Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes.

We have generated a transgenic model consisting of both the human renin and human angiotensinogen genes to study further the role played by the renin-angiotensin system in regulating arterial pressure. Transgenic mice containing either gene alone were normotensive, whereas mice containing both genes were chronically hypertensive. Plasma renin activity and plasma angiotensin II levels were both markedly elevated in the double transgenic mice compared with either single transgenic or nontransgenic controls. The elevation in blood pressure caused by the human transgenes was independent of the genotype at the endogenous renin locus and was equal in mice homozygous for the Ren-1c allele or in mice containing one copy each of Ren-1c, Ren-1d, or Ren-2. Chronic overproduction of angiotensin II in the double transgenic mice resulted in a resetting of the baroreflex control of heart rate to a higher pressure without significantly changing the gain or sensitivity of the reflex. Moreover, this change was not due to the effects of elevated pressure itself since angiotensin-converting enzyme inhibition had minimal effects on the baroreflex in spontaneously hypertensive BPH-2 control mice, which exhibit non-renin-dependent hypertension. This double transgenic model should provide an excellent tool for further studies on the mechanisms of hypertension initiated by the renin-angiotensin system.

Distribution of angiotensin-(1-7) and ACE2 in human placentas of normal and pathological pregnancies.

This work was designed to study the expression of the vasodilator peptide angiotensin-(1-7) [Ang-(1-7)] and its generating enzyme (ACE2) in the uteroplacental interface. Placentas were obtained from 11 early pregnancy failures (5 miscarriages and 6 ectopic pregnancies), 15 normotensive, and 10 preeclamptic gestations. In placental villi, the main sites of immunocytochemical expression of Ang-(1-7) and ACE2 were the syncytiotrophoblast, cytotrophoblast, endothelium and vascular smooth muscle of primary and secondary villi. Syncitial Ang-(1-7) expression in samples obtained from miscarriages and ectopic pregnancies was increased compared to normal term pregnancy [2.0 (2.0-2.25 for the 25 and 75% interquartile range) vs 1.3 (1.0-1.9), p<0.01]. In the maternal stroma, Ang-(1-7) and ACE2 were expressed in the invading and intravascular trophoblast and in decidual cells in all 3 groups. Ang-(1-7) and ACE2 staining was also found in arterial and venous endothelium and smooth muscle of the umbilical cord. The expression of Ang-(1-7) and ACE2 was similar in samples obtained from normal term or preeclamptic pregnancies, except for increased expression of ACE2 in umbilical arterial endothelium in preeclampsia [0.5 (0.5-0.8) vs 0.0 (0.0-0.0), p<0.01]. The uteroplacental location of Ang-(1-7) and ACE2 in pregnancy suggests an autocrine function of Ang-(1-7) in the vasoactive regulation that characterizes placentation and established pregnancy.

Maternal and neonatal outcomes in obese women who lose weight during pregnancy.

OBJECTIVE: To evaluate neonatal and maternal outcomes in obese pregnant women whose weight gain differed from the Institute of Medicine (IOM) recommendations. STUDY DESIGN: Maternal and neonatal outcomes associated with weight change in pregnancy were retrospectively investigated in women with obesity (body mass index (BMI) ⩾30 kg m(-2); N=10734) who gave birth at 12 hospitals. Using a 1:1:1:1 design (n=778 matched groups), we matched women with obesity who lost, maintained, gained appropriate (IOM recommended) and gained excessive weight during pregnancy by gestational age at delivery, maternal age, race/ethnicity, prepregnancy BMI, chronic hypertension, pregestational diabetes and smoking status. Regression techniques were used to adjust for confounders and compare outcomes across weight change categories. RESULT: Compared with IOM recommendations, weight loss was associated with twofold greater odds of low birth weight infants and a mean decrease in estimated blood loss of 30 ml; excessive weight gain was associated with doubled odds of gestational hypertension or preeclampsia, fourfold greater odds of macrosomia and a mean decrease in 5-min APGAR of 0.09. From lost to excessively gained weight, the odds of cesarean delivery increased 1.4 times and mean infant birth weight increased by 197 g. In contrast, the odds of small-for-gestational age were 1.8 times greater for women who lost than gained excessive weight. CONCLUSION: Weight loss in obese pregnant women is associated with increased risk for low birth weight neonates but significantly decreased or maintained risk for other maternal and neonatal morbidities, as compared with appropriate or excessive weight gain. This study supports re-evaluation of the current IOM guidelines for women with obesity.

Control of adrenocorticotropin secretion and adrenocortical sensitivity in neurohypophysectomized conscious dogs: effects of acute and chronic vasopressin replacement.

We examined the effect of neurohypophysectomy with and without vasopressin replacement on the ACTH response to hypotension and ovine CRF infusion and on the adrenocortical response to ACTH and angiotensin II infusion in conscious dogs. Nitroprusside hypotension (decrease in mean arterial pressure of 25 mm Hg) in the intact state resulted in large increases in plasma arginine vasopressin (pAVP; from 2.6 +/- 0.3 to 296 +/- 63 pg/ml) and ACTH (from 35 +/- 6 to 395 +/- 92 pg/ml). Neurohypophysectomy resulted in greatly attenuated pAVP (8.4 +/- 1.6 pg/ml) and ACTH (80 +/- 10 pg/ml) responses to hypotension which were not normalized by physiological low dose vasopressin replacement (6-18 pg/kg.min continuously, iv, for 2 weeks). However, acute administration of vasopressin (4-6 ng/kg.min) simultaneously with hypotension in the neurohypophysectomized (neurohypox) dog, which produced pAVP levels equivalent to the hypotensive response to intact dogs, almost completely normalized the ACTH response to hypotension (to 248 +/- 74 pg/ml). The ACTH response to 20 ng/kg.min ovine CRF, iv (from 43 +/- 8 to 268 +/- 77 pg/ml), was not attenuated by neurohypophysectomy. The cortisol responses to infusion of 0.5 and 2 ng/kg.min ACTH-(1-24), iv, were essentially normal in neurohypox dogs. However, the ACTH and aldosterone responses to 5 ng/kg.min angiotensin II infusion iv were attenuated in neurohypox dogs off AVP replacement. Histological examination revealed normal adrenal glands and anterior pituitaries in neurohypox dogs. Immunocytochemical staining for vasopressin and neurophysin revealed normal cell bodies in the paraventricular and supraoptic nuclei of the hypothalami from neurohypox dogs. However, median eminence staining for AVP and neurophysin was greatly diminished in neurohypox dogs. In summary, neurohypophysectomy 1) attenuated the ACTH response to hypotension and angiotensin II, but not to CRF, and 2) attenuated the aldosterone response to high dose angiotensin II. Furthermore, the deficit in ACTH secretion was almost completely normalized by increasing plasma AVP levels to those observed in the intact dogs. We conclude that an action of circulating pAVP increases ACTH secretion by a direct effect at the pituitary and by activating afferent input to the hypothalamus.

Are hypertensive effects of aldosterone, angiotensin, vasopressin, and norepinephrine chronically additive?

The effects of chronic combined administration of angiotensin II, norepinephrine, aldosterone, and arginine vasopressin were compared with the response to each of these hormones administered alone. The studies were performed in dogs to determine the extent to which moderately inappropriate elevations of these hormones could enhance each other's ability to produce chronic hypertension and influence Na and water homeostasis. Blood pressure sensitivity to Na intake was also evaluated by infusing the hormones for 11 days at normal levels of Na intake followed by 11 days at high Na intake with ad libitum drinking. Combined hormone administration did not enhance each hormone's singular hypertensive actions. With aldosterone infusion alone and normal Na intake, mean arterial pressure rose nearly 15 mm Hg and an additional 3 mm Hg during high Na intake. Combined hormone infusion also resulted in a nearly 15 mm Hg rise during normal Na intake and an additional 3 mm Hg rise in mean arterial pressure during high Na intake. Marked Na retention and hypernatremia were observed with aldosterone infusion, while hyponatremia characterized arginine vasopressin infusion. The combined hormone infusion resulted in a tendency toward hypernatremia, although daily Na balance was not significantly changed. Daily water turnover was substantially increased and urine osmolality fell to hypoosmotic levels, despite elevated arginine vasopressin levels. Even with high Na intake, dogs receiving either angiotensin II, arginine vasopressin, or norepinephrine at the same concentrations showed 4 to 10 mm Hg increases in mean arterial pressure. Thus, humoral summation or synergism of these hormones probably does not play a major role in the development of chronic hypertension.

Effect of plasma sodium on aldosterone secretion during angiotensin II stimulation in normal humans.

Studies were carried out in normal male subjects (n = 6, age 20-35 years) to determine the interaction of angiotensin II and plasma sodium on aldosterone secretion. These relations were quantified by elevation of plasma sodium with an infusion of 5% sodium chloride (4 ml/kg/30 min i.v.) with measurements of plasma aldosterone, atrial natriuretic factor (ANF), and arginine vasopressin (AVP) over 3 hours. Two hours before sodium chloride infusion, an intravenous infusion of angiotensin II was begun at 0.5 or 5.0 ng/kg/min and continued throughout the study. Plasma potassium was maintained constant by the addition of potassium to the infusate. NaCl/KCl infusion raised plasma sodium 4 meq/l with no decreases of plasma potassium. Plasma aldosterone averaged 7 +/- 1.8 ng/dl before NaCl infusion in subjects infused with 0.5 ng angiotensin II and was not significantly reduced with sodium chloride infusion. Angiotensin II infused at 5 ng/kg/min resulted in average plasma aldosterone levels of 31 +/- 3.6 ng/dl, which sodium chloride infusion decreased to 16.6 +/- 1.3 ng/dl (p less than 0.05) in 60 minutes. Plasma aldosterone remained depressed for the remaining period of study. Plasma ANF increased from 40 to 60 pg/ml with sodium chloride infusion. We conclude that small physiological elevations of plasma sodium concentrations can signal substantial decreases of plasma aldosterone in normal human subjects in situations where plasma angiotensin II is moderately elevated. The precise mechanisms of these responses remain to be determined.

Randomized, double-masked comparison of oxytocin dosage in induction and augmentation of labor.

OBJECTIVE: To test the hypothesis that high-dose oxytocin, when used in a masked fashion, would result in shorter labors and less need for cesarean delivery. METHODS: We conducted randomized, double-masked trials of high-dose compared with low-dose oxytocin for augmentation and induction of labor. Patients were randomly assigned to receive oxytocin by either a low-dose protocol (1.5 mU/minute initially, increased by 1.5 mU/minute every 30 minutes) or a high-dose protocol (4.5 mU/minute initially, increased by 4.5 mU/minute every 30 minutes). Oxytocin solutions were prepared by a central pharmacy and infusion volumes (mL/hour) were identical, thus ensuring double masking. RESULTS: A total of 1307 patients were randomized (induction, 816; augmentation, 491). In the group receiving oxytocin for induction, high-dose oxytocin was associated with a significant shortening of labor (oxytocin to complete dilatation: 9.7+/-0.3 compared with 7.8+/-0.2 hours, P<.001; oxytocin to delivery: 10.5+/-0.3 compared with 8.5+/-0.3 hours, P<.001). The cesarean delivery rate with low-dose oxytocin was 15.0%, compared with 11.3% with high-dose oxytocin (P = .17). For nulliparous women undergoing induction, cesarean delivery rates were as follows: Total 17.3% (low dose) compared with 11.7% (high dose), P = .15; cephalopelvic disproportion 11.9% (low dose) compared with 5.9% (high dose), P = .06. When used for augmentation, high-dose oxytocin again was associated with a significant shortening of labor without a significant difference in cesarean birth rates. No differences in neonatal outcomes were noted between the groups for either augmentation or induction. CONCLUSION: When used in a double-masked fashion, high-dose oxytocin is associated with significantly shorter labors without any demonstrable adverse fetal or neonatal effects.

Treatment of metastatic prostate cancer. Factors that influence treatment selection and methods to increase acceptance of orchiectomy.

Orchiectomy is the preferred method for treating patients with metastatic adenocarcinoma of the prostate (MAP) because it is safer and more reliable than estrogen therapy. Nonetheless, a survey of Northern California urologists showed that 57 percent of their patients with MAP were treated with diethylstilbestrol (DES) rather than orchiectomy. Factors which determined treatment selection include the physician's belief that estrogen therapy was either equally (35%) or more (22%) effective than orchiectomy and the patients' rejection of orchiectomy even if it were recommended to them (20-30%). The survey also showed that previous attempts to increase the acceptability of orchiectomy by performing a subcapsular procedure have failed because urologists do not believe the procedure is effective (45%), or that subcapsular orchiectomy provides a satisfactory cosmetic result (20%). Recent laboratory and clinical investigations have shown that complete and subcapsular orchiectomy were equally effective in reducing serum testosterone. Patient acceptance of subcapsular orchiectomy may be increased by utilizing the term testicular curettage, which does not imply castration, to describe the procedure and by implantation of intracapsular testicular prostheses to restore normal testicular anatomy after the testicles' hormone-producing tissue has been removed.

Electroanalgesia in urologic surgery.

Transcutaneous electrical nerve stimulation (TENS) was employed to reduce postoperative pain in 40 patients who had either radical nephrectomy, radical prostatectomy, or implantation of an inflatable penile prosthesis. These patients used 68 per cent less pain medication and made 84 per cent fewer requests for meperidine hydrochloride (Demerol) injections than did 40 control patients who had similar surgical procedures. The TENS units were easy to use, and there were no complications to electroanalgesia. The TENS program also was costeffective. TENS provided a simple, safe method of reducing postoperative pain in the three surgical procedures tested. Electroanalgesia may have application in other types of urologic surgery, and TENS should be particularly useful in patients who have outpatient surgery.

Clinical evaluation of FasTENS, an inexpensive, disposable transcutaneous electrical nerve stimulator designed specifically for postoperative electroanalgesia.

Previous studies have shown that electroanalgesia is an effective method of reducing postoperative pain in patients who have urologic surgery. All prior studies of postperative transcutaneous electrical nerve stimulation (TENS) have employed TENS stimulators which were designed for the control of chronic pain. Disadvantages to the use of standard TENS stimulators in postoperative patients include the high cost of the devices and their operative complexity which make it difficult for staff and patients to use them. FasTENS is a lightweight, relatively inexpensive disposable TENS stimulator which has been designed specifically for use in postoperative patients. We evaluated the effectiveness of FasTENS in patients who had implantation of an inflatable penile prosthesis, radical retropubic prostatectomy, or radical nephrectomy. Patients treated with FasTENS used 60 percent less pain medication (P less than 0.001) and made 61 percent fewer requests for Demerol injections (P less than 0.001) than did control patients who were not treated with postoperative electroanalgesia. FasTENS was most effective in patients who had radical prostatectomy or penile prosthetic surgery. FasTENS was not cost-effective or practical in patients who had radical nephrectomy.

Failure to control postprostatectomy urinary incontinence by urethral compression.

A modification of Kaufman's urinary incontinence device was implanted unsuccessfully in 5 patients. This device achieved passive urinary continence in each of these patients; however, all patients continued to experience moderate to severe stress incontinence. The results of this study challenge the concept that static urethral compression can achieve total urinary continence in patients with postprostatectomy incontinence.

Clinical experience with Mentor inflatable penile prosthesis in 206 patients.

The Mentor inflatable penile prosthesis (IPP) has been implanted in 206 patients with organic (95.2%) or psychologic (4.8%) impotency. The patients have been followed up for an average of 18.1 (4-42) months. A satisfactory result has been achieved in 98 per cent of these patients. A life analysis of the series shows that 88 per cent of all devices implanted will survive forty-two months without mechanical failure. One hundred sixty-four of these patients had not had previous penile surgery while 42 had had one or more penile prostheses implanted previously. The projected forty-two-month survival for the Mentor prosthesis in these subgroups is 94 per cent and 74 per cent, respectively. The improved life expectancy of the Mentor IPP, compared with the Scott IPP, is due to the superior durability of Mentor's polyurethane cylinders and to the increased reliability of the Mentor snap-on connector system. In this respect, there have been only one cylinder failure and 3 connector failures in the Mentor series. The connector failures occurred early in the series before the development of connector pliers; there have been no connector failures in the last 202 consecutive implantations. Wear-induced tubing leaks, the most common cause of device failure, occurred in 2.9 per cent of all implantations. Tubing failures were more common in patients who have had previous surgery, occurring in 9 per cent of salvage procedures and 1.3 per cent of primary implantations. The reason for the difference in tubing survival in virgin and salvage procedures is unknown; possibly the subcutaneous scar tissue present in secondary surgical procedures increases the chance of tubing segments touching and abrasing each other. Laboratory studies suggest that the nylon-reinforced tubing used in the manufacture of devices implanted since 1985 is more durable than is the standard silicone tubing used in the construction of devices implanted previously.

Mentor inflatable penile prosthesis.

The new Mentor prosthesis is similar in appearance to the Scott inflatable penile prosthesis, consisting of a pump, a reservoir, and two penile cylinders. The penile cylinders of the Mentor prosthesis are constructed of Bioflex polyurethane, a new polymer which is more durable and less elastic than silicone. The use of Bioflex cylinders should increase device longevity and eliminate cylinder aneurysms. It also may be possible to correct penile deformities produced by silicone cylinders which have formed aneurysms by replacing the dilated cylinders with Bioflex cylinders. The new Mentor prosthesis utilizes snap-on connectors which rely on plastic clamps rather than suture ties to fix tubings to connectors. This method of attaching tubing to connectors will reduce operating time and should reduce the incidence of connector leaks.

Clinical experience with Scott inflatable penile prosthesis in 150 patients.

The Scott inflatable penile prosthesis was implanted in 150 patients with organic (89%) and psychologic (11%) impotency from 1979 to 1982. The patients were followed up for an average of twenty-five (6-46) months. A satisfactory result was achieved in 133 (89%) patients. Forty-nine major complications occurred in 38 patients. Forty-four surgical procedures were performed in 33 patients to correct mechanical or technical complications (32), replace the device (9), or remove the device (3). Two patients refused corrective surgery, and the complications could not be corrected in 2 patients. Cylinder leaks (15), leaks at tubing/connector junctions (14), and cylinder aneurysms (7) were responsible for most of the mechanical failures. Additional refinements in surgical technique will not eliminate these problems. Device modifications should be made to increase cylinder durability, to eliminate the need for suture ligation of tubing/connector junctions, and to assure symmetrical cylinder expansion.

Mentor inflatable penile prosthesis. Preliminary clinical results in 30 patients.

The Mentor inflatable penile prosthesis was designed to decrease the incidence of mechanical failures associated with the Scott inflatable penile prosthesis. The penile cylinders of the Mentor prosthesis are manufactured from Bioflex polyurethane, a new polymer which is more durable and less elastic than silicone. The Mentor prosthesis also has a connector system which employs plastic clamps rather than suture ties to fix tubings to connectors. The new prosthesis has been implanted in 30 patients with organic impotency. These patients have been followed for an average of 7.7 (5-12) months. All patients achieved a satisfactory cosmetic and functional result from the procedure.

A case of giant prostatic hyperplasia.

Giant prostatic hyperplasia (GPH) is an uncommon pathologic entity with only 10 reported cases of prostate glands exceeding 500 g. We report the uncomplicated removal of a 526-g prostatic adenoma by simple retropubic prostatectomy.

Comparative study of air and water measurements of peak and stabilized static urethral pressures.

Air and water were forced through female dogs' urethras to determine static urethral pressures. The cauda equina was sectioned to eliminate reflex responses to urethral manipulation, and the urethras were compressed circumferentially with inflatable Silastic cuffs. The peak and stabilized urethral pressures were recorded at flow rates between 20 and 150 ml./min. while cuff pressures were varied between 0 and 100 cm. of water. When the fluid recordings of static urethral pressure were compared with Millar transducer tip catheter measurements of urethral pressure, there were no statistically significant differences between the air cystometer, aneroid sphygmomanometer, and Millar catheter recordings of urethral pressure. At these high flow rates, the water recordings of urethral pressure were significantly higher than the Millar catheter determinations of static uretheral pressure.

Effect of baclofen and dantrolene on bladder stimulator-induced detrusor-sphincter dyssynergia in dogs.

The effect of baclofen (Lioresal) and dantrolene (Dantrium) on bladder stimulation-induced detrusor-sphincter dyssynergia was studied in normal and chronic T-10 paraplegic dogs. Dantrolene, which depresses skeletal muscle contractility, had little effect on electrically evoked contractions of the urethral sphincter in dogs. Baclofen, which acts centrally by potentiating presynaptic inhibition, depressed the pudendal to pudendal nerve reflex and decreased urethral resistance during bladder stimulation.

Patient satisfaction with Mentor inflatable penile prosthesis.

Patient satisfaction with the Mentor inflatable penile prosthesis was assessed by sending a thirty-six-item questionnaire to 251 patients who had undergone implantation of the device by the senior author (D.C.M.). A total of 152 (61%) of the patients responded. Recovery time, satisfaction, reasons for dissatisfaction, perceptions of erection quality, and psychosexual parameters were evaluated. Eight-eight percent of the patients were engaging in regular sexual activity. Depending on the definition of satisfaction, 81-89 percent of the respondents reported that they were satisfied with the prosthesis. Sixty-eight percent of the survey group were satisfied with the length, width, and firmness of their prosthetic-induced erection. The majority of patients reported improvement in psychosexual functioning after implantation. Reasons for dissatisfaction included inadequate penile length, insufficient firmness, and difficulty with inflation and deflation of the penile cylinders.

Use of scrotal skin to cover cutaneous defects resulting from palliative lymph node dissections in groin and suprapubic area.

Scrotal skin was employed to cover skin defects resulting from palliative groin and suprapubic dissections designed to remove large masses of tumor which had eroded the skin. This technique provides a simple and effective alternative to more complex procedures using rotational skin and myocutaneous flaps to achieve primary skin closure in similar circumstances.