Mercuric chloride inhibition of vasopressin release from the isolated neurointermediate lobe of the rat pituitary.

The effects of HgCl2 and ouabain on vasopressin release and Ca2+ uptake and distribution was examined in the neurointermediate lobe of the rat pituitary. HgCl2 (0.5 mM) inhibited vasopressin release by approx. 90% in both basal and potassium depolarized states. With 0.1 mM HgCl2 vasopressin release was inhibited by 50% in the depolarized state, but release was not effected in basal state. On the other hand, ouabain (0.5 mM) caused a 3-fold stimulation of vasopressin release in the depolarized state. Both HgCl2 (0.5 mM) and ouabain (0.5 mM) increased net 45Ca+2 uptake by about 80% in groups of neurointermediate lobes. Following 45Ca+2 uptake, HgCl2 (0.5 mM), which is absorbed by the neurointermediate lobe, produced an increase in cytosolic 45Ca+2 content and a decrease in mitochondrial 45Ca+2 content compared to control. In comparison, ouabain (0.5 mM), which does not penetrate the neurointermediate lobe, gave no change in cytosolic 45Ca+2, but an increase in mitochondrial 45Ca+2. These results suggest that HgCl2 inhibits vasopressin release from the neurointermediate lobe of the rat pituitary at a point distal to Ca+2 uptake by the gland.

Intravenous dilevalol. Effects of the R-R optical isomer of labetalol in patients with severe hypertension.

Dilevalol hydrochloride, the R-R optical isomer of labetalol hydrochloride, was administered intravenously to subjects with severe hypertension. Twelve subjects with supine diastolic blood pressure of more than 115 mm Hg (mean, 124 +/- 2 mm Hg) were studied. Initial doses of 25 mg of dilevalol administered as a slowly given bolus reduced blood pressure by 14/16 mm Hg. With subsequent additional boluses to a total dose of up to 600 mg, supine diastolic blood pressure was reduced to less than 95 mm Hg in ten of 12 subjects studied (mean reduction, 28 mm Hg). Side effects were minimal and upright blood pressure at the time of reduction of blood pressure to goal was not significantly different from supine blood pressure. Plasma renin activity decreased in 11 of 11 subjects studied. Plasma epinephrine concentrations did not change significantly, whereas plasma norepinephrine concentrations increased 2 1/2-fold, probably reflecting the effect of beta 2-agonism on norepinephrine release. Dilevalol appears to be a safe and effective way of lowering blood pressure short term when intravenous antihypertensive therapy is indicated.

Antihypertensive effectiveness of intravenous labetalol in accelerated hypertension.

Labetalol, an antihypertensive agent that blocks both beta- and alpha-adrenergic receptors, was administered intravenously to 19 patients with accelerated hypertension who required rapid lowering of blood pressure. Systolic blood pressure was lowered from 209 +/- 4 to 143 +/- 2 mm Hg; diastolic blood pressure was reduced from 140 +/- 2 to 93 +/- 2 mm Hg. Side-effects were minimal and included nausea, epigastric burning, rhinorrhea, and premature ventricular contractions. One patient became hypotensive and required treatment. Overall, the study demonstrates labetalol to be a safe and effective agent for the emergency lowering of blood pressure, with demonstrated results comparable to other parenteral agents.

Renal function effects of dilevalol, a nonselective beta-adrenergic blocking drug with beta-2 agonist activity.

The effects of dilevalol, a new beta-adrenergic blocking agent with beta-agonism, on renal function were determined in two groups of patients. Patients in group 1, all with normal renal function, received either dilevalol or atenolol. Patients in group II, all with impaired renal function, received either dilevalol or metoprolol. Parameters of renal function determined before and after chronic oral treatment included glomerular filtration rate (GFR), effective renal plasma flow, filtration fraction, mean arterial pressure (MAP), renal blood flow, and renal vascular resistance. Dilevalol lowered MAP by 14 mm Hg (P less than 0.005) in group I and 25 mm Hg (P less than 0.01) in group II but had no effect on other parameters of renal function, at either peak or trough drug levels. Atenolol and metoprolol also lowered MAP by 11 mm Hg (P less than 0.01) and 15 mm Hg (P less than 0.05), respectively. Atenolol reduced GFR by 23% at peak drug level, an effect that was partially ameliorated at trough drug level. The effect of atenolol on GFR appeared to vary as a function of baseline renal function in that greater reductions were seen in groups of patients with increasing baseline GFR. Metoprolol significantly decreased renal vascular resistance by 17% (P less than 0.05). These data suggest that dilevalol effectively lowers blood pressure in hypertensive patients with normal or compromised renal function with no negative impact on parameters of renal function.

Pharmacokinetics, pharmacodynamics, and minimum effective clinical dose of intravenous nicardipine.

Nicardipine hydrochloride was administered intravenously to two groups of hypertensive patients: one group of 37 patients with mild to moderate hypertension and one group of 20 patients with severe hypertension. In the first group, doses of 0.5, 1, 2, and 4 mg/hr, as well as placebo, were infused for 48 hours in a double-blind fashion. Blood pressure and heart rate were monitored for this period and for the 24 hours after the infusion was discontinued. Significant decrements in blood pressure were noted with all doses; 4 mg/hr produced lowering that was greater than all other doses; 1 and 2 mg/hr produced lowering that was greater than 0.5 mg/hr but that were not different from each other. Excellent correlation of blood pressure reduction and plasma level was observed and linear kinetics existed. In the severe hypertensive patients, 1, 2, 4, 5, and 8 mg/hr were infused to established minimal and ineffective doses. One milligram per hour was an ineffective dose; 4, 5, and 8 mg/hr all produced significant reductions over the course of the study that were undistinguishable from each other. Two milligrams per hour produced modest reductions in blood pressure. Blood pressure reduction also correlated with plasma levels in the severe hypertensive group.

Intravenous nicardipine for the treatment of severe hypertension.

PURPOSE: Severe hypertension responds to treatment with nifedipine given orally or sublingually. Nicardipine hydrochloride, a water soluble dihydropyridine analogue similar to nifedipine, has less of a negative ionotropic effect and produces less reflex tachycardia than nifedipine. Our purpose was to assess the antihypertensive efficacy and safety of intravenous nicardipine in a group of patients with severe hypertension (defined as a supine diastolic blood pressure of more than 120 mm Hg). PATIENTS AND METHODS: Eighteen patients with severe hypertension received treatment with intravenous nicardipine. Nicardipine titration was performed using doses of 4 to 15 mg/hour to achieve therapeutic goal (diastolic blood pressure 95 mm Hg or less or decrease in diastolic blood pressure of more than 25 mm Hg). After this therapeutic end-point was reached, patients received maintainance therapy with nicardipine for varying lengths of time: one hour (Group I), six hours (Group II), or 24 hours. When blood pressure control was lost, patients in Groups I and II entered a second maintenance period lasting a maximum of 24 hours. Onset and offset of action of nicardipine at various infusion rates and times of infusion were measured. RESULTS: Onset time to achieve therapeutic response was rapid at 15 mg/hour (0.31 +/- 0.13 hours) when compared with lower doses (1.11 +/- 0.36 hours at 4 mg/hour; 0.54 +/- 0.09 hours at 5 mg/hour; 0.52 +/- 0.09 hours at 7 to 7.5 mg/hour). Those who showed a therapeutic response received maintenance infusions with nicardipine for one (n = 7), six (n = 6), or 24 (n = 5) hours. Sustained blood pressure control at a constant rate of nicardipine infusion was seen in all patients during the maintenance period. After discontinuation of nicardipine, the time for offset of action (increase in diastolic blood pressure of 10 mm Hg or more) was independent of duration of infusion. Decreases in both systolic and diastolic pressures correlated well with plasma nicardipine levels. Heart rate increased by about 10 beats/minute, but this increase did not correlate with plasma nicardipine levels. Side effects were minimal, consisting of headache and flushing. In seven patients, local phlebitis developed at the site of infusion. This occurred after at least 14 hours of infusion at a single site, and the incidence can probably be reduced by shortening the infusion time at a single site. CONCLUSION: Nicardipine appears to be a safe and effective drug for intravenous use in the treatment of severe hypertension.

Effects of dilevalol on renal function.

Renal function was measured in a total of 35 volunteers and patients who were given dilevalol, the R,R optical isomer of labetalol. Young normotensive volunteers (n = 6) and elderly normotensive volunteers (n = 12) received single 400- and 200-mg doses of dilevalol, respectively. Renal function was determined in these subjects on the same day before and after dosing. In addition, patients with mild to moderate essential hypertension (n = 11) and hypertensive patients with renal insufficiency (n = 6) were treated with placebo to establish baseline blood pressure and then were given dilevalol, 400 to 1,600 mg/day, for 2 to 6 weeks until blood pressure was controlled. Renal function was determined at the end of the baseline period and again at the end of dilevalol treatment. A subgroup of elderly hypertensives from the 2 protocols used to study hypertensive patients was treated as a separate study group. The only effect on parameters of renal function seen in any of the study groups was a statistically significant 15% decrease in glomerular filtration rate after single-dose treatment in the elderly normotensive group. Effective renal plasma flow, filtration fraction, renal blood flow and renal vascular resistance were unchanged before and after treatment in all groups. Mean arterial pressure was reduced significantly in all groups except in the elderly normotensive volunteers. Dilevalol appears to be a well-tolerated, effective therapeutic agent that is neutral regarding its effect on renal function and potentially useful in a variety of patient populations.

Intravenous nicardipine in severe systemic hypertension.

Sixty-six patients with severe hypertension were treated with intravenous nicardipine in 3 separate protocols. Each protocol had a common end point: Diastolic blood pressure would either reduce 25 mm Hg or measure below 95 mm Hg. Each of the 66 patients studied attained the desired clinical response end point. Intravenous nicardipine produced a gradual reduction in blood pressure, was effective in maintaining blood pressure control during constant infusion and had few undesirable effects. These observations suggest that intravenous nicardipine maybe a useful addition to a limited number of therapeutic agents currently available to the physician for treatment of hypertensive urgencies.

The renal function and blood pressure effects of dilevalol in the normotensive and hypertensive elderly.

Dilevalol, the R-R optical isomer of labetalol, is a nonselective beta adrenergic blocking drug with selective beta-2 agonist properties. In a double-blind, crossover study the renal function effects of dilevalol were compared to placebo in 12 normotensive elderly volunteers before and after single dose administration. In addition, chronic treatment (greater than 4 weeks) effects of dilevalol were determined in eight elderly patients with mild to moderate essential hypertension. Renal function was determined by plasma disappearance curves from single injections of 99mTc-DTPA and 131I-orthohippurate. In both study populations renal function tests commenced two hours after dosing at expected peak plasma levels of dilevalol. Normotensive volunteers had an acute decrease in glomerular filtration rate of 10.3 ml/min, which was significant (P less than 0.05), while hypertensive patients had no change in glomerular filtration rate. There were no significant changes in other parameters of renal function measured. In the hypertensive elderly dilevalol treatment resulted in significant reductions, 18 and 19 mmHg respectively, of systolic (P less than 0.01) and diastolic (P less than 0.001) blood pressure. Heart rate was reduced by 5 beats per minute, and the change was not statistically significant. Dilevalol appears to be an excellent agent for treatment of hypertension in the elderly hypertensive patient, and does not change renal function when administered chronically to the hypertensive patient. Small but significant decrements in glomerular filtration rate occur with acute administration to normotensive volunteers.

Monoexponential analysis of plasma disappearance of 99mTc-DTPA and 131I-iodohippurate: a reliable method for measuring changes of renal function.

Glomerular filtration rate and effective renal plasma flow were measured in 170 subjects using monoexponential analysis of plasma disappearance curves for 99mTc-DTPA and 131I-iodohippurate after single injection. In the current study population, glomerular filtration rate and effective renal plasma flow decreased with increasing age, were less in females than in males, and were less in hypertensives than in normotensives. Differences in glomerular filtration rate according to age and sex in the current study were similar to those reported using traditional creatinine clearance methodology. Monoexponential treatment of plasma isotope disappearance gave reproducible values for both glomerular filtration rate and effective renal plasma flow when measured either during the day or on a daily basis. Intraindividual coefficient of variation was less than 10% for both 99mTc-DTPA and 131I-iodohippurate clearances derived from monoexponential analysis. These results demonstrate that monoexponential analysis of plasma disappearance curves for 99mTc-DTPA and 131I-iodohippurate after a single injection is a useful method for evaluating changes in renal hemodynamics either during chronic drug therapy or acutely after single dose administration.

The effects of mercuric chloride on calmodulin-mediated Ca2+ transport in rat brain.

We have shown previously that mercuric chloride (HgCl2) inhibits in vitro vasopressin release from the isolated rat neurohypophysis with maximum inhibition occurring with 0.5 mM HgCl2. Associated with the inhibition of hormone release is an increase in 45Ca+2 uptake, an increase in cytosolic 45Ca+2, and a reduction of 45Ca+2 accumulation by mitochondria in the intact gland. In the present series of studies, the effect of HgCl2 on calmodulin (CM) function in neural tissue preparations is reported. Mercuric chloride (0.5 mM) reduced 45Ca+2 binding to CM purified from bovine neurohypophyses by 20% and inhibited endogenous CM-stimulated Ca,Mg-ATPase activity from rat brain mitochondria in a dose-dependent fashion. Ca,Mg-ATPase activity was inhibited by 50 and 80% with 0.5 and 5.0 mM HgCl2, respectively. CM-stimulation of Ca,Mg-ATPase activity was inhibited by calmidazolium (CMZ) with maximal inhibition seen with 0.1 mM CMZ. Reversibility of the HgCl2 interaction with CM was demonstrated using CM-stimulated phosphodiesterase (PDEase) activity from rat brain. HgCl2 inhibited both basal and CM-stimulated PDEase activity in a dose-dependent manner with maximum inhibition occurring with 1.0 mM HgCl2. Preexposure of CM to an inhibitory concentration (1.0 mM) of HgCl2 resulted in no loss of stimulatory PDEase enzyme activity. From these results, we conclude that HgCl2 reversibly interferes with 45Ca+2 binding to CM and also inhibits CM-regulated Ca+2 pumping enzyme systems in the neurohypophysis. The inhibition of vasopressin release from the intact gland in the presence of HgCl2 thus, may be associated with a disruption of calcium in the neurohypophysis.

Intravenous nicardipine: an effective new agent for the treatment of severe hypertension.

Fifty-six patients with severe hypertension were treated with intravenous nicardipine for infusion periods of eight to twenty-four hours. Each patient achieved satisfactory blood pressure control during the infusion period with a mean controlling dose of 7.85 mg/hr. The dose of nicardipine needed for sustained blood pressure control correlated with untreated diastolic blood pressure but not with untreated systolic blood pressure. These results demonstrate the potential usefulness of intravenous nicardipine for the treatment of severe hypertension requiring rapid lowering, and they suggest also that the severity of pretreatment diastolic hypertension might be a useful indicator of the dose required for blood pressure control.

Early polyuria in the rat following single-dose cis-dichlorodiammineplatinum (II): effects on plasma vasopressin concentration and posterior pituitary function.

Central effects associated with DDP-induced early polyuria are described. Male Sprague-Dawley rats injected intraperitoneally with DDP (5 mg/kg) have a threefold increase in urine volume in the first 24 hr after treatment. This is accompanied by a corresponding decrease in Uosm but no decrease in renal function as indicated by serum creatinine or GFR. Treated animals having free access to water have reduced levels of plasma AVP, 1.42 +/- 0.14 pg/ml compared to 2.63 +/- 0.47 for control, at 8 hr after injection, and treated animals deprived of water have decreased plasma AVP at 12 and 24 hr after injection. The early polyuria in DDP-treated animals can be prevented by the administration of exogenous AVP. At 8 hr after DDP injection, posterior pituitary AVP content is identical in treated and control rats. In vitro studies with isolated pituitaries show that DDP, either 0.85 and 1.7 mM, in the medium inhibits AVP release by 60% to 90% during two successive 10 min incubation periods. These results suggest that DDP inhibits AVP release from the posterior pituitary but has no effect on AVP synthesis. This inhibition of AVP release results in lowered plasma AVP levels, which reduces water reabsorption and causes polyuria.

Antimetabolites of pantothenic acid, ureido- and carbamoyl-derivatives.

Pantothenic acid analogs have been synthesized that contain alkyl and/or arylureido and carbamate functions in the beta-alanyl portion of the amide moiety of the vitamin. The analogs are inhibitory to growth of lactic acid bacteria at concentrations as low as 0.6 mug/ml, and the inhibitions are competitively reversed by supplements of pantothenic acid. The carbamate derivatives are more toxic to growth of Lactobacillus plantarum 8014 and Pediococcus cerevisiae 8042 than the ureido analogs, and chloro-substitutents on the aryl group significantly increase the toxicity of the analogs.

Renal versus hindquarter hemodynamic responses to vasopressin in conscious rats.

Experiments were performed on conscious rats to (a) compare the responsiveness of the renal and hindquarter vascular beds to infusions of exogenous arginine vasopressin (AVP), and (b) determine whether either bed demonstrates V2-vasopressinergic vasodilation when the vasoconstrictor properties of AVP are blocked. Rats were chronically instrumented with pulsed Doppler flow probes on either the left renal artery or the distal abdominal aorta as well as with femoral arterial and venous catheters. One series of experiments examined the vascular responses of these two beds to exogenous AVP infused intravenously (i.v.) at 0.2, 2.0, or 5.0 ng/min. The lowest infusion rate was associated with no detectable changes in mean arterial blood pressure (MAP), heart rate (HR), renal or hindquarter blood flow (RBF or HQBF), or vascular resistance in these beds. In contrast, the higher infusion rates caused a marked increase in MAP, a decrease in HR, and a reduction in HQBF; RBF was unaffected, however. A second series of experiments tested for the presence of a V2-vasodilatory influence during infusion of AVP at 5 ng/min by selectively blocking V1-vasopressinergic receptors or both V1- and V2-receptor types. Little evidence for V2-mediated vasodilation was found in either vascular bed, however. We conclude that although the renal vasculature appears relatively insensitive to exogenous AVP, this insensitivity probably is not due to vasodilation mediated by activation of V2-receptors.

Changes of plasma renin activity and atrial natriuretic factor during intravenous nicardipine treatment of severe hypertension.

Intravenous nicardipine was given to 32 severe hypertensive patients in an increasing dose, titration fashion. Samples for plasma renin activity and plasma atrial natriuretic factor concentration were obtained at the following times: before treatment, at the time of titration response and at the end of a maintenance period. The mean time required to achieve the titration response was 29 min. Plasma renin activity was increased by 32% (p less than 0.05) at the titration response and 181% (p less than 0.005) at the end of an 8-12 h maintenance nicardipine infusion. Atrial natriuretic factor concentration was unchanged from baseline at titration response and was decreased by 25% (p less than 0.005) at the end of maintenance. Mean plasma nicardipine dose was 6.95 mg/h at the titration response and 8.76 mg/h at the end of maintenance. These results suggest that alterations in plasma renin activity and atrial natriuretic factor concentrations may be associated with blood pressure reduction rather than with a direct drug action on release mechanisms.

Hemodynamic responses to vasopressinergic antagonism in water-deprived conscious rats.

Experiments were performed on conscious, chronically instrumented rats to determine the role of arginine vasopressin (AVP) on the systemic and regional hemodynamic effects of 48-h water deprivation. Arterial and venous catheters as well as pulsed Doppler flow probes were implanted in rats to measure cardiac output (CO), mesenteric blood flow (MBF), renal blood flow (RBF), or hindquarter blood flow (HQBF). After adequate recovery from surgey, euhydrated animals were administered a specific V1-vasopressinergic antagonist [d(CH2)5Tyr(Me)AVP, 10 micrograms/kg iv], a combined V1, V2-antagonist [d(CH2)5DTyr(Et)VAVP, 30 micrograms/kg iv], or saline vehicle (100 microliter/100 g). Neither antagonist was associated with any change in mean arterial blood pressure (MABP), heart rate (HR), systemic or regional flow or vascular resistance. All animals were subsequently water deprived for 48 h, at which time the experiments were repeated. Dehydration was associated with an increase in plasma AVP levels, hematocrit, and MABP but with a decrease in HR. Administration of either the combined V1, V2-antagonist or vehicle had no effect on any systemic or regional hemodynamic variables measured after 48-h dehydration. In contrast, although MABP, CO, MBF, and RBF were unaffected, V1-antagonism resulted in elevated HR, increased HQBF, and decreased hindquarter vascular resistance. In conclusion, AVP does not have a major effect on systemic hemodynamics in the dehydrated rat. However, certain beds may be affected by the relatively moderate levels of plasma AVP elicited during dehydration.

Nicardipine in severe hypertension: oral therapy following intravenous treatment.

Nicardipine is an investigational dihydropyridine calcium-channel blocker. In the present study, 21 patients with severe hypertension were treated with oral nicardipine, alone or in combination with beta-blockers and diuretics for 4-5 weeks, following initial control of their blood pressure with intravenous nicardipine. Each of the 21 patients had a satisfactory response to intravenous nicardipine which was administered as an infusion following initial blood pressure lowering. At 1 h prior to discontinuation of the intravenous treatment, oral nicardipine therapy was begun as a 40 mg dose. Oral nicardipine, 40 mg t.i.d., was continued for the remainder of hospitalization and for a 4-5-week outpatient follow-up period. The dose of oral nicardipine was downtitrated and additional antihypertensive drugs, beta-adrenergic blocking agents and/or diuretics, were added to maintain blood pressure in an acceptable range. Compared to baseline, mean supine systolic blood pressure was lowered significantly (p less than 0.001) by 57 mmHg at the end of intravenous maintenance and by 50 mmHg at the end of oral treatment. Likewise, significant (p less than 0.001) decreases in diastolic blood pressure of 43 and 32 mmHg, respectively, were observed for the same time periods. At the end of oral treatment, 6 patients remained on nicardipine monotherapy, 8 patients were on two-drug therapy and 7 patients required three-drug therapy. Side-effects were mild except for a moderate headache reported in one patient during intravenous treatment. From these observations we conclude that oral nicardipine is a useful new agent for initial, single treatment of chronic severe hypertension, although a significant number of patients eventually need additional antihypertensive therapy.