Differentiated response of the sympathetic nervous system to angiotensin-converting enzyme inhibition in hypertension. (1/19)

Hypertension with renal artery stenosis is associated with both an activated renin-angiotensin system and elevated sympathetic activity. Therefore, in this condition it may be favorable to use a therapeutic modality that does not reflexly increase heart rate, renin secretion, and sympathetic nervous activity. The purpose of the present study was to assess overall, renal, and muscle sympathetic activity after short-term administration of an angiotensin-converting enzyme inhibitor (enalaprilat) and a nonspecific vasodilator (dihydralazine) to hypertensive patients with renal artery stenosis. Forty-eight patients undergoing a clinical investigation for renovascular hypertension were included in the study. An isotope dilution technique for assessing norepinephrine spillover was used to estimate overall and bilateral renal sympathetic nerve activity. In 11 patients simultaneous intraneural recordings of efferent muscle sympathetic nerve activity were performed. Thirty minutes after dihydralazine administration, mean arterial pressure fell by 15%, whereas plasma angiotensin II, muscle sympathetic nerve activity, heart rate, and total body norepinephrine spillover increased (P<0.05 for all). In contrast, after enalaprilat administration a fall in arterial pressure similar to that for dihydralazine was followed by decreased angiotensin II levels and unchanged muscle sympathetic nerve activity, heart rate, and total body norepinephrine spillover, whereas renal norepinephrine spillover increased by 44% (P<0.05). Acute blood pressure reduction by an angiotensin-converting enzyme inhibitor provokes a differentiated sympathetic response in patients with hypertension and renal artery stenosis, inasmuch that overall and muscle sympathetic reflex activation are blunted, whereas the reflex renal sympathetic response to blood pressure reduction is preserved.  (+info)

The impact of maternal plasma volume expansion and antihypertensive treatment with intravenous dihydralazine on fetal and maternal hemodynamics during pre-eclampsia: a clinical, echo-Doppler and viscometric study. (2/19)

OBJECTIVES: To establish the effects of plasma volume expansion (PVE) followed by intravenous dihydralazine (DH) administration on maternal whole blood viscosity (WBV) and hematocrit, uteroplacental and fetoplacental downstream impedance and umbilical venous (UV) volume flow in pre-eclampsia. METHODS: In 13 pre-eclamptic women maternal and fetal hemodynamics were established by means of combined measurement of maternal arterial blood pressure (BP), WBV, hematocrit and uterine artery (UtA) resistance index (RI) in addition to umbilical artery (UA) pulsatility index (PI) and UV volume flow obtained from UV vessel area and UV time-averaged flow velocity. In each woman all parameters were measured four times at baseline, after PVE, after DH and 24 h after the start of treatment. RESULTS: Maternal diastolic BP, hematocrit and WBV display a significant reduction after PVE. In the fetus UA PI decreases significantly whereas a significant increase in UV cross-sectional area was detected. After maternal DH administration, arterial systolic and diastolic BP and UA PI show a significant decrease compared with the measurements following PVE. At 24 h, only maternal systolic and diastolic BP display a significant further decrease. No significant changes were established for the UtA RI, UV time-averaged velocity and UV volume flow during the entire study period. CONCLUSIONS: During pre-eclampsia, maternal PVE followed by DH administration results in a significant reduction in maternal diastolic BP, maternal hematocrit and WBV. Maternal PVE is associated with a significant increase in UV cross-sectional area and a non-significant rise of 11% in UV volume flow. Maternal DH administration does not result in any change in UV cross-sectional area. However, UA PI decreases significantly after both PVE and DH treatment.  (+info)

Hypertension in children with chronic renal failure. (3/19)

Systemic hypertension (HTN) is one of the major problems associated with chronic renal failure (CRF). HTN is a symptom and complication of CRF. The prevalence of HTN varies with the cause of CRF. The incidence of HTN increased up to 90% with progressive deterioration of the glomerular filtration rate (GFR). HTN is the major risk factor for decline in renal function and progression of CRF. It is the most important risk factor for cardiovascular diseases and morbidity and mortality in patients with CRF and end-stage renal disease (ESRD) on dialysis. The target blood pressure for hypertensive children with CRF should be under the 95th percentile for sex and age. The therapeutic approach in CRF is directed at reducing volume expansion and sodium retention, and decreasing peripheral vascular resistance. Diuretics are first-line therapy for HTN in patients with CRF with sodium and water retention. ACE inhibitors are the first-class drugs because of their renoprotective effect in preventing deterioration of kidney function. Calcium channel blockers are excellent first-line antihypertensive drugs. Recently angiotensin II receptor blockers and ACE inhibitors have been efficiently used together for the treatment of HTN and to prevent further decline in renal function.  (+info)

Progress curve analysis of CYP1A2 inhibition: a more informative approach to the assessment of mechanism-based inactivation? (4/19)

Mechanism-based cytochrome P450 inactivation is defined as a time- and NADPH-dependent inactivation that is not reversible upon extensive dialysis. Current methodologies use dilution approaches to estimate the rate of inactivation and offer limited mechanistic insight and are significantly influenced by experimental conditions. We investigated the potential of progress curve analysis because this experimental design allows investigation of both the reversible (K(iapp)) and irreversible (K(i), K(inact)) components of the reaction mechanism. The human liver microsomal CYP1A2 inactivation kinetics of resveratrol, oltipraz, furafylline, and dihydralazine (Fig. 2) were evaluated. The inactivation results for furafylline (K(i), 0.8 microM; K(inact), 0.16 min(-1)) are within 2-fold to published data (K(i), 1.6 microM; K(inact), 0.19 min(-1)). Resveratrol and dihydralazine results are within a 4.3-fold range of published data, which compares well with ranges of estimates of these parameters across publications (e.g., furafylline has estimates ranging of K(i) from 1.6 to 22.3 microM and K(inact) from 0.19 to 0.87 min(-1)). This range of estimates highlights the potential caveats surrounding the existing methodologies that have been previously discussed in depth. In addition to these inactivation parameters, we have been able to demonstrate a variation in balance of reversible versus irreversible inhibition within these inactivators. Oltipraz and resveratrol have K(iapp) values similar to their K(i), indicating a significant early onset reversible inhibition, whereas furafylline and dihydralazine are dominated by irreversible inactivation. This approach allows a more mechanistic investigation of an inactivator and in the future may improve the prediction of clinical drug-drug interactions.  (+info)

Maternal and fetal hemodynamic effects induced by nitric oxide donors and plasma volume expansion in pregnancies with gestational hypertension complicated by intrauterine growth restriction with absent end-diastolic flow in the umbilical artery. (5/19)

OBJECTIVE: To evaluate the effect of plasma volume expansion (PVE) and nitric oxide (NO) donors, in addition to antihypertensive therapy for gestational hypertensive pregnancies complicated by intrauterine growth restriction (IUGR) with absent end-diastolic flow (AEDF) in the umbilical artery (UA). METHODS: This was a case-control study into which 32 gestational hypertensive pregnancies with IUGR and AEDF were enrolled. Sixteen of these were treated with antihypertensive drugs, NO donors and PVE (Group A), and 16, matched for maternal age, gestational age and fetal conditions, were treated with antihypertensive drugs only (Group B). All patients underwent fetal and uteroplacental assessment and maternal echocardiography to evaluate total vascular resistance (TVR) and cardiac output before and 5-14 days after initiation of treatment. RESULTS: After 5-14 days of treatment, the maternal TVR in Group A fell from 2170 +/- 248 to 1377 +/- 110 dynes.s.cm(-5) (P < 0.01), and that in Group B fell from 2090 +/- 260 to 1824 +/- 126 dynes.s.cm(-5) (P < 0.01), with the reduction being greater in Group A than in Group B (P < 0.01). There was a significant increase in cardiac output in Group A after 5-14 days of treatment vs. baseline (6.19 +/- 0.77 vs. 4.32 +/- 0.66, P < 0.001), and, after treatment, cardiac output was significantly greater in Group A than it was in Group B (6.19 +/- 0.77 vs. 4.70 +/- 0.44, P < 0.001). Reappearance of end-diastolic flow in the UA occurred in 14/16 patients in Group A but in no patients in Group B (87.5% vs. 0%, P < 0.05). The interval between detection of UA-AEDF and delivery was 28 +/- 16 days in Group A and 11 +/- 6 days in Group B (P < 0.05). CONCLUSION: Administration of NO donors and PVE in gestational hypertensive pregnancies affected by IUGR and UA-AEDF appears to improve both maternal and fetal hemodynamics, inducing prolongation of gestation.  (+info)

Regression of glomerulosclerosis in subtotally nephrectomized rats: effects of monotherapy with losartan, spironolactone, and their combination. (6/19)

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Suppression of renin secretion in the rat kidney by a nonvascular alpha-adrenergic mechanism. (7/19)

We studied the effect of alpha-adrenergic stimulation, using phenylephrine, on basal and isoproterenol-provoked renin secretion in the isolated perfused rat kidney. Infusion of phenylephrine increased renal perfusion pressure and prevented the response in renin secretion to isoproterenol. No suppression of basal secretion was observed. Renal vasoconstriction was abolished, and the response in renin secretion to isoproterenol was restored by alpha-adrenoceptor blockade with phenoxybenzamine. In contrast, when renal vasoconstriction was prevented by dihydralazine, suppression of renin release by phenylephrine still occurred. These observations support an inhibitory effect of a nonvascular alpha-adrenergic mechanism on renin release. We suggest that the alpha receptor mediating this effect is related directly to the juxtaglomerular cell.  (+info)

Anti-liver endoplasmic reticulum autoantibodies are directed against human cytochrome P-450IA2. A specific marker of dihydralazine-induced hepatitis. (8/19)

Sera from patients with dihydralazine-induced hepatitis were shown to contain anti-liver microsomal autoantibodies (anti-LM) by indirect immunofluorescence. These anti-LM antibodies were different from anti-liver/kidney microsomes (anti-LKM) 1 or 2 autoantibodies which have been previously described. Sera recognized a single 53,000 = Mr polypeptide in human liver microsomes as judged by immunoblotting, and the target antigen was identified as cytochrome P-450IA2 (P-450IA2) by (a) comparison of immunoblotting patterns with anti-human P-450IA2 and anti-rat P-450IA2 and with five anti-LM sera, and (b) specific immunoinhibition of microsomal ethoxyresorufin and phenacetin O-deethylation activities (both P-450IA2 supported reactions) by anti-LM antibodies. Finally, purified human P-450IA2 was recognized by these anti-LM sera. The anti-LM antibodies are specific for the disease because none of the other antisera tested behaved in the same manner as anti-LM, even those from patients treated with dihydralazine and without hepatic disease. A possible role of P-450IA2 in the metabolism of dihydralazine was suggested by competitive inhibition of ethoxyresorufin-O-deethylase observed in microsomal incubations. Thus, a new example is presented in which a cytochrome P-450 may be a target for autoantibodies in drug-induced hepatitis.  (+info)

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