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PubMed1983

[Effects of guanabenz on the cardiovascular system, in comparison with clonidine and guanethidine].

Cardiovascular actions of guanabenz, a new antihypertensive agent, were studied in comparison with those of clonidine and guanethidine. Guanabenz, administered intravenously, produced a rise of blood pressure which was followed by a prolonged fall in anesthetized dogs. Guanabenz also decreased the heart rate, inhibited the respiration, and produced an alteration in T wave and a prolongation of PQ or TP interval in the ECG of the dog. Such effects of guanabenz on blood pressure and heart rate were observed in the cat, rabbit and rat, but there was a slight species-difference in the effects. Clonidine, but not guanethidine, produced responses similar to those of guanabenz. The potency of guanabenz to produce hypotension and bradycardia was approximately 1/10 that of clonidine and 10 times higher than that of guanethidine. The depressor effect of guanabenz was not observed in the spinal cats; thus, the blood pressure rose after the administration. When guanabenz was administered intracerebroventricularly or into the nucleus tractus solitarius of rats, the initial pressor response was not produced, and the depressor and bradycardiac responses were observed. Guanabenz, administered intravenously or intra-arterially, produced an inhibition of cardiac functions, decreased the blood flow of common carotid and femoral arteries, and elevated the perfusion-pressure of the hindlimb in the dog. In the isolated rabbit and guinea-pig atria, guanabenz produced negative inotropic and chronotropic effects and attenuated the rate of rise of the action potential. The contractile responses to serotonin and histamine in the isolated rabbit thoracic aorta were noncompetitively inhibited by guanabenz. From these results, it is suggested that the hypotensive and bradycardiac actions of guanabenz are mediated via central actions, as well as those of clonidine. Furthermore, in addition to the central actions, it was found that guanabenz acts directly on cardiovascular tissues and attenuates the responsiveness.

Animals↗
PubMed1991

Guanabenz-induced inhibition of aldosterone secretion from isolated rat adrenal glomerulosa cells.

The authors examined the effects of the alpha 2-adrenergic agonist guanabenz and other alpha-adrenergic ligands on aldosterone secretion and cyclic nucleotide content in isolated rat adrenal glomerulosa cells. Guanabenz inhibited aldosterone secretion stimulated by potassium, angiotensin II (AII), and adrenocorticotropic hormone (ACTH), exhibiting IC50 values of 35 microM, 43 microM, and 58 microM for stimulation by 10 mM K+, 1 nM AII, and 10 pM ACTH, respectively. Guanabenz did not affect the cGMP content of purified adrenal glomerulosa cells but inhibited ACTH stimulation of cAMP accumulation. Guanabenz inhibition of ACTH-induced cAMP may represent a mechanism for inhibition of aldosterone secretion, however, guanabenz also inhibited aldosterone secretion stimulated by the cAMP analog dibutyryl cAMP. The effect of guanabenz on the early and late pathways of steroidogenesis was tested in the isolated rat glomerulosa cells using 25-OH cholesterol and steroid precursors to aldosterone. Guanabenz inhibited the steroidogenic response to 25-OH cholesterol stimulation of aldosterone secretion but induced a much smaller inhibition of the steroidogenic response to exogenous pregnenolone, progesterone, and 11-deoxycorticosterone. These results suggested that guanabenz inhibited aldosterone secretion primarily through inhibition of the early component of the steroidogenic pathway prior to pregnenolone formation. The effects of guanabenz were not mimicked by other alpha-adrenergic ligands suggesting that these effects of guanabenz were not mediated through activation of alpha-adrenergic receptors.

Adrenocorticotropic Hormone↗
PubMed2006

Tetrahydrobiopterin protects against guanabenz-mediated inhibition of neuronal nitric-oxide synthase in vitro and in vivo.

It is established that guanabenz inhibits neuronal nitric-oxide (NO) synthase (nNOS) and causes the enhanced proteasomal degradation of nNOS in vivo. Although the time- and NADPH-dependent inhibition of nNOS has been reported in studies where guanabenz was incubated with crude cytosolic preparations of nNOS, the exact mechanism for inhibition is not known. Moreover, even less is known about how the inhibition of nNOS triggers its proteasomal degradation. In the current study, we show, with the use of purified nNOS, that guanabenz treatment leads to the oxidation of tetrahydrobiopterin and formation of a pterin-depleted nNOS, which is not able to form NO. With the use of 14C-labeled guanabenz, we were unable to detect any guanabenz metabolites or guanabenz-nNOS adducts, indicating that reactive intermediates of guanabenz probably do not play a role in the inhibition. Superoxide dismutase, however, prevents the guanabenz-mediated oxidation of tetrahydrobiopterin and inhibition of nNOS, suggesting the role of superoxide as an intermediate. Studies in rats show that administration of tetrahydrobiopterin prevents the inhibition and loss of penile nNOS due to guanabenz, indicating that the loss of tetrahydrobiopterin plays a major role in the effects of guanabenz in vivo. Our findings are consistent with the destabilization and enhanced degradation of nNOS found after tetrahydrobiopterin depletion. These studies suggest that drug-mediated destabilization and subsequent enhanced degradation of protein targets will likely be an important toxicological consideration.

Animals↗
PubMed1982

Comparative antihypertensive effects of guanabenz and clonidine.

The safety and efficacy of guanabenz and clonidine were compared in 188 hypertensive patients during a 6-month double-blind trial. Mean supine diastolic blood pressure (SDBP) decreased from 103 to 88 mm Hg (p less than 0.01) among guanabenz patients and from 101 to 88 mm Hg (p less than 0.01) among clonidine patients who completed 6 months of b.i.d. therapy. Clinically significant individual SDBP decreases occurred in 85% of the guanabenz patients and 83% of the clonidine patients after 6 months. Adverse effects, consisting primarily of drowsiness, dry mouth, dizziness, and weakness, were similar in the two therapy groups. The responses obtained with guanabenz (b.i.d.) were maintained, along with a decrease in adverse effects, by an equivalent single daily dose of guanabenz during a second 6 months of therapy. Seventy-six per cent (13/17) of the patients whose blood pressure was not adequately controlled by guanabenz alone after 8 weeks of therapy subsequently responded to a combination of guanabenz and hydrochlorothiazide. Similarly, 85% (17/20) of the patients who failed to respond to clonidine alone subsequently responded to guanabenz either alone or in combination with hydrochlorothiazide. These results suggest that guanabenz or the combination of guanabenz and hydrochlorothiazide is effective therapy for the majority of hypertensive patients.

Adult↗
PubMed1981

Effect of guanabenz and hydrochlorothiazide on blood pressure and plasma renin activity.

Patients with mild to moderate essential hypertension were treated with guanabenz plus placebo (26 patients) or guanabenz plus hydrochlorothiazide (26 patients) for one year. Ambulatory plasma renin activity was determined during placebo treatment, after four weeks and one year of treatment with the study drugs, and one month after discontinuation of guanabenz while continuing the same hydrochlorothiazide dosage. Treatment with guanabenz plus hydrochlorothiazide proved more satisfactory than treatment with guanabenz plus placebo in that fewer patients were treatment failures, a smaller dosage of guanabenz was required, better control of supine blood pressure was achieved, and no increase in guanabenz dosage was needed to maintain chronic blood pressure control. Drowsiness, dry mouth, and dizziness were the side effects noted most commonly. Plasma renin activity was not significantly suppressed by chronic guanabenz therapy. Thus, guanabenz is an effective new antihypertensive that provides optimal blood pressure control when used with a diuretic.

Adult↗
PubMed1996

Inhibition of sympathetic noradrenergic transmission by guanabenz and guanethidine in rat isolated mesenteric artery: involvement of neuronal potassium channels.

The present study investigated the effects of the alpha 2-adrenoceptor agonist guanabenz and the adrenergic neurone blocking drug guanethidine on the resting and stimulation-induced (S-I) effluxes of radioactivity from rat isolated mesenteric artery preparations in which the noradrenergic transmitter stores had been radiolabelled with [3H]-noradrenaline. The efflux of radioactivity evoked by electrical field stimulation of periarterial sympathetic nerves (60 s trains of 1 ms pulses, 2 Hz, 12 V) was taken as an index of transmitter noradrenaline release. Guanabenz (0.1-10 microM) decreased, in a concentration-dependent manner, both the resting and S-I effluxes of radioactivity. Guanethidine (0.1 and 1 microM) also decreased S-I efflux but increased resting efflux, both effects being concentration dependent. The inhibitory effects of guanabenz on both resting and S-I effluxes were reduced by blockade of the neuronal amine carrier with desipramine (1 microM). The inhibitory effect of guanabenz on resting efflux was prevented by inhibition of monoamine oxidase with pargyline (100 microM). The inhibitory effect of guanabenz on S-I efflux was not due to activation of prejunctional alpha 2-adrenoceptors since the inhibition was not blocked by the selective alpha 2-adrenoceptor antagonist idazoxan (0.1 microM). However, the inhibitory effect of guanabenz and guanethidine on S-I efflux was reduced by the inhibitor of Ca(2+)-activated potassium channels apamin (0.1 microM). The findings suggest that guanabenz, like guanethidine, enters noradrenergic nerve terminals by the neuronal amine carrier. The inhibition of resting efflux produced by guanabenz may be due to inhibition of neuronal monoamine oxidase. The enhancement of resting efflux produced by guanethidine is attributable to its indirect sympathomimetic action. Finally, guanabenz and guanethidine may inhibit transmitter noradrenaline release by activating potassium channels on sympathetic noradrenergic nerve terminals. These findings may be relevant to the mechanism of adrenergic neurone blockade.

Adrenergic Agents↗
PubMed1986

Guanabenz: a centrally acting, natriuretic antihypertensive drug.

Guanabenz is acutely natriuretic and diuretic in saline expanded animals. In man, guanabenz has not resulted in sodium retention as seen with other comparable antihypertensives. To directly define the action of guanabenz on sodium and water excretion in man, we performed clearance studies during water diuresis on eight hypertensive subjects under metabolic balance conditions. Each subject underwent three studies: 1) baseline study: no drug, a water diuresis study; this was followed by a saline load (= 2% BW); 2) acute study (24 hr after baseline): 16 mg guanabenz PO; and 3) chronic study: after one week of guanabenz 8 mg PO BID. In the acute guanabenz studies there were: 1) no changes in GFR or ERPF; 2) an increase in both sodium excretion and fractional sodium excretion; 3) a rise in free H2O clearance (CH2O) and (CH2O/GFR) X 100%. These findings were not sustained in the chronic guanabenz studies. We conclude that in man (preconditioned with prior saline loading) guanabenz is acutely natriuretic and water diuretic. These effects are due to decreased tubular sodium and water reabsorption, probably related to inhibition of alpha adrenergic activity. The data are consistent with selectively reduced renal sympathetic activity affecting sodium transport and provide a basis for the absence of edema and sodium retention associated with guanabenz therapy.

Adult↗
PubMed1984

Inhibition of hepatic cholesterol and triglyceride synthesis by guanabenz acetate.

Abundant evidence exists for the cumulative adverse effects of hypertension and hypercholesterolemia on the progression of coronary heart disease. The antihypertensive drug guanabenz acetate has been shown to lower serum cholesterol levels, but the mechanism for this effect is unclear. To explore this problem, suspensions of rat liver cells were incubated with guanabenz and labeled lipogenic precursors. Guanabenz produced an inhibition of cholesterol production from [14C]acetate that ranged from 10% at 0.005 mM guanabenz to 90% at 0.20 mM guanabenz. Inhibition of cholesterol production from [14C]mevalonate was half as great as inhibition from [14C]acetate. Thus, guanabenz inhibits hepatic cholesterol production at both pre- and postmevalonic sites in the sterol pathway. Synthesis of triglycerides from [14C]palmitate also was inhibited by guanabenz, whereas oxidation of [14C]palmitate to 14CO2 was stimulated. Therefore, the inhibition of triglyceride formation from fatty acid produced by guanabenz may be due to the stimulation of fatty acid oxidation. The clinical effects of guanabenz on serum lipid levels may relate to its direct actions on hepatic cholesterol and triglyceride biosynthesis.

Animals↗
PubMed1987

The antiinflammatory action of guanabenz is mediated through 5-lipoxygenase and cyclooxygenase inhibition.

Guanabenz (2,6-dichlorobenzylidene amino guanidine acetate), an alpha 2-agonist, possesses antiinflammatory activity. Since leukotrienes (LT) and prostaglandins (PG) are proinflammatory substances, the effect of guanabenz on LT and PG synthesis by inflammatory cells was investigated. Guanabenz, but not clonidine, B-HT 920 or B-HT 933 inhibited zymosan-induced LTC4 (IC50 = 13 microM) and PGE2 (IC50 = 10.9 microM) synthesis with no concomitant reduction in zymosan phagocytosis or cell viability. Similarly, guanabenz reduced LTB4 (IC50 = 37.4 microM) and PGE2 (IC50 = 13.8 microM) synthesis by A23187-stimulated rat glycogen elicited neutrophils. Furthermore, guanabenz did not inhibit platelet 12-lipoxygenase or phospholipase A2. In vivo, guanabenz was orally active against rat carrageenan paw edema and adjuvant arthritis (ED50s = 9 and 10 mg/kg, respectively). Topically applied guanabenz reduced arachidonic acid (AA)- or tetradecanoyl phorbol acetate (TPA)-induced ear inflammation (ED50s: AA-induced ear edema, 1.4 mg/ear; PMA-induced ear edema, 0.013 mg/ear). Therefore, the antiinflammatory activity of guanabenz may be due to its ability to inhibit the formation of 5-lipoxygenase and cyclooxygenase products.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1984

Dose-response relationship of single oral doses of guanabenz in hypertensive patients.

A single-blind, placebo-controlled study was conducted to determine the dose-response relationship of guanabenz, administered as single oral doses to patients with mild or moderate hypertension. Twelve hypertensive patients received ascending oral doses of 2, 4, 8, 16, 24, and 32 mg of guanabenz. Dose-response relationships were evaluated for the nine patients who received placebo and all six guanabenz doses. The greatest maximum response (40/24 mm Hg) was seen for the 16 mg guanabenz dose. Since eight of the nine patients had mild hypertension, they may have responded maximally to the lower guanabenz doses, precluding larger decreases with the 24 and 32 mg doses. The mean onset of satisfactory blood pressure reduction decreased from 4 to 2 h and the mean duration increased from 6 to 22 h as the oral dose was increased from 2 to 32 mg. In eight patients, the responses to 16 mg of guanabenz administered sublingually and orally were compared. The sublingual and oral routes produced similar mean (20/13 mm Hg) and maximum (33/24 mm Hg) blood pressure decreases as well as mean onset (2 h) and duration (16.5 h) of satisfactory response. Additional studies involving patients with more severe hypertension are needed to further characterize the dose-response relationship of oral guanabenz and to establish a dose-response relationship for sublingual guanabenz.

Administration, Oral↗
PubMed1980

Effects of placebo versus guanabenz on hypertensive out-patients.

The objectives of this study were two-fold: (1) 1 4-week multicentre, randomized, double-blind efficacy comparison of placebo and guanabenz acetate, a new centrally acting antihypertensive drug, in 168 hypertensive out-patients and (2) a more accurate determination of the incidence of drug-related, non-specific side-effects. Both treatment groups were comparable: 68% female, 63% black, mean age 53 years; 57% mild, 32% moderate, 11% moderately severe hypertensives. Seventy-six placebo patients completed 4 weeks and had a mean supine diastolic blood pressure (SDBP) decrease from 105 to 101 mm Hg (p < 0.01). Seventy-nine guanabenz patients completing 4 weeks had a mean SDBP decrease from 104 to 92 mm Hg (p < 0.01). All of the placebo responses and 10/12 mm Hg of the guanabenz response occurred during Week 1. Clinically significant individual SDBP decreases occurred in thirty-one (41%) placebo and fifty-five (70%) guanabenz-treated patients (p < 0.01). Mean daily guanabenz dose was 24 mg. Drug-related biochemical or electrocardiographic abnormalities were absent. Side-effects of sedation and dry mouth were recorded two and three times more frequently, respectively, in guanabenz as compared to placebo patients. Side-effects usually occurred within Week 1 and diminished in incidence thereafter. Consequently, in these patients it appeared that: (1) guanabenz was an effective, well-tolerated drug, (2) placebo effects on efficacy were significant, occurred early and remained stable, and (3) placebo and guanabenz side-effects were mainly sedation and dry mouth.

Adult↗
PubMed2003

The detection and biotransformation of guanabenz in horses: a preliminary report.

Guanabenz (2,6-dichlorobenzylidene-amino-guanidine) is a centrally acting antihypertensive drug whose mechanism of action is via alpha2 adrenoceptors or, more likely, imidazoline receptors. Guanabenz is marketed as an antihypertensive agent in human medicine (Wytensin tablets, Wyeth Pharmaceuticals). Guanabenz has reportedly been administered to racing horses and is classified by the Association of Racing Commissioners International as a class 3 foreign substance. As such, its identification in a postrace sample may result in significant sanctions against the trainer of the horse. The present study examined liquid chromatographic/tandem quadrupole mass spectrometric (LC-MS/MS) detection of guanabenz in serum samples from horses treated with guanabenz by rapid i.v. injection at 0.04 and 0.2 mg/kg. Using a method adapted from previous work with clenbuterol, the parent compound was detected in serum with an apparent limit of detection of approximately 0.03 ng/ml and the limit of quantitation was 0.2 ng/ml. Serum concentrations of guanabenz peaked at approximately 100 ng/ml after the 0.2 mg/kg dose, and the parent compound was detected for up to 8 hours after the 0.04 mg/kg dose. Urine samples tested after administration of guanabenz at these dosages yielded evidence of at least one glucuronide metabolite, with the glucuronide ring apparently linked to a ring hydroxyl group or a guanidinium hydroxylamine. The LC-MS/MS results presented here form the basis of a confirmatory test for guanabenz in racing horses.

Animals↗
PubMed1987

[Does guanabenz have a non-specific effect on spontaneous contractions of isolated guinea pig atria?].

Guanabenz was found to produce a concentration-dependent depression of the isometric contractility of the isolated, spontaneously beating atria of the guinea-pig. It also depressed the atrial rate of the isolated, spontaneously beating atria of the guinea-pig. The effect of the increasing concentrations of guanabenz on the heart rate was weaker than its effect on the isometric contraction. A time-dependent depression of both the isometric contraction and of the atrial rate after the addition of a single dose of guanabenz was also found up to 10th min. Guanabenz did not change the maximal driving (following) frequency of the atria. Aminophylline partially, isoprenaline almost completely and calcium completely antagonized the negative inotropic action of guanabenz. They, however, did not antagonize the negative chronotropic action of guanabenz. It seems, regardless of what the precise mechanism(s) of action of guanabenz may be (probably nonspecific on the isolated guinea-pig atria), that all these substances (aminophylline, isoprenaline and calcium) restore the contractility of the isolated atria by compensating the calcium balance which has been previously changed by guanabenz.

Aminophylline↗
PubMed1997

Formation of guanoxabenz from guanabenz in human liver. A new metabolic marker for CYP1A2.

The in vitro N-hydroxylation of guanabenz as well as the corresponding N-dehydroxylation of guanoxabenz has been previously detected in biotransformation studies with microsomal fractions of different species including human hepatic microsomes. Furthermore, the N-hydroxylation of guanabenz was found to be catalyzed by enriched cytochrome P450 (P450) fractions in reconstituted systems. Strong correlations between 7-ethoxyresorufin O-deethylation (r = 0. 96; p < 0.001), caffeine N-demethylation (r = 0.92; p < 0.001), respectively, and guanabenz N-hydroxylation activities were demonstrated in 10 human liver microsomal preparations. Studies with microsomes from human B-lymphoblastoid cell lines expressing human cytochrome P450 enzymes proved that CYP1A2 is the major isozyme responsible for this metabolic pathway. Further, P450 isozymes did not show any detectable conversion rates. The reaction was inhibited in presence of the potent CYP1A2 inhibitors alpha-naphthoflavone (7, 8-benzoflavone) and furafylline. The N-reduction of guanoxabenz to guanabenz exhibits a significant correlation to the benzamidoxime N-reduction after incubation with 10 human liver microsomal preparations (r = 0.97; p < 0.001). The formation of benzamidine from benzamidoxime was described previously to be catalyzed by the benzamidoxime reductase. These results suggest that the guanabenz N-hydroxylation is mediated via CYP1A2, whereas the corresponding guanoxabenz N-reduction is catalyzed by an enzyme system composed of cytochrome b5, NADH cytochrome b5-reductase, and benzamidoxime reductase. The high affinity of guanabenz to CYP1A2 and the distinct selectivity of this P450 isozyme toward guanabenz confirms the in vitro guanabenz N-hydroxylation to be a suitable metabolic marker for CYP1A2 in biotransformation studies.

Antihypertensive Agents↗
PubMed1982

Presynaptic dual inhibitory actions of guanabenz on adrenergic transmission.

Actions of guanabenz, clonidine and guanethidine on adrenergic transmission were studied in rabbit atria and ilea with intact nerves. While guanabenz 3 X 10(-6) M and clonidine 3 X 10(-7) M inhibited to a similar degree atrial positive chronotropic responses to nerve stimulation at 2 Hz, no inhibition was seen at 10 Hz. Phentolamine 3 X 10(-6) M completely antagonized the inhibition by clonidine, but a partial antagonism was seen against guanabenz. Cocaine 10(-5) M prevented the phentolamine-resistant inhibition by guanabenz. Guanethidine 10(-5) M inhibited the responses to 2 and 10 Hz. In ilea, guanabenz 10(-5) M inhibited frequency-independent relaxation responses to 2-20 Hz. Clonidine 10(-5) M inhibited preferentially the responses to lower frequencies. After the temperature of the bathing solution was kept at 4 degree C during the period of drug application, guanabenz no longer produced an inhibition of the transmission, whereas clonidine produced the usual inhibition. Thus, guanabenz appears to have both presynaptic alpha-receptor stimulating and adrenergic neuron blocking actions.

Animals↗
PubMed1998

Differential effects of rANF and chronic guanabenz to presynaptic and postsynaptic alpha 2-adrenoceptor-mediated cardiovascular response in pithed rats.

1. In normal rats, intracerebroventricular (i.c.v.) guanabenz induced a decrease in blood pressure (BP) and heart rate (HR), and this hypotension or bradycardia was not changed by rANF pretreatment (3 micrograms i.c.v.). 2. In pithed rats, intravenous (i.v.) guanabenz, an alpha 2-adrenoceptor agonist, produced an increase in mean blood pressure (MBP) in a dose-dependent manner. The pressor response by guanabenz was attenuated by infusion of rANF. This attenuation was additive when incubated in combination with yohimbine. 3. In pithed rats, the pressor response due to the increase of sympathetic outflow with electrical stimulation was partially blocked by rANF infusion or chronic guanabenz treatment. This reduction was not augmented by chronic guanabenz plus rANF treatment. 4. The inhibitory action of guanabenz in tachycardia evoked by electrical stimulation at the C7-T1 site was attenuated by rANF, but not by chronic treatment with guanabenz.

Adrenergic alpha-Agonists↗
PubMed2003

Therapeutic effects of evening administration of guanabenz and clonidine on morning hypertension: evaluation using home-based blood pressure measurements.

OBJECTIVE: To clarify the effects of bedtime administration of the centrally acting alpha(2)-agonists, guanabenz and clonidine, on morning hypertension. METHODS: Patients with morning hypertension were assigned to receive once-daily evening administration of guanabenz (2 mg/day, n = 81; 4 mg/day, n = 2) or clonidine (75 microg/day, n = 40; 150 microg/day, n = 10) for 4 weeks, and the blood pressure (BP)-lowering effects of these drugs in the morning and evening were evaluated by assessing self-monitored BP in the home environment. The subjects were then subdivided into different groups according to their evening BP, and the effects of guanabenz and clonidine on evening BP were evaluated further for each group. In addition, as a substitute for the trough/peak ratio, the evening/morning (E/M) ratio was calculated to assess the duration of action of the two alpha(2)-agonists. RESULTS: Evening dosing with guanabenz or clonidine lowered morning BP significantly. Both drugs decreased evening BP in the subgroup of subjects with a high evening BP, but not in those with a normal evening BP. The individual E/M ratios for guanabenz, but not for clonidine, were significantly greater in those with a high evening BP than in those with a normal evening BP. In the early treatment period, treatment with guanabenz resulted in a higher diastolic E/M ratio in those subjects with a high evening diastolic BP than did treatment with clonidine. CONCLUSION: The results suggest that evening administration of the central alpha(2)-agonists guanabenz and clonidine effectively suppresses the morning BP elevation in treated hypertensive patients.

Aged↗
PubMed1984

Endocrinologic effects of antihypertensive therapy with guanabenz or hydrochlorothiazide.

The effect of antihypertensive therapy with guanabenz or hydrochlorothiazide (HCTZ) on the secretion of growth hormone, prolactin, insulin, and glucagon was evaluated in double-blind fashion in 45 patients. Fifteen patients were treated with HCTZ, 50 mg twice daily, and 30 patients were treated with twice-daily dosages of guanabenz ranging from 4 to 32 mg. Blood samples for hormone analysis were collected during maintenance therapy when blood pressure was controlled as well as 1 week after the withdrawal of the antihypertensive medications. Serum levels of growth hormone and prolactin were within the normal ranges and were unchanged during treatment with HCTZ or guanabenz at any dose level. Interpatient variability in insulin levels was high, although within-subject insulin levels generally were consistent. No treatment effects were seen for insulin levels among guanabenz- or HCTZ-treated patients. Glucagon levels generally were above the expected range for fasting patients and were lower in patients receiving 4 or 8 mg of guanabenz twice daily than in those receiving 16 mg twice daily (p less than 0.05) and in those treated with HCTZ (p less than 0.01). However, analysis of paired data revealed no changes in glucagon levels upon withdrawal of guanabenz, whereas glucagon levels were higher during HCTZ treatment than after drug withdrawal (p = 0.012). Since guanabenz treatment did not affect the secretion of pancreatic or pituitary hormones, it may be preferable to other centrally acting agents and thiazide diuretics for hypertensive patients who are elderly, overweight, or diabetic.

Adult↗