Biomedical subjects
Publications and source records attributed to H R Brunner.
A simple in-vitro enzyme system has been used to demonstrate that human angiotensin I interacts competitively with the two non-thiol converting enzyme inhibitors CGS 13934 and MK-422 to inhibit the hydrolysis of a synthetic substrate by human plasma ACE.
The inhibitor of the pressor effect of arginine vasopressin (AVP), d(CH2)5Tyr(Me)AVP, at a dose of 5 micrograms/kg iv was shown in four healthy volunteers to antagonize the blood pressure, heart rate, and skin blood flow response to a lysine vasopressin infusion of 1 mIU X kg-1 X min-1. The inhibition lasted for more than 2 h. When the same dose of the vasopressin antagonist was administered to 10 healthy normally hydrated volunteers with their renin system intact or acutely blocked by 25 mg of captopril po, none of the above parameters changed. It is concluded that circulating vasopressin, even in the face of a blocked renin-angiotensin system, does not actively contribute to maintenance of cardiovascular homeostasis.
A total of 75 male Wistar rats with one-kidney, one-clip renal hypertension was maintained on either a regular (RNa) or a low-salt (LNa) diet for 3 wk after clipping. Blood pressure in the unanesthetized rats was equally elevated independent of sodium intake. Plasma renin activity was higher in LNa animals, and blood pressure was renin dependent only in this group, as evidenced by the blood pressure response to 10 mg/kg captopril iv. There was no significant difference in plasma catecholamines between RNa and LNa rats, although in the former the sympathetic nervous system is believed to play a major role in sustaining high blood pressure. The acute intravenous administration of 0.5 mg/kg prazosin did not induce a more pronounced blood pressure fall in the RNa rats. Prazosin enhanced plasma norepinephrine levels similarly in both groups, but epinephrine levels only rose in the LNa animals. Prazosin also markedly stimulated plasma renin activity rendering blood pressure renin dependent even in RNa rats. Thus, using alpha 1-adrenoceptor blockade, it has not been possible to demonstrate that the blood pressure elevation of salt-repleted one-kidney, one-clip renal hypertensive rats is due to an enhanced sympathetic nerve activity. Data obtained with sympatholytic agents must be interpreted with great caution if renin activity cannot be kept unchanged.
The effect of vasopressin released by cigarette smoking on blood pressure (BP), heart rate (HR), and skin blood flow (SBF) was investigated in 12 normotensive habitual smokers. At a 1-wk interval, each subject smoked within 10 min two cigarettes before and after intravenous injection of either the specific vascular vasopressin antagonist d(CH2)5Tyr(Me)AVP (5 micrograms/kg) or its vehicle administered in double-blind fashion. SBF was assessed with a laser Doppler flowmeter. Smoking increased plasma vasopressin (P less than 0.01). In six subjects subsequently treated with the antagonist, plasma vasopressin rose to greater than 10 pg/ml and SBF fell by 18.2 +/- 4.8%. This SBF reduction was prevented by the vasopressin antagonist. In contrast, the vehicle had no effect. In the 24 studies taken together, there was a significant correlation (r = -0.60, P less than 0.01) between the SBF decrease during the first smoking period and the plasma vasopressin levels measured afterwards. The BP and HR rise caused by smoking was not modified by the antagonist. Thus it appears that the decrease in SBF induced by smoking is due to enhanced vasopressin secretion.
To determine whether plasma renin activity in addition to catecholamines could be used as risk indicators, these parameters were measured in 19 patients with acute myocardial infarction. During the course of hospitalization, five patients developed ventricular fibrillation and three, cardiogenic shock. On admission, heart rate, plasma norepinephrine, epinephrine, and renin levels of these eight patients were significantly higher than those of the other patients with uncomplicated course. Peak creatine kinase MB activity was positively related to initial plasma renin activity (r = 0.62, p less than 0.01). Thus, the patients with the highest sympathetic activity following an acute myocardial infarction also had the highest plasma renin levels. They seem particularly prone to develop large infarcts and life-threatening complications.
In a study carried-out in double-blind fashion it was possible to demonstrate that skin vasoconstriction induced by cigarette smoking in normal volunteers is due to a concomitant enhancement of arginine vasopressin release. The skin blood flow reduction occurring after smoking was indeed more pronounced in the subjects reaching the highest levels of arginine vasopressin and this effect was curtailed by the administration of a specific vasopressin antagonist acting at the vascular site.
Current radioimmunoassays do not demonstrate total absence of angiotensin II during converting enzyme inhibition. To assess the meaning of plasma angiotensin II determinations during converting enzyme inhibition, plasma angiotensin I and II levels of normotensive humans during maximal converting enzyme inhibition by single oral doses of CGS 13945, MK 421, or MK 521 were compared with those of anephric rats (18 hr after nephrectomy) after intravenous administration of MK 422 (1 mg/kg). Prior to radioimmunoassay, plasma was extracted with Dowex for angiotensin II and blood extracted with ethanol for angiotensin I. During converting enzyme inhibition, in the 20 normotensive subjects plasma angiotensin II was 6.3 +/- 2.3 pg/ml (mean +/- S.D.) and blood angiotensin I was 65 +/- 59 pg/ml. In the nephrectomized rats, plasma angiotensin II was 8.9 +/- 2.3 pg/ml without converting enzyme inhibitor (n = 15) and 7.6 +/- 2.8 with MK 422 (n = 14), and blood angiotensin I was 9.8 +/- 2.4 pg/ml and 8.2 +/- 0.7, respectively. Dowex extraction of Tris buffer containing no angiotensin II provided blank values ranging from 5.0 to 7.8 pg/ml (n = 5). Thus plasma angiotensin II of normotensive humans treated with converting enzyme inhibitors fell to blank levels even in the presence of markedly elevated plasma angiotensin I. Angiotensin II concentrations in anephric rats with or without converting enzyme inhibition were the same. We therefore conclude that plasma levels of angiotensin II below 8 pg/ml measured after Dowex extraction probably reflect complete converting enzyme inhibition and virtual absence of angiotensin II generation.
The active fragment derived from factor XII (factor XIIf) was purified from human plasma and administered intravenously to normotensive conscious rats. Factor XIIf-mediated hypotension was dose-dependent and augmented by pretreatment with captopril, an inhibitor of the bradykinin-processing enzyme kininase II. These results therefore suggest that factor XIIf-mediated hypotension is due to the formation of bradykinin.
Thirty patients with uncomplicated essential hypertension were treated for an average of 44 months by 14 internists in private practice. All patients had previously participated in a controlled comparative trial of antihypertensive drugs carried out by the same physicians in their offices. During the long-term follow-up period, ie, after completion of the initial trial, the physicians administered antihypertensive therapy based on their best judgment; the drugs they most commonly prescribed were diuretics (80% of patients) and beta-blocking agents (60% of patients). Although 80% of the patients received at least two different antihypertensive agents, diastolic pressures fell below 96 mmHg in approximately 60% of the patients and below 90 mmHg in only a small fraction. Thus it appears that it is not easy for physicians in private practice to optimally reduce blood pressure levels in hypertensive patients despite the availability of numerous antihypertensive drugs. The tendency of practitioners to approximate blood pressure levels to multiples of 5 or even 10 mmHg may be partially responsible for the unsatisfactory results.
A direct radioimmunoassay for aldosterone in unextracted plasma was developed using a highly sensitive and specific antiserum and 125I-labeled aldosterone. This new method was compared with the previously used assay based on methylene chloride extraction and column chromatography and with a micromethod utilizing methylene chloride extraction alone. Concentrations of 2 pg/ml aldosterone can be measured in 25 microliter plasma. The within-assay coefficient of variation ranged between 4.0% and 5.3% over a sixfold range of aldosterone concentrations, and the between-assay coefficient of variation ranged between 5.0% and 9.4% over a tenfold range. The correlation coefficients among the three methods varied between 0.97 and 0.99, and results were virtually identical between the new direct and the standard chromatography methods. Normal values on unrestricted salt intake were 68 +/- 28 pg/ml (n = 30, mean +/- SD) in seated humans. In conclusion, this is an extremely simple, truly direct microradioimmunoassay for plasma aldosterone that is accurate over a wide range of plasma concentrations, is exquisitely sensitive, and provides results identical to those obtained with established methods.
The usefulness of captopril in managing hypertensive emergencies was evaluated in 9 untreated patients. During the 30 minutes following oral administration of 25 mg of this angiotensin converting enzyme inhibitor, blood pressure decreased from 239/134 to 204/118 mm Hg (p less than 0.05). At that time, furosemide (20 mg i.v. or 40 mg orally) had to be added in 5 patients to further decrease pressure levels. Ninety to 120 minutes after starting therapy, an additional dose of captopril (100 mg orally) was given to all patients. 12 and 24 hours after admission respectively, blood pressure averaged 140/93 and 139/86 mm Hg in the patients treated with captopril alone and 166/107 and 153/91 mm Hg in those treated with both captopril and furosemide. The blood pressure fall was well tolerated and no adverse effect was induced by captopril. These results show that captopril given alone or in association with a diuretic makes it possible to deal quickly and effectively with hypertensive crises without necessarily requiring monitoring in an intensive care unit.
To assess the reliability of the Remler system, a semi-automatic pressure recording device, several blood pressures were measured simultaneously by the conventional auscultatory method and by the Remler in 12 normotensive volunteers. In all situations tested both the Remler and auscultatory blood pressures were very close, thus demonstrating the reliability of this new technique. Ambulatory blood pressure recordings were then obtained with the Remler in 245 untreated patients referred for hypertension by their private physicians. Surprisingly, in close to 60% of them the average of all blood pressures recorded during usual activities was within the normal range. Since cardiovascular complications seem to correlate better with ambulatory than with office blood pressure levels, the Remler system appears particularly useful in recognizing those patients who, although hypertensive in the physician's office, remain normotensive during the day and therefore may not require antihypertensive treatment.
The blood pressure and heart rate effects of the specific pressor antagonist of vasopressin d(CH2)5Tyr(Me)AVP, 5 micrograms i.v. was evaluated in conscious normotensive rats. Our results suggest that a baroreceptor reflex mediated decrease in sympathetic nerve activity, as reflected by a slowing in heart rate, returns blood pressure to baseline levels shortly after injections of exogenous vasopressin. This has to be taken into account when interpreting the hemodynamic response to vasopressin antagonists in rats pretreated with this vasopressive hormone.
To cope with an ever-increasing number of patients with end-stage renal disease, a regionalized self-care hemodialysis program was set up and combined with the existing home and center hemodialysis, peritoneal dialysis, and renal transplantation. Five years later, of a total of 105 patients treated by hemodialysis, 66 were dialyzing themselves--31 at home and 35 in seven local self-care facilities. This proportion of patients engaging in autonomous treatment (69%) was obtained without restrictive selection criteria, since we treat 210 patients per million population with hemodialysis. The annual intake of new patients could be managed without increasing the number of center dialysis beds and by only slightly increasing the specialized staff. The cost reduction obtained with this program when compared with all center dialysis treatment represents 37%, or approximately 1,200,000 US dollars per year. These results were obtained without compromising the quality of treatment.
It is often difficult for the physician to decide the need for antihypertensive therapy on the basis of office blood pressure readings. This decision is important for the individual patient since lifelong treatment may be started in some instances though blood pressure is elevated only when taken at the physician's office. For this reason the Remler, a portable and patient-activated blood pressure recorder, appears to be very useful in evaluating ambulatory blood pressure profiles during normal daily activities.
It is now possible to record numerous ambulatory blood pressures by a noninvasive method using the Remler, a portable semi-automatic device. The blood pressure profiles obtained with this recorder in hypertensive patients during customary daily activities have revealed the existence of a circadian blood pressure variation. Thus, blood pressure is highest in the morning, lowest early in the afternoon and tends to increase again late in the afternoon. This circadian variation is not modified by treatment with diuretics and/or betablockers. These blood pressure recordings also made it possible to establish that antihypertensive therapy with these agents does not modify blood pressure variability over the day.
The antihypertensive effect of debrisoquine (20 mg/day), methyldopa (100 mg/day) and propranolol (160 mg/day) was compared to that obtained with a placebo in a controlled trial carried out by a group of 14 internists. Forty-eight patients with uncomplicated essential hypertension were included. Mefruside (25 mg/day) was first given alone for 6 weeks ("open phase" of the trial) and to this diuretic was then added in double-blind fashion and randomized sequence a placebo or an active drug. Each of the 4 blind phases lasted 4 weeks. At the end of the "open phase", blood pressure in seated position averaged 168/111 +/- 19.6/13.5 mm Hg (mean +/- SD). A significant blood pressure decrease was observed after 4 weeks of treatment with the placebo as well as with the investigated compounds. With the placebo blood pressure was reduced to 158/102 +/- 19.6/13.5 mm Hg (p less than 0.001). The magnitude of the additional blood pressure decrease induced by the active drugs was relatively small and varied from 4 (debrisoquine) to 10 mm Hg (methyldopa, p less than 0.01) for the systolic and from 3 (debrisoquine, p less than 0.05) to 5 mm Hg (propranolol, p less than 0.05) for the diastolic. The percentage of patients with systolic pressure of less than or equal to 140 mm Hg and with diastolic pressure of less than 90 mm Hg during administration of either drug was not greater than 40 to 20% respectively. Propranolol appeared to be better tolerated than the other antihypertensive agents. These rather disappointing blood pressure results suggest that the efficacy of antihypertensive agents in private practice cannot be extrapolated from studies carried out in specialized hypertension clinics.
The value of the orally active converting enzyme inhibitor captopril in managing hypertensive crisis was tested in 9 untreated patients admitted to the emergency room, who were in need of rapid blood pressure reduction because of signs and symptoms of neurological and/or cardiac complications. During the 30 min following administration of captopril 25 mg the blood pressure decreased from 239/134 +/- 12/4 mmHg (mean +/- SEM) to 204/118 +/- 8/4 mmHg (p less than 0.05). From that time on, captopril 200 to 300 mg/day was continued for 2 to 5 days. In 5 patients furosemide in a total dose of 40 to 160 mg i.v. or p.o. had also to be given in order to control the blood pressure. 12 and 24 h after admission blood pressure averaged 140/93 and 139/86 mmHg respectively, in the patients treated with captopril alone, and 166/107 and 153/91 mmHg in those treated both with captopril and furosemide. The pronounced fall in blood pressure produced by blockade of the renin system was well tolerated and did not cause tachycardia. It appears, therefore, that captopril given alone or in association with a diuretic makes it possible to treat the hypertensive crisis without the need for monitoring in an intensive care unit.