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

The effect of pure pressure without shear stress or stretch on the release of endothelin-1 was investigated. Elevation of pressure significantly enhanced endothelin-1 release from cultured human umbilical vein endothelial cells. A calcium channel blocker, nifedipine, and a putative stretch-activated channel blocker, gadolinium, did not affect the pressure-induced endothelin-1 increase. On the other hand, a phospholipase C inhibitor, 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate, and protein kinase C inhibitors, 1-5-(isoquinolinylsulfonyl)-2-methylpiperazine and chelerythrine, significantly inhibited the pressure-induced endothelin-1 increase. Moreover, pure pressure reduced basal nitric oxide release, while pretreatment with a nitric oxide synthase inhibitor, NG-monomethyl-L-arginine, had no effect on the pressure-induced endothelin-1 increase. In conclusion, our results show for the first time that pressure enhances endothelin-1 release partially through activation of phospholipase C and protein kinase.
Hypertension 1995 Mar
PMID:Pressure enhances endothelin-1 release from cultured human endothelial cells. 787 71

Angiotensin converting enzyme inhibitors (ACEIs) are a cornerstone of treatment of hypertension and heart failure yet their mechanism of action is still debated. This study was designed to test whether the ACEI captopril increases skin microvascular blood flow by a bradykinin-dependent mechanism. Local changes in microvascular blood flow were measured in the skin of rabbits and of human volunteers using a laser Doppler flow probe. Captopril injected intradermally increased skin blood flow over the dose range of 10(-12)-10(-8) mol site in rabbits and humans. In both species the response was abolished by coinjecting either a nitric oxide synthase (NOS) inhibitor or a cyclooxygenase inhibitor. Intradermal bradykinin also increased rabbit skin microvascular blood flow; at 10(-11) mol site it increased mean +/- SE basal blood flow by 88 +/- 12%. The responses to bradykinin or captopril were abolished by coinjecting a bradykinin antagonist, a specific bradykinin B2 receptor antagonist, or inhibitors of NOS or cyclooxygenase. Injecting a specific angiotensin II receptor antagonist at a dose that antagonized the constrictor effects of exogenous angiotensin II did not cause a significant increase in rabbit skin blood flow. This suggests that endogenous angiotensin II does not influence microvascular blood flow in this model. The results indicate that captopril increases skin microvascular blood flow in rabbits and humans secondary to an increase in endogenous tissue bradykinin; this stimulates B2 receptors with subsequent release of prostaglandins and nitric oxide. ACEIs may increase microvascular perfusion by a bradykinin-dependent mechanism.
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PMID:Captopril increases skin microvascular blood flow secondary to bradykinin, nitric oxide, and prostaglandins. 789 12

Injection of N omega-nitro-L-arginine methyl ester (L-NAME), an L-arginine analogue and a potent inhibitor of nitric oxide (NO) synthase, in dorsolateral periaqueductal gray (PAG) area of freely moving rats at doses from 0.1 to 1 mumol per rat, dose-dependently increased arterial blood pressure (BP). Endothelin-1 (ET-1) injected in the same area at doses from 0.1 to 1 pmol per rat also induced pressor effects. Administration of L-NAME (1 mumol per rat) in the PAG area 10 min before ET-1 significantly (p < 0.01) potentiated ET-1-induced hypertension. Pretreatment with L-arginine (1 mumol per rat), precursor of NO, significantly (p < 0.01) decreased L-NAME-induced potentiation of ET-1 pressor effects. L-Arginine also prevented the ET-induced increase in arterial BP and reversed L-NAME-induced hypertensive effect. Prazosin and propranolol, adrenergic blocking agents, and reserpine, a depletor of catecholamine stores, reduced either ET-1 or L-NAME pressor effects. Our data suggest the presence of NO synthase in the PAG area, considered an important cerebral area in coordinating physiologic responses such as cardiovascular and respiratory adjustment. Moreover, our results suggest that even at the PAG area level, functional antagonism exists between NO and ET-1, possibly contributing, through sympathetic outflow, to central regulation of arterial BP.
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PMID:Relation between L-arginine-nitric oxide pathway and endothelin-1 effects in periaqueductal gray area of rats. 789 82

Endothelial regulation of vasomotor tone occurs largely via the release of nitric oxide or a closely related compound. This process is strikingly altered in a variety of disease states, and alterations of vasomotion may be responsible for the development of hypertension, altered tissue perfusion, and an enhanced propensity for vasoconstriction in several common disorders. In hypercholesterolemia and atherosclerosis, this alteration of vasomotor control occurs not only in larger vessels, but in the microcirculation. Explanations for impaired endothelium-dependent vascular relaxations in hypercholesterolemia include impairments in endothelial cell signal transduction, deficiencies in the substrate (arginine) for the enzyme nitric oxide synthase, alterations in the nitric oxide synthase enzyme or one of its co-factors, and excess destruction of nitric oxide by the superoxide anion. In this review, evidence for these alterations will be considered, potential interventions for restoring endothelium-dependent relaxations examined, and the possible impact of endothelial dysfunction in atherosclerosis considered.
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PMID:Endothelial dysfunction in atherosclerosis. 794 79

1. We assessed regional haemodynamic responses to the vasodilator, MgSO4, in the absence and presence of the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), in conscious chronically instrumented Long Evans rats (n = 9). 2. MgSO4 (loading dose 220 mumol kg-1 min-1 for 7 min, maintenance dose 56 mumol kg-1 min-1 for 7 min), alone, caused slight bradycardia and hypotension accompanied by reductions in renal and mesenteric flows, but a marked hyperaemic vasodilatation in the hindquarters (flow, delta 54 +/- 6%, vascular conductance, delta 77 +/- 5%). 3. L-NAME (183 nmol kg-1 min-1) caused hypertension (29 +/- 2 mmHg) accompanied by bradycardia (-51 +/- 6 beats min-1) and reductions in flow and vascular conductance in the renal (-18 +/- 4% and -35 +/- 3%, respectively), mesenteric (-35 +/- 3% and -49 +/- 3%, respectively), and hindquarters (-26 +/- 3% and -42 +/- 3%, respectively) vascular beds. In the presence of L-NAME, the hypotensive and bradycardic effects of MgSO4 were still apparent, but its hindquarters hyperaemic vasodilator effect was significantly attenuated. 4. In order to determine if the inhibitory action of L-NAME on the hindquarters hyperaemic vasodilator action of MgSO4 was a non-specific effect, due to the change in baseline conditions caused by L-NAME, we also examined responses to MgSO4 in the presence of endothelin-1 (12.5 pmol kg-1 min-1) or angiotensin II (50 pmol kg-1 min-1). In the presence of either peptide, the overall effects of MgSO4 on hindquarters flow and vascular conductance were unchanged. 5. In a separate experiment (n = 8) we determined that the inhibitory effect of L-NAME on the hyperaemic vasodilator response to MgSO4 was prevented by L-arginine, and also demonstrated that the Beta2-adrenoceptor antagonist, ICI 118551, caused significant inhibition of the hindquarters haemodynamic effects of MgSO4.6. We conclude that the hindquarters haemodynamic effects of MgSO4 in conscious rats involve a substantial L-NAME-sensitive component which depends on activation of Beta2-adrenoceptors, probably asa consequence of adrenal medullary adrenaline release.
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PMID:Effects of NG-nitro-L-arginine methyl ester on regional haemodynamic responses to MgSO4 in conscious rats. 801 14

To investigate whether changes in renal blood flow induced by nondepressor doses of L-arginine, the precursor of nitric oxide, are mediated by a sympathetic neural mechanism, we examined the following in conscious rabbits: (1) the effects of intravenous infusion of L- or D-arginine (15 to 200 mumol/kg per minute) on renal blood flow and renal sympathetic nerve activity with or without intravenous infusion of a nonpressor dose of NG-monomethyl-L-arginine (L-NMMA), a nitric oxide synthase inhibitor, and (2) the effects of L-arginine on renal blood flow after renal denervation with or without L-NMMA pretreatment. In renal innervated rabbits, L-arginine (100 and 200 mumol/kg per minute) increased renal blood flow by 9 +/- 2 and 16 +/- 3 mL/min (P < .05, respectively) and decreased renal sympathetic nerve activity by 12 +/- 4% and 19 +/- 3% of control (P < .05, respectively). In contrast, no changes occurred in any variable during D-arginine infusion. L-NMMA attenuated the renal blood flow and renal sympathetic nerve activity responses to L-arginine (P < .05). In renal denervated rabbits, L-NMMA also attenuated the renal blood flow responses to L-arginine (P < .05) and abolished them (P < .05) compared with those in renal innervated rabbits. All renal blood flow responses to L-arginine were accompanied by parallel changes in plasma L-citrulline concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1994 Aug
PMID:Nitric oxide increases renal blood flow by interacting with the sympathetic nervous system. 803 47

1. The use of pharmacological inhibitors of nitric oxide (NO) synthesis to treat patients with septic shock is limited by the observation that they cause a fall in cardiac output in some subjects. The aim of this work was to investigate this fall and to test whether it was reversible by subsequent administration of nicardipine, theophylline or the cyclic GMP-selective phosphodiesterase inhibitor, zaprinast (M&B 22948). 2. In pentobarbitone-anaesthetized pigs, haemodynamic indices were measured before and after intravenous administration of NG-nitro-L-arginine methyl ester (L-NAME) in a dose-response protocol (0.2-20 mg kg-1; n = 6) and as a single bolus of 10 mg kg-1 either alone or followed by increasing doses of nicardipine, theophylline or zaprinast (n = 8 in each group). 3. L-NAME caused a dose-dependent rise in systemic vascular resistance and mean systemic arterial pressure and a dose-dependent fall in cardiac output. A single bolus of L-NAME (10 mg kg-1) produced these effects within 15 min. 4. Subsequent administration of nicardipine (0.05-0.2 mg kg-1) caused complete reversal of systemic vasoconstriction and hypertension and in doing so completely restored cardiac output. Theophylline (7.5-10 mg kg-1) partially reversed the rise in systemic vascular resistance and partially restored cardiac output but the effect was small compared to that of nicardipine. Zaprinast (1-5 mg kg-1) had no significant effect on any of these variables. 5. These results suggest that reduced cardiac output following inhibition of NO synthesis is an effect of increased afterload on the heart and is reversible by nicardipine and to a lesser extent by theophylline.These findings may have potential value for those using NO synthase inhibitors to treat patients with septic shock.
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PMID:Comparison of the ability of nicardipine, theophylline and zaprinast to restore cardiovascular haemodynamics following inhibition of nitric oxide synthesis. 807 60

Recent studies in experimental animals have advanced the concept that neuronal nitric oxide is an important component of the signal transduction pathways that tonically restrain sympathetic vasoconstrictor outflow from the brain stem. To determine whether or not this concept can be extended to the control of sympathetic outflow in humans, we recorded muscle sympathetic nerve activity (microelectrodes, peroneal nerve) in healthy human subjects during intravenous infusion of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) (3.6 to 6.7 mg/kg). The major new finding is that during intravenous L-NMMA mean arterial pressure increased (10 +/- 2 mm Hg, P < .05), whereas heart rate and sympathetic nerve activity decreased (P < .05) by 10 +/- 2 beats per minute and 61 +/- 5%, respectively. These reflex decreases were indistinguishable from those produced when blood pressure was increased comparably with phenylephrine, an internal vasoconstrictor control. When the L-NMMA-induced increase in blood pressure was attenuated experimentally to minimize baroreflex activation, sympathetic nerve activity and heart rate were unchanged. Furthermore, during infusion of L-arginine (323 to 513 mg/kg IV) to increase nitric oxide synthesis, mean arterial pressure decreased (12 +/- 2 mm Hg, P < .05), but heart rate and sympathetic nerve activity increased (P < .05) by 11 +/- 2 beats per minute and 98 +/- 27%, respectively. Thus, our experiments in humans provide no support for the emerging concept that nitric oxide is involved in the tonic restraint of central sympathetic outflow.
Hypertension 1994 Oct
PMID:Is nitric oxide involved in the tonic inhibition of central sympathetic outflow in humans? 808 8

We tested the hypothesis that impairment of flow-dependent dilator mechanisms of skeletal muscle arterioles is one of the underlying reasons for the increased peripheral resistance in hypertension. Isolated, cannulated arterioles (approximately 55 microns) of gracilis muscle of 12-week-old spontaneously hypertensive (SH) and normotensive Wistar (NW) rats were investigated. At a constant perfusion pressure (80 mm Hg), the active diameters of NW and SH arterioles were 57.7 +/- 1.9 and 51.5 +/- 3.2 microns, whereas their passive diameters (Ca(2+)-free solution) were 113.6 +/- 2.9 and 101.7 +/- 2.9 microns, respectively. Flow-induced dilation was elicited by increases in flow of the perfusion solution from 0 to 25 microL/min in 5-microL/min steps. This response was significantly less in arterioles of SH compared with NW rats. For example, at 25-microL/min flow, the diameter of arterioles of SH rats was approximately 56% less (P < .05) than those of NW rats. Indomethacin, an inhibitor of prostaglandin synthesis, significantly attenuated the flow-diameter curve in both strains of rats. In contrast, N omega-nitro-L-arginine, a nitric oxide synthase inhibitor, significantly shifted the flow-diameter curve to the right in NW rats, but it did not affect the flow-diameter curve in SH rats. Thus, the present findings demonstrate that in gracilis muscle arterioles of normotensive rats in response to increases in flow (shear stress), prostaglandins and nitric oxide are co-released, resulting in a dilation. In early hypertension, however, there is a reduced arteriolar dilation to increases in flow that is due to the impairment of the nitric oxide-mediated portion of the flow-dependent arteriolar dilation.
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PMID:Impaired nitric oxide-mediated flow-induced dilation in arterioles of spontaneously hypertensive rats. 811 50

Nitric oxide is widely distributed in the body. It has an important role in the regulation of the circulation and as yet, ill-defined roles in nervous and immune systems. It is derived from L-arginine from a reaction catalysed by a constitutive intracellular enzyme, nitric oxide synthase. It is recognised as the endogenous nitrovasodilator whose action is mimicked by all exogenous nitrovasodilators. After production in the vascular endothelial cell, it diffuses to the smooth muscle cell where it activates the enzyme guanylate cyclase which leads to an increase in cyclic GMP and thence to muscle relaxation. The duration of its action is brief, a few seconds. Disorders of NO metabolism underlie many disease states including endotoxic shock in which prolonged production of nitric oxide may be induced by cytokines. Deficiencies in endogenous production may account for hypertension in various disease states including atherosclerosis and chronic renal failure. NO therapy been used experimentally to successfully treat idiopathic pulmonary hypertension and pulmonary hypertension associated with cardiac and respiratory diseases. However, the long-term benefits have yet to be studied. Administration of NO requires the use of a device to monitor the concentrations of both NO and of NO2. The latter is a noxious agent and a time-related product of the reaction between NO and O2 and is a possible contaminant of preparations of NO. Precautions must be taken to prevent contamination of the work-place atmosphere with NO and NO2. These include gas scavenging and the use of a leak-free system for spontaneous and mechanical ventilation. Using NO in its gaseous form, clinicians have at long last been provided with the means to treat pulmonary hypertension without adversely causing systemic hypotension. The therapy is most suited to short-term use in mechanically ventilated patients. Safe practical long-term NO therapy must await the development of agents which release NO from aerosol preparations.
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PMID:The role of nitric oxide (formerly endothelium-derived relaxing factor-EDRF) in vasodilatation and vasodilator therapy. 812 32


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