摘要:

Recent studies have suggested that coronary endothelial cells produce and release nitric oxide (NO), prostaglandin I2, and epoxyeicosatrienoic acids (EETs). These endothelium-derived vasodilators play an important role in the control of coronary vascular tone. However, the mechanism by which these endothelium-derived vasodilators cause relaxation of coronary arterial smooth muscle has yet to be determined. This study characterized and compared the effects of NO, prostaglandin I (2), and 11,12-EET on the two main types of potassium channels in small bovine coronary arterial smooth muscle: the large conductance Ca2+-activated K+channels (KCa) and 4-aminopyridine-sensitive delayed rectifier K+channels (Kdrf). In cell-attached patches, nonoate, an NO donor, activated both KCaand Kdrfchannels. The open probability of both KCaand Kdrfchannels increased 10- to 25-fold when nonoate was added to the bath at concentrations of 10-6to 10-4mol/L. 11,12-EET (10-8to 10-4mol/L) also increased the activity of the KCachannels in a concentration-dependent manner, but it had no effect on the activity of the Kdrfchannels, even in the highest concentration studied (10-4mol/L). In contrast to the effect of 11,12-EET, iloprost, a prostaglandin I2analogue (10-6to 10-4mol/L), produced a concentration-dependent increase in the activity of Kdrfchannels without affecting the KCachannels. In conclusion, all three endothelium-derived vasodilators act to open potassium channels; however, the channel types that they affect are different. NO activates both KCaand Kdrfchannels; 11,12-EET activates only the KCachannels; and prostaglandin I2activates only the Kdrfchannels. (Hypertension. 1997;29[part 2]:262-267.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Acute exogenous estrogen administration enhances endothelial function in postmenopausal women. To evaluate the effect of endogenous estrogen on endothelium-dependent vasodilation, in 10 fertile normotensive women (age range 45 to 51 years) we studied the changes in forearm blood flow (strain-gauge plethysmography) induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, 15 micro gram [center dot] 100 mL-1[center dot] min-1), an endothelium-dependent vasodilator, or sodium nitroprusside (1, 2, 4 micro gram [center dot] 100 mL-1[center dot] min-1), an endothelium-independent vasodilator, in basal conditions and within 1 month after ovariectomy. As control subjects, 10 matched healthy women were also evaluated. In basal condition, vasodilation to acetylcholine and sodium nitroprusside was similar in patients and control subjects. Ovariectomy was followed by endogenous estrogen deprivation (from 71.6 +/- 31.3 to < 12 pg/mL) and was associated with a significant (P < .01) reduction in acetylcholine-induced vasodilation compared with baseline (maximum percent increase in forearm blood flow: baseline 568.2 +/- 47.1%; ovariectomy 309.5 +/- 37.4%); the response to sodium nitroprusside was unaffected by ovariectomy (maximum percent increase in forearm blood flow: baseline 526.4 +/- 36.5%; ovariectomy 454.7 +/- 47.2%; P = NS). In 6 of 10 patients, the study was repeated after 3 months of estrogen replacement therapy (17 beta-estradiol, 50 micro gram/d by transdermal patches). Exogenous estrogen restored acetylcholine-induced vasodilation (maximum percent increase in forearm blood flow: 548.9 +/- 43.1%; P < .01 versus ovariectomy), which was no longer different from baseline, whereas the response to sodium nitroprusside was not affected (maximum percent increase in forearm blood flow: 480.2 +/- 39.3%; P = NS). These results suggest a protective role of endogenous estrogen on endothelium-dependent vasodilation in the forearm vascular bed of normotensive women. (Hypertension. 1997;29[part 2]:268-273.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

To evaluate whether cyclooxygenase constrictor substances can impair nitric oxide-mediated vasodilation in essential hypertension, in seven normotensive subjects (43.3 +/- 4.1 years; BP, 117 +/- 6/81 +/- 2 mm Hg) and seven essential hypertensive patients (47.1 +/- 5.2 years; BP, 151 +/- 8/98 +/- 4 mm Hg) we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, 15 micro gram [center dot] 100 mL-1[center dot] min (-1)) in basal conditions, during infusion of NG-monomethyl-L-arginine (L-NMMA; 100 micro gram [center dot] 100 mL-1[center dot] min-1), a nitric oxide synthase inhibitor, or indomethacin (50 micro gram [center dot] 100 mL-1[center dot] min-1), a cyclooxygenase inhibitor, or simultaneous indomethacin and L-NMMA. In normotensives, vasodilation to acetylcholine was blunted by L-NMMA (maximum flow increase: 671 +/- 64% and 386 +/- 42%, respectively; P <.01), and this effect was unchanged by indomethacin. In contrast, in hypertensive patients, vasodilation to acetylcholine (maximum flow increase: 458 +/- 33%) was unchanged by L-NMMA. Indomethacin significantly (P < .01) increased the response to acetylcholine (maximum flow increase: 635 +/- 53%) and restored the inhibitory effect of L-NMMA (maximum flow increase: 445 +/- 36%; P < .01 versus indomethacin alone). In an adjunctive seven normotensives (51.4 +/- 4.2 years; BP, 114 +/- 5/79 +/- 3 mm Hg) and seven essential hypertensives (53.2 +/- 7.6 years; BP, 153 +/- 9/100 +/- 3 mm Hg) we repeated the same protocol by replacing L-NMMA with L-arginine (200 micro gram [center dot] 100 mL-1[center dot] min-1), the substrate for NO synthase. In normotensives, vasodilation to acetylcholine was increased by L-arginine (maximum flow increase: 539 +/- 48% and 806 +/- 61%, respectively) and this effect was unchanged by indomethacin. In hypertensive patients, vasodilation to acetylcholine (maximum flow increase: 339 +/- 32%) was unchanged by L-arginine but was significantly (P < .01) increased by indomethacin (maximum flow increase: 592 +/- 38%). Moreover, indomethacin restored the facilitatory effect of L-arginine (maximum flow increase: 804 +/- 56%; P < .01 versus indomethacin alone). Therefore, cyclooxygenase inhibition restores nitric oxide-mediated vasodilation in essential hypertension, suggesting that cyclooxygenase-dependent substances can impair nitric oxide production. (Hypertension. 1997;29[part 2]:274-279.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The infusion of L-arginine induces the production of nitric oxide and stimulates the immediate secretion of insulin. To examine the relationship between insulin resistance and endothelium-dependent vascular relaxation in patients with essential hypertension, we evaluated the renal and insulin responses to L-arginine, 500 mg/kg infused intravenously over 30 minutes, in 23 patients with mild essential hypertension who were neither obese nor diabetic and in 20 normotensive control subjects. We found no difference between the two groups in blood glucose or insulin in the fasting condition. The renovascular relaxation induced by L-arginine was significantly less in patients with essential hypertension than in normotensive control subjects. The increase in plasma cyclic GMP in response to L-arginine was lower in hypertensive patients than in normotensive subjects. Although the serum concentrations of glucose in response to L-arginine were similar in the two groups, the serum insulin response of the essential hypertensives was significantly higher than that of the normotensive subjects. In all subjects, the peak cyclic GMP response to L-arginine was significantly correlated with the peak Delta glucose/Delta insulin ratio response to L-arginine (r = .69, P < .001). Findings suggested that an impairment of endothelium-dependent renal vascular relaxation and a reduced sensitivity to insulin are present in patients with essential hypertension. A link may be present between the abnormality of the L-arginine/nitric oxide/cyclic GMP pathway and insulin resistance in patients with essential hypertension. (Hypertension. 1997;29[part 2]:280-285.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Endothelial function is known to be impaired in essential hypertensive patients. In this study, we examined whether antihypertensive drugs improve forearm vasodilatory response to reactive hyperemia in 26 patients with essential hypertension (62 +/- 2 years) without diabetes mellitus, hyperlipidemia, coronary heart disease, or cerebrovascular disease. Antihypertensive drugs were never given or were discontinued for at least 4 weeks before the study. Patients were treated with monotherapy of either temocapril (2 or 4 mg, n = 15) or amlodipine (2.5 or 5 mg, n = 11) for 6 months. Forearm blood flow was measured by strain-gauge plethysmography. Vasodilator response to the release of upper arm compression at 300 mm Hg for 5 minutes and to sublingual administration of nitroglycerin (0.3 mg) were assessed. Changes of forearm blood flow response to reactive hyperemia were significantly less in hypertensive patients (99 +/- 18%) than in age-matched normotensive control subjects (150 +/- 22%, P < .01, n = 39). Blood pressure (mm Hg) was similarly decreased by the treatment with temocapril (160 +/- 4/94 +/- 2 to 139 +/- 3/83 +/- 3, P < .001) or amlodipine (165 +/- 5/94 +/- 3 to 141 +/- 4/82 +/- 3, P < .001). Response to nitroglycerin was not changed by either drug. Forearm vasodilatory response to reactive hyperemia was improved by temocapril (102 +/- 20% to 168 +/- 25%, P < .01) but not by amlodipine (97 +/- 16% to 114 +/- 14%, NS). These results indicate that the treatment with the angiotensin-converting enzyme inhibitor temocapril improved forearm vasodilatory response to reactive hyperemia, suggesting its beneficial effect on endothelial function. (Hypertension. 1997;29[part 2]:286-290.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Endothelial cell activation is important in the pathogenesis of preeclampsia; however, the nature of the activation is unknown. We investigated 22 patients with preeclampsia, 29 normotensive pregnancies, and 18 nonpregnant women to test the hypothesis that serum from preeclamptic patients induces expression of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) and stimulates intracellular free calcium concentrations [Ca2+]iin cultured endothelial cells. We then asked whether the corresponding integrin adhesive counter receptors lymphocyte function-associated antigen-1 CD11a/CD18), macrophage-1 antigen (CD11b/CD18), p150,95 (CD11 c/CD18), and very late activation antigen-4 (CD49/CD29) are increased in patients with preeclampsia. In the pregnant women, the measurements were conducted both before and after delivery. Integrin expression was measured by fluorescent antibody cell sorting analysis using monoclonal antibodies. ICAM-1 and VCAM-1 were analyzed on endothelial cells by enzyme-linked immunosorbent assay. [Ca2+]iwas measured with fura 2. Serum from preeclamptic patients increased endothelial cell ICAM-1 expression but not VCAM-1 expression. Preeclamptic patients' serum also increased [Ca (2+)]iin endothelial cells compared with serum from normal nonpregnant or normal pregnant women. Endothelial cell [Ca2+]iconcentrations were correlated with the ICAM-1 expression in preeclamptic patients (r = .80, P < .001) before but not after delivery. Expression of the integrin counter receptors on leukocytes was similarly increased in preeclampsia and normal pregnancy compared with the nonpregnant state. The expression decreased significantly after delivery in both groups. Our results demonstrate that serum from preeclamptic women induces increased ICAM-1 surface expression on endothelial cells, while the expression of the integrin counterreceptors was not different. The effect on endothelial cells may be related to an increase in [Ca2+]i. The effect on cultured endothelial cells and the rapid decrease after delivery suggests the presence of a circulating serum factor which increases endothelial cell [Ca2+]iand enhances adhesion molecule expression. (Hypertension. 1997;29[part 2]:291-296.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

We hypothesized that neuronal nitric oxide synthase and cyclooxygenase-2, which both exist in the renal cortex, predominantly in the macula densa, play a role in the control of renal renin tissue content. We studied the possible role of neuronal nitric oxide synthase in regulating renal renin content by using mice in which the neuronal nitric oxide synthase gene has been disrupted (nNOS -/-) compared with its two progenitor strains, the 129/SvEv and the C57BL/6, to determine if the absence of neuronal nitric oxide synthase would result in decreased renal renin content or blunt the increase observed during low sodium intake. Renal renin content from cortical slices was determined in adult mice from all three strains maintained on a normal sodium diet. Renal renin content was significantly reduced in the nNOS -/- mice compared with the 129/SvEv and the C57BL/6 mice (3.11 +/- 0.23 versus 5.66 +/- 0.50 and 7.55 +/- 1.17 micro gram angiotensin I/mg dry weight, respectively; P < .005), suggesting that neuronal nitric oxide synthase may stimulate renal renin content under basal conditions. Neither selective pharmacological inhibition of neuronal nitric oxide synthase using 7-nitroindazole or disruption of the neuronal nitric oxide synthase gene affected the increase in renal renin content observed during dietary sodium restriction. The influence of cyclooxygenase-2 on renal renin content through a macula densa-mediated pathway was studied using a selective cyclooxygenase-2 inhibitor, NS398, in 129/SvEv mice. A low-sodium diet increased renal renin content from 6.97 +/- 0.52 to 11.59 +/- 0.79 micro gram angiotensin I/mg dry weight (P < .005); but this increase was blocked by NS398. In addition, treatment with NS398 reduced renin mRNA in response to a low-sodium diet. Thus, increased renal renin content in response to dietary sodium restriction appears to require the induction of cyclooxygenase-2, while neuronal nitric oxide synthase appears to affect basal but not stimulated renal renin content. (Hypertension. 1997;29[part 2]:297-302.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

We recently identified a subgroup of rabbits (called nonresponders) that were deficient in vascular thromboxane A2receptors. Thromboxane A2-mediatedplatelet aggregation was not different between responders and nonresponders. In the present study, we utilized these nonresponders as a model to study the relative contribution of the platelet and vascular thromboxane A2receptors to the observed hemodynamic responses associated with arachidonic acid-induced sudden death. Mean arterial pressure was slightly but not significantly lower in the nonresponders compared with the responders. However, nonresponders were protected from arachidonic acid-induced sudden death. While 100% of the responders died at the 2.0 mg dose of arachidonic acid, only 27% of nonresponders died at this same dose. Administration of the thromboxane A (2) mimetic U46619 (5 micro gram/kg IV) decreased blood pressure by 41 +/- 6 mm Hg in responders but had no effect in the nonresponders. The affinity and density of thromboxane A2receptors in cultured aortic vascular smooth muscle cells obtained from both responders and nonresponders were assessed using radioligand binding. The Kdvalues were not different (4.4 +/- 1.0 versus 2.4 +/- 0.6 nmol/L, responder versus nonresponder). However, there was a significant decrease in the density of receptors from vascular smooth muscle cells of nonresponders (B (max) = 397 +/- 59 versus 157 +/- 59 fmol/106cells, responder versus nonresponder, P < .01). U46619 produced a concentration-dependent increase in [(3) H]-thymidine incorporation into responder vascular smooth muscle cells but had no effect in the nonresponder cells. Using an anti-thromboxane A2receptor antibody, we compared the amount of receptor expressed in aortic tissue obtained from responders and nonresponders. Consistent with the results observed with [(3) H]-thymidine uptake and radioligand binding assays, the expression of thromboxane A2receptor protein was decreased in nonresponder compared with responder vascular tissue. Platelet thromboxane A2receptor expression was not different. These studies demonstrate that the vascular smooth muscle cells of non-responder rabbits are deficient in the thromboxane A2receptor. Furthermore, the reduction in arachidonic acid-induced sudden death in nonresponders indicates that the vascular smooth muscle thromboxane A2receptor mediates this effect. (Hypertension. 1997;29[part2]: 303-309.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Recent studies suggest that thromboxane (TX) mediates a significant component of angiotensin II (ANG II)-induced hypertension. However, there is little information to support the hypothesis that this relationship is important during chronic, physiological increases in ANG II, particularly while controlling for variation in endogenous ANG II levels induced by TX inhibition. This study tested that hypothesis in 27 chronically instrumented rats. After baseline measurements, suppression of endogenous TX was induced and maintained throughout the study in 13 rats by IV infusion of the TX synthesis inhibitor (TSI) U63557A; the other 14 rats received vehicle. Baseline mean arterial pressure (MAP) was not different between groups and was unchanged by TSI or vehicle. Continuous inhibition of ANG II production was then initiated in both groups of rats by IV infusion of the angiotensin-converting enzyme inhibitor (ACEI) benazepril. ACEI reduced blood pressure similarly in vehicle and TSI rats, from 105 +/- 2 to 91 +/- 2 mm Hg and 103 +/- 1 to 89 +/- 1 mm Hg, respectively. ANG II was then infused at 5 ng [center dot] kg-1[center dot] min-1IV for 7 days in six rats from each group to restore ANG II activity to baseline levels. This dose increased MAP to 103 +/- 2 and 101 +/- 1 mm Hg in vehicle and TSI rats, respectively, values not different from pre-ACEI levels. Seven TSI rats and eight vehicle rats received a higher dose of ANG II (20 ng [center dot] kg-1[center dot] min-1IV). After 7 days, MAP was higher in vehicle than in TSI rats (143 +/- 5 versus 120 +/- 4 mm Hg). These results suggest that endogenous TX is an important determinant of MAP in ANG II hypertension but may have a diminished role in blood pressure regulation when ANG II is at normal and subnormal levels. (Hypertension. 1997;29[part 2]:310-314.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Recent studies have indicated that a deficiency in the production of 20-hydroxyeicosatetraenoic acid (20-HETE) in the outer medulla of the kidney may contribute to the abnormalities in the renal handling of sodium and the development of hypertension in Dahl salt-sensitive rats. To determine whether a reduction in 20-HETE production in the outer medulla is sufficient to induce hypertension, an inhibitor of the renal metabolism of arachidonic acid by P450 enzymes, 17-octadecenoic acid (17-ODYA), was chronically infused directly into the outer medulla of the left kidney of uninephrectomized Lewis rats fed a high salt diet. Renal medullary interstitial infusion of 17-ODYA (400 pmol/min) reduced the formation of 20-HETE in the outer medulla of the infused kidney by 70% compared with values seen in the right kidney collected when the rat was uninephrectomized, but it had no effect on the production of 20-HETE in the renal cortex. After 5 days, mean arterial pressure rose from 115 +/- 2 to 142 +/- 2 mm Hg (n = 6) in the rats infused with 17-ODYA, while mean arterial pressure was not significantly altered in the rats infused with vehicle alone (116 +/- 1 versus 117 +/- 2 mm Hg, n = 6). These results suggest that inhibition of the renal metabolism of arachidonic acid by P450 enzymes in the outer medulla of the kidney is sufficient to induce the development of hypertension in Lewis rats fed a high salt diet and support the view that P450 metabolites of arachidonic acid play an important role in the regulation of renal function and the long-term control of arterial pressure. (Hypertension. 1997;29[part 2]:315-319.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID