A. Pazzola

Effect of endothelin on regional hemodynamics and renal function in awake normotensive rats

Summary: The effects of endothelin on regional hemodynamics and renal function were studied in awake normotensive rats. Intravenous injection of endothelin (700 pmol/kg) transiently lowered mean blood pressure (from 108 ± 2 to 84 ± 2 mm Hg, p < 0.01), due to a reduction in total vascular resistance (38 ± 1%, p < 0.01), and increased stroke volume (29 ± 5%, p < 0.01) and heart rate (from 399 ± 18 to 447 ± 18 bpm, p < 0.05); mesenteric and renal blood flow was reduced (37 ± 13, p < 0.05 and 63 ± 5%, p < 0.01), whereas carotid blood flow was increased (78 ± 5%, p < 0.01). This effect was followed by long-lasting hypertension due to increased total vascular resistance (112 ± 19%, p < 0.01); stroke volume, mesenteric, and renal blood flow were reduced (34 ± 5, 41 ± 4, and 58 ± 4%, respectively, p < 0.05) and carotid blood flow returned to basal levels. Bilateral nephrectomy enhanced the initial hypotensive effect. Pretreatment with nifedipine blocked the hypertensive effect, whereas bilateral nephrectomy did not. A subpressor dose of endothelin (70 pmol/kg) had no effect on stroke volume, mesenteric blood flow, glomerular filtration rate, and plasma renin activity; carotid blood flow was transiently increased (48 ± 16%, p < 0.05), then returned to basal levels; renal blood flow decreased (22 ± 6 and 15 ± 4% at 30 s and 10 min, respectively p < 0.05). Our data show a heterogeneity in the response of regional vascular beds to endothelin, the renal and mesenteric compartments being very sensitive to its vasoconstricting action. Endothelin, acting as paracrine or endocrine hormone, might have an important role in the pathogenesis of high blood pressure.

Low-dose infusion of atrial natriuretic factor in mild essential hypertension.

Intra-arterial blood pressure, cardiac output, heart rate, right heart indexes, urinary electrolytes, and urinary volume were monitored in eight patients with untreated (WHO Class I) essential hypertension. The patients were given synthetic atrial natriuretic factor (ANF) (99-126 alpha-hANP) at 1 and 2 pmol/kg/min in series (phases 1 and 2, 2 hours each dose) or vehicle (hemaccel) in random order on two separate occasions while on their usual diet. Arterial plasma ANF levels increased significantly from basal and time-matched placebo values from 25 +/- 2 and 28 +/- 3 pmol/l to 50 +/- 4 and 83 +/- 9 pmol/l at the end of phases 1 and 2, respectively (p less than 0.001). After 30 minutes during phase 2, systolic blood pressure decreased significantly by 20 +/- 4 mm Hg (p less than 0.001) from basal and time-matched placebo values and remained significantly reduced (-17 +/- 4 mm Hg, p less than 0.001) by the end of the recovery period (2 hours after infusions were completed). Pulmonary systolic blood pressure decreased by 5 +/- 1 mm Hg (phase 2, p less than 0.05). Cardiac output decreased by 0.5 +/- 0.1 l/min below baseline at the end of phase 2 of ANF infusion, whereas it increased significantly (p less than 0.02) by 0.6 +/- 0.1 l/min during vehicle infusion. Systemic diastolic, pulmonary diastolic, right atrial, and wedge pressures were not significantly changed during ANF or vehicle infusions, nor were pulmonary vascular resistance or heart rate altered. Systemic vascular resistance did not change significantly during both infusions, whereas during recovery, systemic vascular resistance decreased significantly after ANF infusion was discontinued (p less than 0.05). Microhematocrit levels increased dose dependently during ANF. The maximum increase was observed at the end of phase 2 (+4.7 +/- 1.7%), whereas the microhematocrit level decreased to -2.4 +/- 0.6% with vehicle (p less than 0.001) at the end of phase 2. Urinary sodium excretion increased significantly (p less than 0.02) by the end of phase 2 under ANF infusion (+38 +/- 15%), whereas it decreased (-10 +/- 6%) under placebo infusion by the end of phase 2. Urinary magnesium excretion was significantly increased during ANF infusion from phase 1 (p less than 0.02), whereas urinary potassium levels, calcium levels, creatinine levels, volume, and glomerular filtration rate did not differ significantly between the two infusions. Plasma renin, angiotensin II, aldosterone, and catecholamine concentrations did not change significantly during ANF or vehicle infusions.(ABSTRACT TRUNCATED AT 400 WORDS)

Efficacy and tolerability of doxazosin alone or in combination with chlorthalidone in essential hypertension

Abstract This study investigated (1) the efficacy and safety of doxazosin versus enalapril when added to a diuretic regimen in essential hypertensive patients and (2) the effect of doxazosin alone or combined with chlorthalidone on postural hemodynamics, the renin-angiotensin-aldosterone system, renal function, and plasma catecholamines. Doxazosin reduced blood pressure comparably to enalapril; when added to chlorthalidone, doxazosin showed an additive effect, although to a lesser extent than that obtained when enalapril was added to chlorthalidone. One patient treated with doxazosin alone stopped therapy because of severe headache. The hemodynamic and humoral response to tilting was comparable for doxazosin and enalapril either alone or in combination with chlorthalidone. In particular, no patient experienced symptomatic orthostatic hypotension after the first dosing of doxazosin even when the diuretic regimen was initiated. These findings confirm the efficacy and safety of doxazosin alone or in combination with diuretics.

Effect of angiotensin converting enzyme inhibition on the menstrual cycle of hypertensive women.

Angiotensin II was reported to play a key role in ovulation in rats and it seems also to be involved in the regulation of LH release. Thus, we studied the effect of chronic ACE inhibition on the menstrual cycle, measuring daily plasma estradiol, progesterone, LH and FSH, and renin and prorenin before and during the third month of treatment with enalapril (10 mg b.i.d.) in 10 mild essential hypertensive women. Blood pressure was normalized by treatment. The cyclical changes of steroids and gonadotrophins were unaffected in their temporal relationships and in the magnitude of their variation during the experimental cycle compared with the basal cycle. A synchronization of plasma prorenin with the other hormones was seen both before, as previously reported, and during enalapril treatment. Our data show that peripheral blockade of angiotensin I conversion does not affect the pituitary guidance of the ovarian hormonal response or the ovarian prorenin release during the menstrual cycle. Our data are in agreement with the hypothesis that circulating angiotensin II does not play a key role in the human fertility process and that hydrophilic ACE inhibitors can be safely used in the treatment of hypertensive women of reproductive age.

Effect of verapamil versus nicardipine on 24-hour blood pressure

Thirty patients with uncomplicated, mild to moderate essential hypertension entered a comparative open study of the efficacy and tolerability of slow-release verapamil versus nicardipine. After a 2-week washout period, patients were randomly allocated to receive either verapamil SR 240 mg once daily or nicardipine 40 mg BID for 6 weeks. Lisinopril 10 mg once daily was added after 3 weeks of treatment if the sitting diastolic blood pressure was >95 mmHg. Twenty-four-hour blood pressure monitoring was performed at week 0 and after 3 and 6 weeks of treatment. Within the first 2 weeks, four patients in the nicardipine group withdrew from the study because of tachycardia (n = 2) or headache (n = 2). Three patients in both groups needed the addition of lisinopril. A significant and comparable reduction in systolic and diastolic blood pressures over 24 hours was obtained after 3 and 6 weeks with both treatments (P < 0.01). We conclude that verapamil SR 240 mg once daily is an effective and well-tolerated antihypertensive drug that does not interfere with the circadian rhythm of blood pressure. Its once-a-day formulation may increase patient compliance with the antihypertensive treatment.

Correlates of atrial natriuretic factor in chronic renal failure

Plasma atrial natriuretic factor (ANF), blood pressure, age, plasma renin activity and creatinine were measured in 50 normal volunteers, 141 essential hypertensives, 35 patients with chronic renal failure who had never been dialysed and 27 patients with end-stage renal failure on constant haemodialysis. Plasma ANF was correlated positively with age in the normal group (r = 0.52, P less than 0.01) and with blood pressure in the essential hypertensives (r = 0.50, P less than 0.001), and negatively with renin in the normal and end-stage renal failure patients (r = -0.47, r = -0.34; P less than 0.01, P less than 0.05, respectively). When patients without left ventricular hypertrophy were matched for age and blood pressure, plasma ANF was significantly different between the essential hypertensives and the normal and end-stage renal failure patients (16 +/- 1, 38 +/- 6 and 148 +/- 24 pmol/l, respectively; P less than 0.001). Cardiac factors are therefore not the only determinant of circulating plasma ANF in humans with chronic renal failure.

Effects of nitrendipine on blood pressure, renin-angiotensin system, and kidney function in essential hypertension.

The effects of nitrendipine (10 mg b.i.d.) on blood pressure, renin-angiotensin-aldosterone system, and kidney function (by means of glomerular and tubular function) were studied in comparison to captopril (50 mg b.i.d.) and to nitrendipine (10 mg q.d.) + captopril (25 mg b.i.d.) in 30 untreated essential mild-to-moderate hypertensives. The blood pressure lowering effect was similar with either regimen. Nitrendipine showed an acute and chronic natriuretic effect not accompanied by modifications of kidney function. All regimens were well tolerated by the patients without any appreciable side effects over the 4-week study period.

Circulating prorenin and renin in response to intravenous adrenocorticotrophic hormone in essential hypertension.

Plasma prorenin and renin changes after a bolus injection of 25 U intravenous adrenocorticotrophic hormone (ACTH, synacthen) were studied in seven untreated uncomplicated essential hypertensives over a period of 24 h. Plasma prorenin did not change significantly during the study, whereas renin after 24 h was higher than at baseline (4.3 +/- 0.6 versus 2.3 +/- 0.9 ng angiotensin I (Ang I)/ml per h, P less than 0.01). We conclude that endogenous glucocorticoid stimulation induced by exogenous ACTH and ACTH itself seem to induce a secondary or tertiary rather than a primary effect on the human renin gene.