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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Effects of a novel soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), were characterized on guanylyl cyclase activity in cytosolic fraction of COS-7 cells overexpressing the alpha 1 and beta 1 subunits of the rat soluble enzyme. ODQ was a noncompetitive inhibitor of soluble guanylyl cyclase with respect to Mn2+ or Mn(2+)-GTP and was a mixed competitive/noncompetitive inhibitor with respect to nitric oxide (NO) donation. ODQ (10 mumol/L) reduced deta nonoate-stimulated cGMP production in COS-7 cells overexpressing soluble guanylyl cyclase and in rat aortic vascular smooth muscle cells. ODQ did not inhibit particulate forms of the enzyme rat guanylyl cyclase-A, -B, or -C, did not block NO synthase, and did not auto-oxidize deta nonoate-donated NO in the presence of cells at physiological pH. Therefore, ODQ is a selective inhibitor of soluble guanylyl cyclase. Using ODQ in isolated aortic ring preparations, we tested the hypothesis that soluble guanylyl cyclase mediates vasorelaxant activity associated with NO. Phenylephrine (100 nmol/L)-precontracted, isolated rat aortas were relaxed in a concentration-dependent manner by deta nonoate (0.01 to 100 mumol/L) and nitroglycerin (0.01 to 300 mumol/L). ODQ (10 mumol/L) attenuated deta nonoate- and nitroglycerin-mediated relaxation of contracted aortas. ODQ had no effect on natriuretic peptide-, 8-bromo-cGMP-, isoproterenol-, or bimakalim-mediated aortic relaxation. These results support the hypothesis that soluble guanylyl cyclase mediates vasorelaxant activity associated with nitric oxide.
Hypertension 1997 Jan
PMID:Selective guanylyl cyclase inhibitor reverses nitric oxide-induced vasorelaxation. 903 11

We studied the effects of phenylephrine-stimulated proliferation and migration of vascular smooth muscle cells and the role of 12-lipoxygenase-mediated pathways under normal as well as high glucose conditions. Phenylephrine-induced increases in cellular proliferation and migration were attenuated by the specific 12-lipoxygenase inhibitor baicalein. In contrast, neither of the cyclo-oxygenase inhibitors, indomethacin or ibuprofen, had any effect. Direct addition of the 12-lipoxygenase product, 12-S-hydroxyeicosatetraenoic acid (12-HETE), increased the proliferation and migration of vascular smooth muscle cells treated with both phenylephrine and nordihydroguaiaretic acid. Furthermore, we observed that phenylephrine induced greater increases in the proliferation and migration of vascular smooth muscle cells and also that the 12-lipoxygenase inhibitor prevented the enhancement of proliferation and migration of vascular smooth muscle cells induced by phenylephrine in the presence of high glucose (25 mmol/l). These results suggest that 12-lipoxygenase activation plays a key role in phenylephrine-induced responses of vascular smooth muscle cells under normal and hyperglycemic conditions. 12-lipoxygenase may be a good pharmacological target for treatment of vascular disease of hypertension and diabetes mellitus.
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PMID:Role of the lipoxygenase pathway in phenylephrine-induced vascular smooth muscle cell proliferation and migration. 938 42

In situ expression of c-fos observed in response to phenylephrine (PE)-induced hypertension provided a basis for characterizing the organization and neurotransmitter specificity of neurons at nodal points of medullary baroreflex circuitry. Sustained hypertension induced by a moderate dose of PE provoked patterns of c-fos mRNA and protein expression that conformed in the nucleus of the solitary tract (NTS) to the termination patterns of primary baroreceptor afferents and in the caudal ventrolateral medulla (CVLM) to a physiologically defined depressor region. A majority of barosensitive CVLM neurons concurrently displayed markers for the GABAergic phenotype; few were glycinergic. Phenylephrine-sensitive GABAergic neurons that were retrogradely labeled after tracer deposits in pressor sites of the rostral ventrolateral medulla (RVLM) occupied a zone extending approximately 1.4 mm rostrally from the level of the calamus scriptorius, intermingled partly with catecholaminergic neurons of the A1 and C1 cell groups. By contrast, barosensitive neurons of the NTS were found to be phenotypically complex, with very few projecting directly to the RVLM. Extensive colocalization of PE-induced Fos-IR and markers for the nitric oxide phenotype were seen in a circumscribed, rostral, portion of the baroreceptor afferent zone of the NTS, whereas only a small proportion of PE-sensitive neurons in the NTS were found to be GABAergic. PE treatment parameters have been identified that provide a basis for defining and characterizing populations of neurons at the first station in the central processing of primary baroreceptor input and at a key inhibitory relay in the CVLM.
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PMID:Organization and transmitter specificity of medullary neurons activated by sustained hypertension: implications for understanding baroreceptor reflex circuitry. 941 14

Reduced clearance of insulin from plasma contributes to the hyperinsulinemia associated with essential hypertension (EH); however, the association between impaired insulin clearance and EH remains unexplained. Whether elevated blood pressure (BP) affects insulin clearance is unknown; therefore, we used the hyperinsulinemic euglycemic clamp to determine the effects of BP elevation on insulin clearance and sensitivity in eight healthy volunteers. Placebo infusion increased mean BP by 2.6+/-1.6 mm Hg, which was significantly less than rises produced by phenylephrine, an alpha1-adrenoceptor agonist (+11+/-1.8 mmHg, P<.05), or by angiotensin II (+13+/-1.3 mmHg, P<.01). Although beta-adrenoceptor stimulation with isoproterenol did not change mean BP (+3.6 mm Hg, P=NS), it significantly increased systolic pressure (+23+/-2.8 mm Hg versus +2.3+/-4.6 mm Hg with placebo P<.01). Insulin secretion (ie, C-peptide concentrations) was not affected by any of the treatments; however, phenylephrine significantly reduced the metabolic clearance rate of insulin (MCRinsulin) (16.6+/-1.0 mL/kg per minute with placebo versus 13.6+/-0.7 mL/kg per minute with phenylephrine, P<.01) and thereby increased plasma insulin concentrations (66+/-5.1 microU/mL with placebo versus 79+/-4.1 microU/mL with phenylephrine, P<.05). Phenylephrine also increased glucose utilization (42+/-5.8 micromol/kg per minute during placebo versus 58+/-4.8 micromol/kg per minute during phenylephrine, P<.05); however, this was proportional to the increased insulin concentrations; therefore, insulin sensitivity was unchanged. MCRinsulin and plasma insulin concentrations were not affected by angiotensin II; however, glucose utilization increased to 51+/-2.7 micromol/kg per minute (P<.01 versus placebo), indicating insulin sensitivity was increased. MCRinsulin was unaffected by isoproterenol. Thus, alpha-adrenergic stimulation but not increased BP per se is a potent regulator of insulin clearance and plasma insulin concentrations.
Hypertension 1998 Jan
PMID:Acute effects of blood pressure elevation on insulin clearance in normotensive healthy subjects. 944 99

Nitric oxide is an important regulator of vascular tone. Deficiencies in nitric oxide release have been implicated in hypertension. In the present study we evaluated vascular reactivity to phenylephrine and acetylcholine in isolated aorta ring preparations from sham and aortic coarctation-induced hypertensive rats and nitric oxide release under resting conditions and after stimulation with acetylcholine. Aortic vessels were divided in upper segment and lower segment in relation to the coarctation; both segments were tested for vascular reactivity and nitric oxide release. Phenylephrine produced higher vasoconstriction in upper segments from hypertensive rats compared to sham operated animals. Lower segments in both experimental groups were not significantly different. Relaxation produced by acetylcholine showed a higher EC50 in the upper segments from hypertensive rats; lower segments in both experimental groups were not significantly different. Aortic rings from hypertensive rats had a higher level of nitric oxide release compared to sham operated rats. Lower segments from hypertensive rats released significantly more nitric oxide. These results suggest that shear stress induced nitric oxide release in lower aortic segments from aortic coarctation-induced hypertensive rats.
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PMID:[The effect of aortic coarctation on nitric oxide production by the vascular endothelium]. 981 Mar 64

Both aging and hypertension decrease the responsiveness of several receptor systems. The purpose of this study was to investigate the effect of aging versus hypertension on the blood pressure (BP), heart rate, and left ventricular (LV) responses to the alpha1-agonist phenylephrine in humans. Fourteen young (age, 21-40 years; range, 30+/-1 years; mean +/- SEM), and 18 older (age, 50-73 years; range, 60+/-1 years) healthy volunteers, as well as 10 young (age, 30-39 years; range, 36+/-1 years) and 15 older (age, 50- 64 years; range, 58+/-1 years) hypertensive subjects were studied. Phenylephrine was administered at four incremental rates for 8 min each. Cardiac responses were assessed by echocardiography. Phenylephrine caused twofold larger increases in systolic BP in young and older hypertensives and older normotensives, compared with young normotensives, but similar decreases in heart rate in all four groups. Younger normotensive subjects exhibited the largest decreases in stroke volume index, ejection fraction, and cardiac index in response to phenylephrine, despite similar increases in end-systolic stress for all groups. There is an age- and hypertension-related decrease in reflex vagal restraint in response to alpha1-adrenoceptor stimulation in humans, which leads to significant attenuation of the decrease in heart rate as well as in LV function in response to a pressor stimulus, and presumably therefore to enhanced systolic BP responses relative to young normotensive subjects.
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PMID:Effects of age and hypertension on cardiac responses to the alpha1-agonist phenylephrine in humans. 1009 Mar 42

Insulin resistance, without frank diabetes, is associated with sudden cardiac death. We postulated that a potential mechanism for this association is autonomic dysfunction. Male Sprague-Dawley rats were randomized into one of two groups: (a) insulin resistant (IR; n = 15), or (b) control (n = 11). Animals were made insulin resistant with a fructose-rich diet, whereas control animals received standard rat chow. Four weeks after randomization, arterial pressure and baroreceptor reflex were assessed. Baroreflex sensitivity was defined as the heart-rate response to acute blood pressure changes caused by nitroprusside (0.5-18 micrograms) or phenylephrine (0.2-3 micrograms). To determine the role of vagal stimulation specifically, each animal was randomized to receive atropine sulfate (1 mg/kg) or vehicle (normal saline) before administration of phenylephrine. Mean arterial pressure and fasting insulin concentrations were increased in the insulin-resistant group, whereas there were no differences in body weight, fasting glucose concentrations, or resting heart rate. Phenylephrine increased arterial blood pressure to a maximum of 54 +/- 2 mm Hg for control and 45 +/- 6 mm Hg for IR, p = 0.7. The maximal heart-rate change response to the increased blood pressure was markedly blunted in IR as compared with control (-88 +/- 12 beats/min for IR vs. -238 +/- 18 beats/min for control; p < 0.001). Thus the baroreflex sensitivity (BRS) was threefold less in IR versus the control group (-1.8 +/- 0.2 vs. -4.6 +/- 0.7 beats/min/mm Hg; p = 0.001). Pretreatment with atropine sulfate decreased the BRS in both groups, eliminating the difference between groups (-0.96 +/- 0.5 beats/min/mm Hg for control and -0.56 +/- 0.3 beats/min/mm Hg for IR; p = 0.2). Thus atropine sulfate caused the phenylephrine-induced heart rate and arterial blood pressure response to be equal between groups. On the other hand, BRS to nitroprusside-induced blood pressure changes were similar between groups. Insulin resistance, without the confounding factors of obesity, diabetes, and significant hypertension, is associated with a large reduction in vagal activity, which occurs via attenuation in reflex activity. In contrast, the insulin-resistant syndrome does not affect baroreflex sensitivity via sympathetic reflex.
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PMID:Impaired vagal reflex activity in insulin-resistant rats. 1022 55

Reduction in uterine perfusion and the ensuing placental ischemia during late pregnancy have been proposed to trigger increases in systemic vascular resistance and pregnancy-induced hypertension; however, the intermediary mechanisms involved are unclear. The purpose of the present study was to test the hypothesis that reduced uterine perfusion pressure during late pregnancy is associated with impaired endothelium-dependent vascular relaxation and, consequently, enhanced systemic vascular reactivity. Active stress was measured in aortic strips isolated from late pregnant Sprague-Dawley rats and a hypertensive pregnant rat model produced through the long-term reduction in uterine perfusion pressure (RUPP). Phenylephrine (Phe, 10(-5) mol/L) caused an increase in active stress to 4.5+/-0.4x10(3) N/m(2) in normal pregnant rats and a larger increase to 9.4+/-0. 7x10(3) N/m(2) in RUPP rats. Removal of the endothelium significantly enhanced Phe-induced stress in pregnant (6.4+/-0. 6x10(3) N/m(2)) but not RUPP (9.95+/-0.95x10(3) N/m(2)) rats. In endothelium-intact strips, acetylcholine (ACh) was more potent in inducing relaxation of Phe contraction in pregnant (ED(50) 0. 1x10(-6) mol/L) than in RUPP (ED(50) 1.2x10(-6) mol/L) rats. Pretreatment of endothelium-intact strips with N(G)-nitro-L-arginine methyl ester(100 micromol/L), to inhibit nitric oxide (NO) synthase, significantly inhibited ACh-induced relaxation and enhanced Phe-induced stress in pregnant (6.2+/-0.5x10(3) N/m(2)) but not RUPP (9.5+/-0.85x10(3) N/m(2)) rats. Pretreatment of endothelium-intact strips with methylene blue (10 micromol/L), to inhibit cGMP production in smooth muscle, also inhibited ACh-induced relaxation and enhanced Phe-induced stress in pregnant (6.9+/-0.65x10(3) N/m(2)) but not RUPP (9.3+/-0.7x10(3) N/m(2)) rats. In endothelium-denuded strips, relaxation of Phe contraction with the exogenous NO donor sodium nitroprusside was not significantly different between pregnant and RUPP rats. These results suggest that an endothelium-dependent relaxation pathway involving the release of NO from endothelial cells and increased cGMP production in smooth muscle is inhibited in systemic vessels of late pregnant rats with reduced uterine perfusion pressure and may in part explain the increased vascular resistance in pregnancy-induced hypertension.
Hypertension 2000 Jan
PMID:Decreased endothelium-dependent vascular relaxation during reduction of uterine perfusion pressure in pregnant rat. 1064 26

The effects of acetylsalicylic acid (ASA) on aortic smooth muscle contractility were studied in aortic rings of male SHR and WKY rats. The rats were administered two intraperitoneal injections of 10 mg/kg of ASA per week for ten weeks. Blood pressure of each rat was monitored twice weekly prior to the i.p. injections. Twenty four hours after the last injection the aortic smooth muscles were evaluated for generation of active tension in response to KCl, Phenylephrine (PE), Clonidine and Norepinephrine (NE). In another set of experiments calcium conductance was evaluated in the presence or absence of endothelium both in ASA treated and non treated animals. We report that aortic rings from ASA-treated SHR animals were more responsive to contractile agents than rings from non-treated SHR male rats. Also, the Ca2+ conductance in vitro was enhanced appreciably in SHR aortic rings denuded of their monolayer of endothelium in response to ASA treatment. No decrease in systolic blood pressure was observed in response to ASA treatment in SHR male rats. These results suggest that acetylsalicylic acid not only may modulate aortic smooth muscle contractility through the metabolites of arachidonic acid but may repair to a great extent the hypertension associated plasma membrane permeability defect of vascular myocytes.
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PMID:Effect of aspirin on the contractility of aortic smooth muscle and the course of blood pressure development in male spontaneously hypertensive rats. 1084 15

The effect of sesamin, a lignan from sesame oil, on altered vasodilator and vasoconstrictor responses in aortic rings from deoxycorticosterone acetate (DOCA)-salt-induced hypertensive rats, were examined. The systolic blood pressure after 5-weeks DOCA-salt treatment was 195.0+/-2.8 mmHg, which was much higher than that of sham-operated control animals (131.2+/-2.4 mmHg). Sesamin feeding significantly suppressed the development of this hypertension (167.1+/-8.6 mmHg). Acetylcholine (ACh)-induced endothelium-dependent relaxation of aortic rings was markedly decreased in the DOCA-salt hypertensive animals, compared with cases of the control (pD2, 7.0+/-0.1; maximal response, 64.8+/-3.4% versus pD2, 7.7+/-0.2; maximal response, 93.3+/-2.7%). These changes were partially but significantly improved by the sesamin feeding. This improvement seems to be related to a nitric oxide (NO)-dependent component of ACh-induced action, because sesamin feeding did not affect the responses to ACh in the presence of NO synthase inhibitor. A spontaneous NO releaser (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR 3) which exerts endothelium-independent vasodilatation, produced the same patterns of responses as those observed with ACh in cases of DOCA-salt treatment and sesamin feeding. Phenylephrine-induced vasoconstriction was enhanced by the DOCA-salt treatment, both in preparations with and without endothelium, but these enhancements were almost completely normalized by sesamin feeding. Thus, dietary sesamin could efficiently improve the abnormal vasodilator and vasoconstrictor responses in DOCA-salt hypertensive animals. These effects may contribute to the antihypertensive activity of sesamin.
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PMID:Effects of sesamin on altered vascular reactivity in aortic rings of deoxycorticosterone acetate-salt-induced hypertensive rat. 1099 1


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