Efficacy of a low-dose leuprolide acetate depot in the treatment of uterine leiomyomata in Japanese women.

OBJECTIVE: To compare the efficacy of two different doses, 1.88 mg and 3.75 mg, of a monthly depot injection of a gonadotropin-releasing hormone agonist (GnRH-a) in the treatment of uterine leiomyomata. DESIGN: A prospective randomized study. SETTING: Hospital department of gynecology and obstetrics. PATIENTS: Forty-one premenopausal Japanese women, 25 to 53 years of age, with uterine leiomyomata. INTERVENTIONS: Depot type of GnRH-a, leuprolide acetate (LA) 1.88 mg or 3.75 mg was administered subcutaneously every 4 weeks for 24 weeks. MAIN OUTCOME MEASURES: Efficacy of treatment was assessed in terms of uterine volume, serum levels of estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and adverse symptoms during treatment. RESULTS: In both groups, a significant reduction in uterine volume, 52% in 1.88 mg group and 47% in 3.75 mg group, was obtained at week 24, with near maximal reduction (41%, 45%) apparent by 12 weeks. No significant difference was observed between the groups in percent uterine volume reduction at each treatment week. Both groups showed significant and equal suppression of serum levels of E2, LH, and FSH. In addition, the incidence of adverse symptoms was not significantly different between the two groups. CONCLUSIONS: Monthly injection of 1.88 mg or 3.75 mg LA depot has equivalent treatment efficacy in reducing uterine volume. Twelve weeks of treatment is enough to obtain near maximal reduction.

[Study on relationships between sonographic endometrial images and ovarian hormone levels].

Sixty-seven and 109 sonographic endometrial images obtained from 67 infertile patients and 5 healthy volunteers with normal ovulatory cycles, respectively, were investigated with regard to serum estradiol (E2) and progesterone (P) levels. The ultrasound devices used were sector electronic scanners (3.5 MHz). 1) Endometrial images were able to be classified into four pattern types, according to the criteria reported by Sakamoto (1985), using a gray-scale contact compound scan. Pattern 1: linear cavity echo, pattern 2: thick hypoechoic endometrium surrounded by thin border echo, pattern 3: thickened border echo, pattern 4: entire echogenic endometrium. 2) Both E2 and P levels were low in pattern 1. The E2 level was significantly higher in pattern 2 than in pattern 1 (p less than 0.01), indicating pattern 2 reflects E2 surges prior to ovulation. The P level was high in pattern 3; and in pattern 4, it was significantly higher than in patterns 1 and 2 (p less than 0.01), indicating that patterns 3 and 4 are in the early and mid-luteal phase, respectively. 3) Sonograms obtained from 12 cases with suspicious luteal phase defects showed an abnormal pattern in the mid-luteal phase. These results indicate that the sonographic endometrial images reflect respective ovarian hormone levels.

Lowering calcium in the nucleus tractus solitarius causes hypotension and bradycardia.

It has been shown that saline microinjected into the region of the nucleus tractus solitarius (NTS) causes, but artificial cerebrospinal fluid (CSF) in the same volume does not cause, hypotension and bradycardia. This study was done to examine the possibility that the difference in effects between saline and artificial CSF may be due to the lack of calcium ions in saline. In anesthetized rats, saline or artificial CSF with or without calcium ions was microinjected into the region of the NTS. Saline microinjected in volumes of 0.2 and 0.5 microliter produced the volume-dependent decreases in arterial pressure and heart rate. Saline with added calcium ions and artificial CSF did not elicit the hypotensive and bradycardic response, but artificial CSF without calcium ions produced hypotension and bradycardia. These results suggest that the lack of calcium ions in the injected solutions is the factor that determines the hypotensive and bradycardic response. These results suggest that lowering the local availability of calcium to the NTS neurons results in hypotension and bradycardia.

Arterial pressure and heart rate responses to calcium channel blockers administered in the brainstem in rats.

The study examined the possibility that organic calcium channel blockers alter autonomic nervous system function by acting on brainstem neurons. Intracisternal administration of diltiazem or verapamil produced dose-related decreases in arterial pressure and heart rate. Diltiazem administered by drop on the dorsal surface of the brainstem at the obex or microinjected directly into the nucleus tractus solitarius also decreased arterial pressure and heart rate. The responses were absent or markedly attenuated in rats previously treated with 6-hydroxydopamine or with bilateral electrolytic lesions of the nucleus tractus solitarius but were preserved in rats treated with atropine or with sham nucleus tractus solitarius lesions. Nifedipine or ethylene glycol-bis-(beta-aminoethyl ether)N,N'-tetraacetic acid administered on the dorsal surface of the brainstem at the obex decreased arterial pressure and heart rate. Vehicle, acid saline, or sucrose solution failed to alter arterial pressure or heart rate. These results suggest that organic calcium channel blockers produce excitation of the nucleus tractus solitarius neurons, directly or indirectly, which results in the withdrawal of sympathetic nervous activity and in the decrease in arterial pressure and heart rate. The results suggest that calcium ion plays an important role in maintaining integral function of neurons in the brainstem, particularly in the nucleus tractus solitarius.

Blood pressure and heart rate responses to microinjection of vasopressin into the nucleus tractus solitarius region of the rat.

The nucleus tractus solitarius (NTS) region in the rat has been shown to receive arginine vasopressin (AVP) and oxytocin (OT) neurophysin-containing neuronal projections from the suprachiasmatic (SNC) and paraventricular nucleus (PVN). Thus, vasopressin and oxytocin might have central influences on the circulation. This as investigated by measuring arterial blood pressure and heart rate (HR) responses following microinjection of vasopressin and oxytocin (0.1, 1.0 and 10.0 ng) into the right nucleus tractus solitarius region of rats anesthetized with urethane. Injections of vasopressin into nucleus tractus solitarius produced dose-related increases in blood pressure and heart rate. The effect of oxytocin on the blood pressure and heart rate was of a lesser magnitude without showing a dose-response relationship. Equivolumetric injections of vehicle and luteinizing hormone-releasing hormone (LH-RH) peptide had no detectable effect on blood pressure and minimal effect on heart rate. Injections of vasopressin into three different sites in the brain stem (1 mm anterior, posterior, and lateral to the tractus solitarius) did not produce significant hemodynamic changes. Intravenously injected vasopressin produced increments in blood pressure only at the highest dose level (10.0 ng) and a decrease rather than an increase in heart rate. Ganglionic blockade significantly reduced pressor responses to vasopressin injected into the nucleus tractus solitarius region and completely eliminated HR responses. Pretreatment of the nucleus tractus solitarius with a vasopressin antagonist abolished the blood pressure and heart rate responses produced by injection of vasopressin. These results suggest that vasopressin acts in the region of the nucleus tractus solitarius to exert a central action on the circulation.

Central mechanisms in DOC-salt hypertensive rats.

These experiments were intended to elucidate the role of central mechanisms in the maintenance of high blood pressure produced by deoxycorticosterone (DOC) and salt in rats. We investigated the central effect of angiotensin (AII) on systemic arterial blood pressure and plasma arginine vasopressin (AVP) in DOC-salt and control rats. There was a pronounced augmentation of the pressor responsiveness to centrally injected AII in DOC-salt hypertensive rats; but there was no difference in AII induced AVP release in DOC-salt hypertensive rats compared to sham controls. The increase in vascular resistance of the perfused hindquarters induced by stimulation of the lumbar sympathetic chains did not change in DOC-salt hypertensive rats although the increases induced by norepinephrine (NE) were potentiated at the higher doses. Pressor responsiveness of the DOC-salt hypertensive rats to i.v. administration of AII, AVP and NE was shown to be augmented by factors of 3.6, 2.5 and 1.8 respectively in DOC-salt rats. Reflex bradycardia to these pressor responses was attenuated indicating impairment of baroreflex function. The potentiation of pressor responses to centrally injected AII in DOC-salt hypertensive rats was greater than could be explained by augmented pressor responsiveness to iv NE and AVP. Neither baroreflex dysfunction, facilitated release of NE at sympathetic terminals, nor augmented release of AVP into the circulation could explain the potentiation. Therefore, our data suggested that selective central amplification of sympathetic vasomotor responses to centrally injected AII stimuli may play a role in the hypertension after 3 weeks of DOC-salt treatment in rats.

Acute interaction of vasopressin and neurogenic mechanisms in DOC-salt hypertension.

We investigated the relative role of vasopressin and neurogenic factors in the control of vascular resistance in rats treated with desoxycorticosterone (DOC) and salt and in control rats. DOC-salt-treated rats had elevated hindquarter vascular resistance (P less than 0.05). Vasopressin and neurogenic tone contributed significantly (P less than 0.05) to increased resistance. Vasodilator responses to a specific vasopressin antagonist, I-deaminopenicillamine, 4-valine, 8-D-arginine vasopressin (dPVDAVP), and lumbar sympathectomy in separate DOC-salt groups accounted for 40 +/- 5 (SE) and 43 +/- 6%, respectively, of the total vasodilator capacity. In contrast, corresponding responses to dPVDAVP and lumbar sympathectomy in control rats were smaller (P less than 0.01), were significantly different (P less than 0.05), and accounted for 8 +/- 3 and 20 +/- 3%, respectively, of the total vasodilator capacity. Effects of dPVDAVP compared in innervated hindquarters of DOC-salt-treated and control rats were greater in DOC-salt-treated rats (P less than 0.001); in the denervated hindquarters the effects of dPVDAVP were similar in DOC-salt-treated and control rats. Therefore, effects of vasopressin on vascular resistance were augmented in DOC-salt-treated hypertensive rats; furthermore this augmented effect was dependent on an intact innervation.

Pressor response to vasopressin and impaired baroreflex function in DOC-salt hypertension.

Baroreflexes and pressor responses to intravenous arginine vasopressin (AVP) and phenylephrine (PE) were evaluated in conscious, less severely hypertensive desoxycorticosterone (DOC)-salt-treated rats, hypertensive DOC-salt-treated rats, and control rats (n = 6, each group). Pressor responses were retested after ganglionic blockade. In control rats pressor responses to AVP were augmented more than those to PE after ganglion blockade; thus AVP appeared uniquely to augment baroreflex buffering. In hypertensive DOC-salt-treated rats baroreflexes were impaired (P less than 0.05); pressor responsiveness to AVP was augmented compared with control rats (P less than 0.05). After ganglion blockade augumentation of pressor responses was similar for AVP and PE. In less severely hypertensive rats baroreflexes were normal; pressor responses to AVP and PE were like those in control rats before and after ganglion blockade. These results suggest that AVP augments baroreflex buffering, which imposes a restraint on pressor effects of AVP that is not evident with PE. In hypertensive DOC-salt-treated rats a defect in baroreflex buffering during infusion of AVP may contribute to augmented pressor effects of AVP.

Abnormal baroreflex control of heart rate in prehypertensive and hypertensive Dahl genetically salt-sensitive rats.

This study tested the hypothesis that in the Dahl model of genetic hypertension abnormal baroreflex function may precede and contribute to the development of hypertension. Sensitivity of baroreflex control of heart rate was assessed in conscious sensitive (S) and resistant (R) Dahl rats fed a high or low salt diet. Sensitivity of baroreflex control of heart rate was lower in S rats fed low salt although arterial pressure was not different from that of R rats. Hypertensive S rats showed resetting of baroreflexes to the higher pressure level without any further change in sensitivity. Pressor responses to phenylephrine were augmented in both prehypertensive and hypertensive S rats compared to R rats. Ganglionic blockade abolished this difference. In hypertensive S rats, ganglionic blockade decreased arterial pressure to levels not different than similarly treated R rats, indicating that neurogenic mechanisms contribute importantly to the early stages of hypertension in the Dahl model. These studies have identified impaired baroreflex function in prehypertensive and hypertensive Dahl S rats. This defect augments responses to pressor stimuli and may contribute to the development of salt-induced hypertension in the Dahl strain.

Does vasopressin contribute to salt-induced hypertension in the Dahl strain?

A humoral factor has been implicated in Dahl salt-sensitive genetically hypertensive rats. The goal of this study was to evaluate the pressor role of vasopressin (AVP) in Dahl rats. Salt-sensitive (S) and resistant (R) rats were fed either high (8%) or low (.04%) NaCl diets for 6 to 8 weeks. Blood pressure was elevated in S rats fed high salt diets (p less than 0.05). Plasma AVP increased with high salt diet in both groups (p less than 0.05), but was higher in S than R rats (2.0 +/- 0.3 and 1.3 +/- 0.2 microU/ml respectively, mean +/- SE, p less than 0.05). With low salt diet, plasma AVP did not differ significantly in S and R rats (1.0 +/- 0.2 and 0.7 +/- 0.2 microU/ml respectively). Pressor responses to intravenous injection of AVP were greater in S than R rats (p less than 0.05), but this difference was also observed with pressor responses to norepinephrine (S greater than R, p less than 0.05); there was no difference in pressor responses to AVP in S rats fed high vs low salt diet. Injection of 50 micrograms of d(CH2)5 VDAVP, which selectively inhibits vasoconstrictor effects of AVP, failed to lower blood pressure in S and R rats fed high or low salt diets despite the fact that this dose decreased pressor responses to 8 microU of AVP more than 90%. Although plasma AVP and vasopressor responses to AVP and NE are slightly elevated in S rats fed high salt, results with d(CH2)5 VDAVP suggest that vasoconstrictor effects of AVP do not play an important role in the maintenance of hypertension in Dahl S rats.

Effect of coronary occlusion on arterial baroreflex control of heart rate.

To determine whether the baroreflex control of heart rate is altered during acute myocardial ischaemia, the baroreflex slope was measured at the control state, during coronary occlusion, and at the recovery phase in nine conscious dogs. The baroreflex slope was obtained by relating the R-R interval to the preceding systolic pressure during phenylephrine-induced transient hypertension. The baroreflex slope was reduced during coronary occlusion (18.8 +/- 3.8 ms.kPa-1, mean +/- SE) compared with that at the control state (41.4 +/- 6.0 ms.kPa-1). This reduction in the baroreflex slope during coronary occlusion was also present after propranolol, which suggests that this reduction of the slope during myocardial ischaemia is not due to a simultaneous increase in beta-adrenergic activity. These results suggest that the reflex originating from the cardiac receptors may modulate heart rate response to arterial baroreceptor stimulation.

Early closure of the tricuspid valve in a case of Ebstein's anomaly with type B Wolff-Parkinson-White Syndrome.

Echocardiographic studies of a 19-year-old female with Ebstein's anomaly and type B Wolff-Parkinson-White syndrome showed an earlier closure of the anterior tricuspid leaflet (ATL) than of the anterior mitral leaflet (AML), contrary to the previous reports. The interval between the closure of the ATL and the AML was 20 msec and 30 msec, respectively, before and after administration of edrophonium chloride. However, closure of the AML preceded that of the ATL after administration of atropine sulfate and during supraventricular tachycardia by 10 msec and 60 msec, respectively, concomitant with the shortening of the duration of the QRS complex. We conclude that early closure of the ATL may depend on preexcitation of the right ventricle.

Mahaim conduction producing left axis deviation and normal QRS.

An unusual patient is described in whom electrophysiological studies strongly suggest the occurrence of Mahaim conduction. The patient whose electrocardiogram previously showed a left anterior hemiblock pattern then developed advanced atrioventricular (AV) block (AH block). Beats conducted through the atrioventricular node always had a short HV interval (20 ms) and QRS complexes of left anterior hemiblock pattern. Junctional escape beats always had a normal HV interval (50 ms) with normal intraventricular conduction. His bundle pacing showed the StV interval and QRS contour of escape beats. These findings suggest the existence of an accessory pathway (Mahaim fibres) passing from the area of block, presumably the uppermost portion of the His bundle, to the posteroinferior division of the left bundle-branch. The surface electrocardiogram did not show the characteristic delta wave of the Wolff-Parkinson-White syndrome. Our observations suggest that patients in whom there is conduction along Mahaim fibres may show only the pattern of intraventricular conduction defect without a delta wave.

The effect of graded coronary stenosis on myocardial blood flow and left ventricular wall motion.

The effect of graded coronary stenosis on resting regional myocardial flow and left ventricular (LV) wall motion was studied in 18 anesthetized dogs. The left circumflex coronaary artery (LC) was constricted. The degree of LC stenosis and the changes in LV wall motion were determined by cineangiography of the coronary artery and LV. Regional myocardial flow was determined by tracer microspheres (TM), labeled with two different isotopes, Sr85, Sc46 or Ce141. The first TM1 and the second TM2 were infused after LC stenosis, and during a temporary complete LC occlusion respectively. Resting flow in areas with 70% stenosis was reduced, with a greater reduction of subendocardium and posterior papillary muscle, but minimum impairment of LV wall motion. No ST elevation was found. Animals with 80--90% stenosis showed a marked reduction of flow and wall motion, a significant ST-elevation and a delayed antegrade run-off in coronary arteriography.

Effects of collateral circulation on regional myocardial blood flow and left ventricular wall motion (A preliminary note).

The effect of collateral circulation on regional myocardial flow and wall motion of left ventricle was studied on 5 anesthetized dogs with a surgically implanted constrictor on the left circumflex coronary artery (LC). The grade of LC stenosis and wall motion of left ventricle (LV) were determined by cineangiography of the coronary artery and LV at the period of acute and chronic occlusion. Regional myocardial flow was determined by tracer microspheres (TM), labeled with four different isotopes, Sr85, Cr51, Sc46, Ce141. The first TM1 was infused after LC stenosis, TM2 during a temporary complete LC occlusion at the period of acute occlusion; TM3 and TM4 in a similar way 3 to 4 weeks after the acute LC stenosis. Three to four weeks after LC stenosis, i.e. chronic period of occlusion, the degree of LC stenosis progressed from 70--80% to 100% occlusion, but collateral flow and collateral vessels to the ischemic LC area were increased together with an improvement of wall motion of the ischemic LC area. The results may support the idea that collaterals may be an effective compensatory mechanism for ischemia. In contrast to an increase of collateral flow to the ischemic LV free wall in all five dogs, an increase to the posterior papillary muscle was found only in two out of five dogs.

Long-lasting effect of oral molsydomine on exercise performance: a new antianginal agent.

This study examines whether the beneficial effects of molsydomine, a recently introduced antianginal agent, on exercise performance of patients with angina pectoris are long lasting. The hemodynamic effects are known to persist for several hours. The effects of molsydomine on the duration of exercise and the time to the onset of ST depression were compared to those of placebo during two hours after oral administration. Molsydomine prolonged the duration of exercise in all eight patients (average 2.8 min, P less than 0.001) and delayed the onset of ST depression (average 2.2 min, P less than 0.001), while the placebo failed to alter these measurements. The increment of the duration of exercise produced by 2 mg of molsydomine in two hours following oral administration was comparable to the increment produced in a few minutes after 0.3 mg of nitroglycerin given sublingually. The results indicate that molsydomine offers prophylasis for angina pectoris that lasts at least two hours after oral administration.