticoids in the presence or absence of an increased saline intake. Hence, nitric oxide contributes to the adaptative response to mineralocorticoid excess, perhaps through the facilitation of natriuresis and, thus, control of blood pressure.
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PMID:Interaction between nitric oxide and mineralocorticoids in the long-term control of blood pressure. 1072 May 90

Isolated spiral strips of rat thoracic aorta with endothelium were suspended for isometric tension recordings in a physiological salt solution. Endothelium-dependent vasorelaxation was elicited by carbachol 10(-6) and 10(-5) mol litre-1 during norepinephrine-induced contractions, and the effects of 1.5% and 3% halothane were evaluated with concomitant measurement of [Ca2+]i using fura-2-Ca2+ fluorescence. The effects of halothane on endothelium-dependent relaxation were compared with those of nitro G-L-arginine methyl ester 10(-4) mol litre-1 (L-NAME: an inhibitor of nitric oxide synthase). Carbachol reduced norepinephrine-induced contractions in a concentration-dependent manner, but augmented the norepinephrine-induced increase in [Ca2+]i in endothelium intact strips. In contrast, carbachol did not influence muscle tension or [Ca2+]i when the endothelium was completely denuded. Although 3% halothane and L-NAME 10(-4) mol litre-1 inhibited carbachol-induced vasorelaxation in a similar manner, halothane inhibited carbachol-induced increases in [Ca2+]i. These results indicate that halothane inhibited a carbachol-induced increase in [Ca2+]i in the endothelium, which subsequently attenuated the decrease in muscle tension.
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PMID:Halothane attenuates the endothelial Ca2+ increase and vasorelaxation of vascular smooth muscle in the rat aorta. 1074 55

The role of the endothelin-B receptor (ET(B)) in vascular homeostasis is controversial because the receptor has both pressor and depressor effects in vivo. Spotting lethal (sl) rats carry a naturally occurring deletion in the ET(B) gene that completely abrogates functional receptor expression. Rats homozygous for this mutation die shortly after birth due to congenital distal intestinal aganglionosis. Genetic rescue of ET(B)(sl/sl) rats from this developmental defect using a dopamine--hydroxylase (DBH)-ET(B) transgene results in ET(B)-deficient adult rats. On a sodium-deficient diet, DBH-ET(B);ET(B)(sl/sl) and DBH-ET(B);ET(B)(+/+) rats both exhibit a normal arterial blood pressure, but on a high-sodium diet, the former are severely hypertensive. We find no difference in plasma renin activity or plasma aldosterone concentration between salt-fed wild-type, DBH-ET(B);ET(B)(+/+) or DBH-ET(B);ET(B)(sl/sl) rats, and acute responses to intravenous L-NAME and indomethacin are similar between DBH-ET(B);ET(B)(sl/sl) and DBH-ET(B);ET(B)(+/+) rats. Irrespective of diet, DBH-ET(B);ET(B)(sl/sl) rats exhibit increased circulating ET-1, and, on a high-sodium diet, they show increased but incomplete hypotensive responses to acute treatment an ET(A)-antagonist. Normal pressure is restored in salt-fed DBH-ET(B);ET(B)(sl/sl) rats when the epithelial sodium channel is blocked with amiloride. We conclude that DBH-ET(B);ET(B)(sl/sl) rats are a novel single-locus genetic model of severe salt-sensitive hypertension. Our results suggest that DBH-ET(B);ET(B)(sl/sl) rats are hypertensive because they lack the normal tonic inhibition of the renal epithelial sodium channel.
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PMID:Salt-sensitive hypertension in endothelin-B receptor-deficient rats. 1074 72


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