Augmented responses of angiotensin I and II in patients with ischemic heart disease: relation to left ventricular function.

To evaluate the effects of left ventricular (LV) dysfunction upon the sympathetic nervous and renin-aldosterone-angiotensin systems, neurohormonal factors were measured in patients with ischemic heart disease. Eleven patients were divided into two groups by their LV ejection fraction based on previous catheterization; preserved (EF > or = 60%) and impaired (EF < 60%) LV systolic function groups. They performed supine ergometer exercise and blood samples were drawn at rest and at peak exercise. After dynamic exercise, plasma norepinephrine was significantly (p < 0.05) increased in patients with preserved LV function, whereas it was not altered in patients with impaired LV function (norepinephrine 20.8 +/- 20.5 vs 45.8 +/- 41.9, respectively). We observed no differences in basal or peak levels of neurohormonal factors, including plasma renin activity, aldosterone, and brain natriuretic peptide (BNP), between the groups. Although the plasma levels of angiotensin I and II were not different in the two groups at rest or at peak exercise, their increasing ratios from rest to peak exercise were significantly higher in patients with impaired LV function compared to those with preserved LV function (angiotensin I; -18.6 +/- 31.0% vs 64.8 +/- 66.5%, p < 0.05, angiotensin II; -5.9 +/- 41.2% vs 60.7 +/- 40.4% , p < 0.05). These results suggest that the increasing ratios of angiotensin I and II are superior to BNP as predictors of LV dysfunction, and that the sympathetic nervous system has already been activated even at rest and did not respond to dynamic exercise in patients with LV dysfunction in ischemic heart disease.

Effects of antihypertensive therapy on blood pressure and left ventricular hypertrophy in patients with severe hypertension.

The mechanisms responsible for regression of left ventricular (LV) mass with antihypertensive therapy in patients with severe hypertension remain unclear. This study was designed to examine whether systolic and diastolic blood pressures are associated with changes in LV mass. Eighteen patients with essential hypertension whose average seated diastolic blood pressure was >or = 110 mm Hg were enrolled in the study. All patients were administered antihypertensive therapy and underwent M-mode echocardiography before and after 6 months of treatment. In all patients, antihypertensive treatment significantly reduced systolic blood pressure from 175 +/- 21 mm Hg at baseline to 143 +/- 22 mm Hg at 6 months (p < 0.001), and diastolic blood pressure from 116 +/- 7 mm Hg at baseline to 92 +/- 20 mm Hg at 6 months (p < 0.001). LV mass index at 6 months was significantly reduced compared to its baseline value (p < 0.05). Change (value at 6 months-value at baseline) in systolic and diastolic blood pressures correlated positively with the change in LV mass index (r = 0.61, p < 0.01 and r = 0.71, p < 0.001, respectively). The patients were divided into responders. whose LV mass regressed by > or = 10% (n = 9), and nonresponders, whose LV mass regressed by < 10% (n = 9). Systolic (p < 0.001) and diastolic (p < 0.001) blood pressures. interventricular septal thickness (p< 0.05), posterior wall thickness (p < 0.001), and LV mass index (p < 0.001) were significantly decreased in the responders, but not in the nonresponders, at 6 months compared with those at baseline. Systolic (p < 0.05) and diastolic (p < 0.05) blood pressures in nonresponders were significantly higher than those in the responders at 6 months. The changes in systolic and diastolic blood pressures did not correlate with the change in LV mass index in the responders or the nonresponders. The regression of LV mass is strongly affected by reducing blood pressure. This is the first study using antihypertensive therapy to demonstrate that a change in blood pressure correlates positively with changes in LV mass index in severely hypertensive patients.

"White coat effect" induced by therapist's presence during speech therapy for stroke rehabilitation: a single case study.

The excessive pressor response triggered in patients by an alerting reaction to a doctor's presence has been termed the "white coat effect." A 68-year-old man with verbal apraxia after multiple lacunar infarctions was referred to the hospital for speech rehabilitation. He experienced difficulty in talking with the speech therapist during therapy sessions but not when talking with his friends or family. Because the therapist's presence was stressful to the patient, it was considered that his anxiety might produce an excessive increase in blood pressure. Blood pressure monitoring was performed during 2 separate days of speech therapies consisting of two sessions each. In one session, therapy was directed by the therapist; in the other, therapy was self-directed. The therapist-directed approach substantially increased both systolic and diastolic blood pressures, whereas the self-directed therapy slightly increased only systolic pressure. It was concluded that the excessive pressor response seen in this patient during therapist-directed speech therapy resulted from the white coat effect induced by the therapist's presence.

Antagonism of ANG II type 1 receptors protects the endothelium during the early stages of renal hypertension in rats.

The degree of involvement of the renin-angiotensin system in endothelial dysfunction was investigated by using a one-kidney, one-clip (1K,1C) model of renal hypertension. Male Wistar rats received 0.02% enalapril, 0.02% losartan, or tap water for 1 day before and for 48 h after the induction of renal artery stenosis or sham operation. The aorta of 1K,1C rats showed increased contraction and decreased relaxation responses produced by norepinephrine and acetylcholine, respectively, vs. control responses. Exposure to 10(-5) mol/l NG-monomethyl-L-arginine acetate augmented the contractile responses to norepinephrine to a greater extent in control rats than in the 1K,1C rats. The increased contraction and decreased relaxation responses to these agonists in the 1K,1C rats were normalized by enalapril or losartan. The addition of HOE-140 to the bath did not alter these normalized responses. Results suggest that angiotensin II causes endothelial dysfunction and reduces nitric oxide levels in 1K,1C rats. Such endothelial dysfunction enhanced the norepinephrine-induced contraction during the early-stage hypertension in 1K,1C rats.

The somatostatin analog, octreotide, inhibits in vitro outgrowth of smooth muscle cells from canine coronary and carotid atherosclerotic plaque tissues.

Restenosis is caused by excessive neointima formation resulting from smooth muscle cell (SMC) proliferation and migration from the arterial media into the subendothelial space, stimulated by growth factors. A long-acting somatostatin analog, octreotide, activates protein tyrosine phosphatases and can inhibit the stimulatory effects of growth factors. In this study, we evaluated the effect of octreotide on SMC outgrowth from in vitro explants of both coronary and carotid arterial tissues in a canine endothelium-injury model. After 6 days of culture, SMC grew out of 33.3% and 58.3% of the explants from the injured canine carotid and coronary arterial tissues, respectively. In contrast, SMC outgrowth was not observed from any of the explants from normal canine carotid arterial tissue. Octreotide completely inhibited SMC outgrowth from injured canine carotid arterial tissue at a concentration of 10(-6) M. This agent also inhibited SMC outgrowth from injured canine coronary arterial tissue by 57% and 71% of the control value at concentrations of 10(-8) M and 10(-6) M, respectively. We conclude that our explant cell-culture model may prove to be valuable for assessing the effect of agents designed to reduce intimal proliferation, and that the use of the somatostatin analog octreotide in clinical settings may modify the high incidence of restenosis after coronary interventions by reducing SMC proliferation.

Antihypertensive agents prevent nephrosclerosis and left ventricular hypertrophy induced in rats by prolonged inhibition of nitric oxide synthesis.

We investigated the ability of the angiotensin converting enzyme (ACE) inhibitor imidapril hydrochloride, and of the calcium channel blocker amlodipine besilate, to prevent nephrosclerosis and left ventricular hypertrophy (LVH) in rats with hypertension induced by chronic inhibition of nitric oxide (NO). Male Wistar rats were given distilled water (control), NG-nitro-L-arginine methyl ester (L-NAME) 500 mg/L, L-NAME plus imidapril 10 mg/L or 100 mg/L, or L-NAME plus amlodipine 50 mg/L or 100 mg/L in the drinking water (n = 10-12). We then collected 24-h urine samples at 2, 4, and 6 weeks, obtained blood samples at 6 weeks, and histologically examined the kidney and heart. L-NAME markedly reduced the levels of NO metabolites in serum and urine while increasing the tail-cuff blood pressure, the urinary albumin level (1.90 +/- 0.65 v 0.05 +/- 0.02 mg/day/100 g in control), and the area of the left ventricular wall (83.3 +/- 3.0 v 69.8 +/- 1.8 mm2 in control). Nephrosclerosis and myocardial interstitial fibrosis were documented histologically. The plasma renin activity was significantly higher in rats treated with L-NAME than in the control rats. The concomitant administration of imidapril (10 mg/L) with L-NAME completely normalized the tail-cuff pressure, the LVH (70.8 +/- 1.8 mm2), the albuminuria (0.05 +/- 0.01 mg/day/100 g), and the histologic changes. Amlodipine (50 mg/L) also ameliorated the L-NAME-induced effects, but to a lesser extent. Thus, the chronic inhibition of NO synthesis in rats produced nephrosclerosis and LVH that were effectively prevented by giving imidapril at a dose lower than that of amlodipine. We conclude that ACE inhibitors can prevent nephrosclerosis and LVH even in the presence of a reduction in NO production, implying that in rats the inhibition of the renin-angiotensin system is more effective than the blockade of calcium channels in preventing hypertensive tissue injury.

ET(A) receptor antagonist ameliorates nephrosclerosis and left ventricular hypertrophy induced in rat by prolonged inhibition of nitric oxide synthesis.

We investigated the ability of the ETA receptor antagonist T-0115 and the angiotensin-converting enzyme (ACE) inhibitor imidapril hydrochloride to prevent hypertensive complications induced in rats by chronic inhibition of nitric oxide (NO). Male Wistar rats were given distilled water (control), NG-nitro-L-arginine methyl ester (L-NAME) 500 mg/l, or L-NAME plus imidapril 10 mg/l in the drinking water. In rats treated with L-NAME 500 mg/l plus T-0115, T-0115 was given in the food at a dose of 0.2 mg/g food or 0.6 mg/g food. We then collected 24-h urine samples at 2, 4, and 6 wk, obtained blood samples at 6 wk, and histologically examined the kidney and heart. L-NAME markedly reduced the levels of NO metabolites in serum and urine while increasing the tail-cuff blood pressure, the urinary albumin level (1.90+/-0.65 vs. 0.05+/-0.02 mg/d/100 g in control), and the area of the left ventricular wall (83.3+/-3.0 vs. 69.8+/-1.8 mm2 in control). The plasma renin activity was significantly higher in rats treated with L-NAME than in the control rats. The concomitant administration of T-0115 0.6 mg/g food with L-NAME ameliorated the tail-cuff pressure and the albuminuria (0.56+/-0.23 mg/d/100 g), although to a lesser extent than the changes seen with imidapril 10 mg/l. T-0115 0.6 mg/g food prevented left ventricular hypertrophy as effectively as imidapril 10 mg/l (70.8+/-1.8 with T-0115 vs. 68.3+/-2.7 mm2 with imidapril). Chronic inhibition of NO synthesis produced left ventricular hypertrophy and nephrosclerosis. Our results demonstrate that inhibition of the renin-angiotensin system morely effectively prevents nephrosclerosis than does the blockade of ETA receptors in a model of hypertension induced by chronic NO blockade. However, inhibition of the ET-1 pathway appeared to be as effective as ACE inhibitors in preventing left ventricular hypertrophy in this model.

Flow-mediated vasodilation of a conduit artery in relation to downstream peripheral tissue blood flow during reactive hyperemia in humans.

Arterial conduit vessels dilate in response to increased blood flow stimuli. Our objective was to determine precisely how a change in large arterial diameter results in a change in peripheral tissue blood flow. Using high-resolution ultrasound Doppler echography, we measured the diameter of the right femoral artery at rest, during reactive hyperemia, and after administration of 2.5 mg of sublingual isosorbide dinitrate in 10 healthy young men. Reactive hyperemia was induced by distal circulatory arrest followed by reperfusion of the leg ipsilateral (right) or contralateral (left) to the side of arterial diameter measurements. Femoral arterial blood flow was calculated by simultaneous measurement of femoral arterial diameter and blood velocity. The change in skin blood flow was also analyzed simultaneously by laser Doppler flowmetry. Reactive hyperemia induced a 2-fold increase in femoral arterial blood velocity 30 sec after cuff release. During this flow augmentation, the femoral artery dilated. The peak of skin blood flow was coincident with the peak of femoral arterial vasodilation. The time required for the return of arterial diameter to baseline was longer than that for blood flow in both the conduit artery and the peripheral skin tissue. Equivalent cuff occlusion and release of the contralateral limb had no effect on ipsilateral arterial diameter. Isosorbide dinitrate induced dilation in all subjects, despite the absence of a significant increase in blood velocity. These results indicate that the human femoral artery dilates in response to increased blood velocity, and that the flow-mediated vasodilation of a large conduit artery is involved in the adjustments of blood flow in the downstream peripheral tissue.

Immunosuppressive drugs inhibit the production of interleukin-6 and interleukin-8 in cultured cardiac myxoma cells.

Cardiac myxoma cells produce large amounts of interleukin (IL)-6 and IL-8. To determine whether immunosuppressive agents could be used to treat cardiac myxoma, we tested the effects of dexamethasone and three of the newer second-generation immunosuppressive drugs, cyclosporin A, tacrolimus, and deoxyspergualin, on the production of IL-6 and IL-8 in these cells. Cultured cardiac myxoma cells were used as in vitro model of cardiac myxoma. Cells were tested for 24 hours with 10(-7) M dexamethasone, 10(-6) M cyclosporin A, 10(-8) M tacrolimus, and 10(-6) M 15-deoxyspergualin, with aliquots of conditioned medium being assayed for cytokine levels at 0, 6, 12, and 24 hours. Cardiac myxoma cells isolated from 4 patients all produced quantities of IL-6 and IL-8. The concentrations of IL-6 in the medium after 7 days in culture ranged from 79,000 to 2,740,000 pg/ml, and the concentrations of IL-8 ranged from 40,000 to 1,000,000 pg/ml. Exposure of cyclosporin A and dexamethasone almost completely inhibited the production of IL-6 and IL-8 after 24 hours of treatment. Tacrolimus inhibited the production of both cytokines by 55%, while 15-deoxyspergualin reduced IL-6 levels by 24% and IL-8 levels by 48% after separate 24 hour treatments. These results suggest that these newer immunosuppressive agents may be useful in reducing the production of IL-6 and IL-8 in patients with cardiac myxoma.

Rate of nitric oxide release in the lung and factors influencing the concentration of exhaled nitric oxide.

The level of nitric oxide (NO) in exhaled air fluctuates in normal individuals depending on the physiological conditions. We evaluated the effects of duration of exhalation and breath-holding on the exhaled concentrations of NO in 16 normal human volunteers. Exhaled gas corresponding to vital capacity was collected in 6-liter Tedlar bags and analyzed by chemiluminescence. The NO concentration in exhaled gas increased significantly in proportion to the duration of exhalation [P = 0.009 +/- 0.011 (SD)] and was increased after breath-holding. There was no significant difference in the exhaled NO concentration among 10-s phases of a 30-s exhalation, as determined from multiple breath collections. The NO released from the airways is presumably unaffected by fluctuation of exhalation speed. The NO release rate, calculated from a single regression analysis between the NO concentration and the duration of exhalation, was 39 +/- 29 pmol/s, a value which was about fourfold greater in nine patients with bronchial asthma.

Lack of inhibitory effect of dexamethasone on exhalation of nitric oxide by healthy humans.

Nitric oxide (NO) is present in the breath exhaled from healthy humans. The location and subtype of the NO synthase responsible for the expired NO are unknown. As dexamethasone inhibits the induction of NO synthase, we evaluated the effect of administering dexamethasone (4 mg/day for 2 days) on the amount of NO exhaled by eight healthy men. The amount of NO showed a significant linear correlation with the duration of exhalation, allowing the rate of NO release to be calculated. The rate of NO release was 0.047 +/- 0.023 nmol/s before drug administration. There was no significant change in the release rate at the end of the 2-day administration of drug or at 5 days after cessation. Serum concentrations of interferon-gamma and interleukin-1 beta were unaffected by the administration of dexamethasone. These results suggest that the NO released from the human airway under normal conditions is not generated by the action of inducible NO synthase.

Effect of renal perfusion pressure on renal interstitial hydrostatic pressure and sodium excretion. Role of vasopressin V1 and V2 receptors.

Renal interstitial hydrostatic pressure (RIHP) has recently been cited as an important mediator of pressure natriuresis. Our objective was to determine the roles of vasopressin V1 and V2 receptors in mediating the effects of renal perfusion pressure (RPP) on RIHP and sodium excretion (UNaV). The effects of RPP on renal hemodynamics, RIHP, and UNaV were assessed in control Wistar rats (n = 10) and in rats pretreated with intravenous infusion of the specific nonpeptide vasopressin V1 antagonist OPC-21268 (100 micrograms.kg-1.min-1; n = 8) and the V2 antagonist OPC-31260 (40 micrograms.kg-1.min-1; n = 10). Increasing RPP from 95 to 118 mm Hg in control rats increased RIHP (6.4 +/- 1.0 to 9.9 +/- 1.3 mm Hg), UNaV (0.29 +/- 0.03 to 0.52 +/- 0.05 muEq.min-1.g-1), urine flow rate (UFR) (5.2 +/- 0.3 to 7.6 +/- 0.6 microL.min-1.g-1), and the fractional excretion of sodium (FENa). In rats pretreated with V1 antagonist, similar results were obtained for urine osmolality and the responses of RIHP, UNaV, UFR, and FENa to RPP. V2 antagonist reduced urine osmolality (392 +/- 47 compared with 979 +/- 88 mOsm.kg-1 in control rats) and enhanced the responses of UNaV (0.43 +/- 0.08 to 1.32 +/- 0.32 microEq.min-1), UFR (17.8 +/- 3.2 to 29.2 +/- 3.8 microL.min-1.g-1), and FENa to RPP, but the RIHP response resembled that observed in the control and V1 antagonist groups. Renal blood flow and glomerular filtration rate did not differ among the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone response to adrenocorticotrophin and furosemide in primary aldosteronism after prolonged spironolactone treatment.

We evaluated the effects of prolonged spironolactone treatment on aldosterone secretion in patients with primary aldosteronism. The patients were hospitalized and underwent a furosemide test with or without dexamethasone, as well as an adrenocorticotrophin (ACTH) test. In untreated patients, neither plasma renin activity (PRA) nor plasma aldosterone showed a response in the furosemide test. In patients receiving spironolactone, furosemide increased significantly both the PRA and the plasma aldosterone concentration (from 2.6 +/- 0.8 to 7.0 +/- 2.0 micrograms.l-1.h-1 (p < 0.05) and from 345.6 +/- 55.8 to 492.7 +/- 76.8 ng/l (p < 0.05), mean +/- SEM, respectively). Dexamethasone administration had no effect on the results of the furosemide test (p > 0.1). However, dexamethasone tended to decrease the basal plasma aldosterone concentration in the untreated patients, but not in the patients receiving spironolactone. In the ACTH test, the plasma aldosterone concentration increased significantly in the untreated patients (from 549.0 +/- 69.8 to 1169.3 +/- 165.5 ng/l, p < 0.01), but there was no significant aldosterone response in the spironolactone-treated patients (from 885.5 +/- 204.9 to 1260.3 +/- 289.2 ng/l, p > 0.1). We conclude that aldosterone secretion is mainly dependent on ACTH in the untreated patients with primary aldosteronism and is more strongly regulated by the renin-angiotensin system during spironolactone treatment.

Release of nitric oxide in response to acetylcholine is unaltered in spontaneously hypertensive rats.

OBJECTIVE: Although a decreased responsiveness to acetylcholine, an endothelium-dependent vasodilator, has been reported in arteries isolated from spontaneously hypertensive rats (SHR), the precise role of nitric oxide (NO) in the in vivo regulation of blood pressure is not clear. We investigated the effects of acetylcholine and of NG-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, on mean arterial pressure and the production of NO metabolites (nitrate and nitrite) in SHR and in Wistar-Kyoto (WKY) rats, their normotensive control strain. DESIGN: We determined serum levels of nitrate and nitrite before and after the intravenous injection of 40 micrograms/kg acetylcholine following the administration of L-NAME (30 mg/kg) or its vehicle in adult SHR and WKY rats. RESULTS: Acetylcholine administration significantly reduced mean arterial pressure in both SHR and WKY rats, accompanied by a significant rise in serum nitrate and nitrite. Administration of L-NAME significantly increased the mean arterial pressure in SHR and in WKY rats. L-NAME inhibited the hypotension induced by acetylcholine and the rise in serum nitrate and nitrite both in SHR and in WKY rats. CONCLUSION: The release of NO stimulated by acetylcholine was unaltered in SHR, supporting previous in vitro results.

Effect of NG-monomethyl-L-arginine on regional vascular resistance in rats.

This study investigated the effects of intravenous injection of the specific inhibitor of nitric oxide (NO) formation, NG-monomethyl-L-arginine (L-NMMA), on mean arterial pressure and regional vascular resistance in rats (n = 7). Regional vascular resistances of brain, heart, left kidney, intestine (jejunum), left testis and right testis were measured using radiolabelled microspheres before and after injection of 12.5 mg/kg of L-NMMA. Injection of L-NMMA raised mean arterial pressure significantly (p < 0.05) from 119 +/- 4 (mean +/- SEM) mmHg to 139 +/- 7 mmHg, accompanied by a significant (p < 0.05) decrease in both heart rate and cardiac index and an increase in total peripheral resistance. Regional vascular resistances in brain, heart, kidney and intestine increased significantly (p < 0.05) with L-NMMA, but no change was observed in the testes. The results indicate that the resistance of vascular beds is affected by NO synthesis, while the extent of regulation may differ among the various vascular beds.

Use of a thermodilution renal vein catheter to measure renal blood flow in patients with essential hypertension.

Our objective was to investigate the changes in renal hemodynamics, and the role of these changes in the pathogenesis of essential hypertension. We used a thermodilution renal vein catheter and measured left renal blood flow in 21 patients with essential hypertension. Arterial pressure was monitored concurrently. Cardiac output was measured in 11 patients to calculate total peripheral vascular resistance. Systolic, diastolic, and mean arterial pressure were 187 +/- 7 mmHg, 97 +/- 5 mmHg and 127 +/- 5 mmHg, respectively. Left renal blood flow was 8.01 +/- 0.38 ml/s. Left renal vascular resistance, calculated as mean arterial pressure divided by left renal blood flow, was 16.4 +/- 0.8 mmHg ml-1s, and was positively correlated with systolic, diastolic and mean arterial pressures (p < 0.05). However, no significant correlation was observed between arterial pressure and left renal blood flow. Plasma renin activity in left renal venous blood, measured in 15 patients, was not significantly correlated with renal hemodynamics. Cardiac output and total peripheral vascular resistance were 81.4 +/- 6.0 l/min and 1.68 +/- 0.18 mmHg ml-1s, respectively. Total peripheral vascular resistance was not significantly correlated with either left renal blood flow or renal vascular resistance. The data suggest that a rise in renal vascular resistance may parallel the rise in blood pressure, but not that of total peripheral vascular resistance.

Effect of vasopressin V (OPC-21268) and V2 (OPC-31260) antagonists on renal hemodynamics and excretory function.

Our objective was to assess the effect of endogenous AVP on renal hemodynamics and excretory function. We measured mean arterial pressure (MAP), renal blood flow (RBF), glomerular filtration rate (GFR) and urine osmolality before and after the intravenous infusion of a V1 antagonist (OPC-21268), a V2 antagonist (OPC-31260) and their vehicle (saline) in anesthetized male Wistar rats. The infusion of the V2 antagonist increased the urine flow rate and reduced the urine osmolality significantly (p < 0.05). The infusion of saline and the V1 antagonist did not change the urine flow rate or the urine osmolality. The infusion of saline, the V1 antagonist and the V2 antagonist had no effect on MAP, RBF or GFR. These results suggest that endogenous AVP plays a critical role in the regulation of renal water reabsorption mediated through the V2 receptor.

Exaggerated vascular response due to endothelial dysfunction and role of the renin-angiotensin system at early stage of renal hypertension in rats.

We investigated whether endothelial dysfunction might contribute to the exaggerated vasoconstriction that was induced by the administration of norepinephrine at the early stage of one-kidney, one-clip renal hypertension (1K1C) in rats. We also studied the role of the renin-angiotension system in this phenomenon. Male Wistar rats were killed 48 hours after the induction of renal artery stenosis or sham operation, and ring preparations of the thoracic aorta were obtained. The isometric contraction and relaxation of aortic strips produced by norepinephrine and acetylcholine, respectively, were recorded with a force-displacement transducer. The aorta of 1K1C rats showed a significantly (P < .05) exaggerated contractile response to norepinephrine as compared with that of control rats. Rubbing the endothelium and treatment with methylene blue or NG-monomethyl L-arginine acetate augmented the contractile responses to norepinephrine to a greater extent in control rats than in 1K1C rats; therefore, the responses of the groups did not differ significantly. In the second experiment, rats received 0.05% captopril, 0.02% enalapril, or 0.02% nicardipine in the drinking water for 1 day before and for 48 hours after the induction of renal artery stenosis or sham operation. The increased contractile responses of the aorta to norepinephrine in 1K1C rats were normalized to the level of the control rats by treatment with either captopril or enalapril but not with nicardipine. These results suggest that the endothelial dysfunction may contribute to the exaggerated norepinephrine-induced vasoconstriction observed in the 1K1C rats and that angiotensin I-converting enzyme inhibitors can restore the endothelial function.

Role of norepinephrine in the lack of reflex tachycardia after angiotensin converting enzyme inhibitor treatment.

Angiotensin converting enzyme inhibitors decrease blood pressure without causing reflex tachycardia in hypertensives, but do not always do so in normotensives. To investigate this phenomenon, hemodynamic changes in normotensive rabbits receiving a subpressor dose of norepinephrine were studied following captopril or diltiazem treatment. We also investigated the effect of captopril on baroreceptor reflex in relation to norepinephrine infusion; the baroreflex sensitivity was determined by the relationship between mean arterial pressure and pulse interval receiving graded doses of phenylephrine. Captopril infusion decreased mean arterial pressure and pulse interval from 84 +/- 4 to 74 +/- 5 mmHg and 244 +/- 7.4 to 216 +/- 7.6 msec, respectively. In contrast, in rabbits receiving a norepinephrine infusion captopril lowered mean arterial pressure to the same extent (92 +/- 5 to 76 +/- 3 mmHg, p less than 0.05) without producing reflex tachycardia. When diltiazem was administered, reflex tachycardia occurred in rabbits both with and without a norepinephrine infusion. There was no difference in the baroreflex sensitivity between rabbits receiving norepinephrine with and without captopril treatment. However, the baroreflex curve showed a slight shift to lower pressures after norepinephrine infusion in the rabbits receiving captopril. These results suggest that elevating circulating norepinephrine might be involved in preventing reflex tachycardia after captopril.