Prenatal growth markers in schizophrenia: a monozygotic co-twin control study.

OBJECTIVE: This co-twin study investigated monozygotic twins who were discordant for schizophrenia for evidence of prenatal growth differences between the affected and well co-twins. METHOD: Four dermatoglyphic markers of prenatal growth were obtained by established procedures from 26 monozygotic twin pairs discordant for schizophrenia, 13 monozygotic twin pairs concordant for schizophrenia, and several normal monozygotic twin samples. RESULTS: The a-b ridge count differences between the affected and well co-twins were greater than those found for concordant and normal monozygotic pairs. In comparison with their well co-twins, the affected twins, in discordant pairs, had developed fewer epidermal ridges in the a-b interdigital area of their right palms. In contrast, no significant differences were found between the affected twins and their well co-twins on markers associated with fetal development before 13 or after 15 weeks estimated gestational age. CONCLUSIONS: Because the a-b ridges are known to complete development between 13 and 15 weeks estimated gestational age, the results provide physical evidence suggesting that the schizophrenia-affected monozygotic twins alone experienced a time-specific and time-limited dysgenesis during this time. Commonalities in the ontogeny of epidermal and neurological structures are discussed.

An extra-adrenal sodium-retaining factor in congestive heart failure.

The extra-adrenal sodium-retaining factor was first described in Circulation Research in 1964. This factor increases the responsiveness of the renal tubules to aldosterone in heart failure, and marked sodium retention occurs with resultant edema or ascites. Evidence for the extra-adrenal sodium-retaining factor is presented in two models of experimental heart failure in dogs and in dogs with thoracic caval constriction and a low cardiac output. Since the nature of this sodium-retaining factor remains unknown, several of the recently discovered factors that influence kidney function and that might alter the responsiveness of the renal tubules to a mineralocorticoid are described. These factors include atrial natriuretic peptide, nitric oxide, 11 beta-hydroxysteroid dehydrogenase activity, the endothelins, and the intrarenal tissue renin-angiotensin system. It is suggested that the nature and action of the sodium-retaining factor be reinvestigated in lieu of the new knowledge of kidney function. The applicability of newly developed experimental models of heart failure for study of the extra-adrenal factor is discussed; these include coronary artery ligation in rats, cardiac pacing in the dog, and application of transmyocardial direct current shock to local myocardial areas in dogs.

Twins with schizophrenia: genes or germs?

High concordance for schizophrenia in monozygotic (MZ) twins is often cited as evidence for the etiological influence of genetics; however, even if twins are separated at birth, MZ twin concordance is influenced by the shared prenatal environment. Study of the placentation status of MZ twins provides a way to investigate some prenatal influences, including the possible role of viral infections. The probability of shared infections is likely to be greater in monochorionic MZ twin pairs than in dichorionic pairs because of shared fetal circulation in the monochorionic pairs. We drew from published twin studies and used reported concordance for handedness as a retrospective marker of placentation status. We found that MZ twin pairs with opposite-hand preferences were concordant for psychosis in 9 of 15 cases (60%), while only 18 of 56 twin pairs (32%) with same-hand preferences were concordant for psychosis. These results suggest that shared prenatal viral infection may account for much of the high concordance for schizophrenia in identical twins.

Prenatal development of monozygotic twins and concordance for schizophrenia.

While twin concordances for schizophrenia have been used to estimate heritability and to develop genetic models, concordances in subtypes of monozygotic (MZ) twins can also be used to investigate the influence of prenatal development in the etiology of mental illness. We used within-pair variability and mirroring of fingerprints to estimate retrospectively the placentation status of concordant and discordant MZ twins. The results indicate that concordant MZ pairs were more likely to have been monochorionic (MC) and to have shared a single placenta, whereas discordant MZ pairs appear more likely to have been dichorionic (DC) with separate placentas. Pairwise concordances for MZ twins without MC markers averaged 10.7 percent. In contrast, concordances for MZ twins with one or more MC markers averaged 60 percent. This suggests that simple MZ concordance rates may overestimate schizophrenia heritability and that prenatal development may also be important in the etiology of schizophrenia. Because MC (but not DC) twins usually share fetal blood circulation and hence are likely to share infections, these results are consistent with the hypothesis that fetal infections may be a significant etiological factor in schizophrenia.

Atrial natriuretic factor secretion in dogs with experimental high-output heart failure.

The temporal changes in the plasma concentration of immunoreactive atrial natriuretic factor (iANF) were studied in six conscious dogs with an arteriovenous (AV) fistula, a model of chronic high-output heart failure. Following the creation of the AV fistula, the dogs retained sodium avidly for 5 days, and plasma renin activity, plasma aldosterone concentration, and right atrial pressure increased significantly from controls. During this initial stage, iANF increased only modestly. From day 6 to 14, the dogs increased their daily sodium excretion and approached sodium balance. This natriuretic response was associated with a significant rise in iANF, with the return of renin and aldosterone levels to base line, and with a progressive significant elevation in right atrial pressure. Thus, in dogs with an AV fistula and cardiac volume overload, chronic increases in atrial pressure appear to be a sustained stimulus for the release of ANF. It is suggested that following the initial period of sodium retention in this experimental mental model of heart failure, chronic endocrine adjustments for the reestablishment of sodium balance involve an increase in ANF which subsequently can exert a tonic inhibitory action on the renin-aldosterone axis. It is concluded that the ANF endocrine system might function as an effective chronic compensatory mechanism to help promote sodium and water excretion in dogs with an AV fistula through the suppression of the renin-aldosterone system and possibly through its direct renal actions.

Control of atrial natriuretic factor release in conscious dogs.

The aim of this study was to examine the changes in the concentration of plasma immunoreactive atrial natriuretic factor (iANF) that occur in response to expansion or depletion of the extracellular fluid volume in conscious dogs. The plasma iANF concentration was also measured postprandially after the ingestion of a meal containing 125 meq of sodium. Postprandial plasma iANF increased 45% (P less than 0.05) above the base-line concentration, and this increase was accompanied by a brisk natriuresis. After a low-sodium meal, however, plasma iANF and sodium excretion failed to increase. The plasma iANF concentration increased from 57 +/- 5 to 139 +/- 36 pg/ml (P less than 0.05) immediately after volume expansion with intravenous isotonic saline infusion (2.5% body wt) administered over a 30-min period; plasma iANF remained elevated at 90 +/- 14 pg/ml (P less than 0.05) for an additional 30 min before returning toward preinfusion levels. Plasma iANF decreased 45% from 78 +/- 17 to 43 +/- 7 pg/ml (P less than 0.05) in response to the administration of ethacrynic acid (2.0 mg/kg, iv bolus) that produced an estimated 15% depletion of intravascular volume. In additional experiments the infusion of synthetic alpha-human ANF at 100 and 300 ng X kg-1 X min-1 increased (P less than 0.05) both the plasma iANF concentration and the urinary excretion of iANF. This study demonstrates that the secretion of ANF is consistently influenced by changes in the extracellular fluid volume. Furthermore, the results support the concept that ANF functions to increase postprandial sodium excretion following the ingestion of a high-sodium meal.

Effects of atrial appendectomy on circulating atrial natriuretic factor during volume expansion in the rat.

This study examined the changes in the circulating level of endogenous atrial natriuretic factor during diuresis and natriuresis produced by acute volume expansion in anesthetized rats with either bilateral atrial appendectomy (n = 9) or sham operation (n = 9). Following control measurements in the sham-operated rats, 1% body weight volume expansion with isotonic saline produced an increment in urinary sodium excretion of over 4 mueq/min (P less than 0.05) while urine volume increased by more than 20 microliter/min (P less than 0.05). These responses were associated with a significant increase in immunoreactive plasma atrial natriuretic factor from a baseline value of 82 +/- 10 pg/ml to a level of 120 +/- 14 pg/ml (P less than 0.05). In contrast, in the group of rats with bilateral atrial appendectomy an identical degree of volume expansion increased urinary sodium excretion and urine volume by only 0.61 mueq/min (P less than 0.05) and 3.07 microliter/min (P less than 0.05), respectively. In this group, immunoreactive plasma atrial natriuretic factor remained statistically unchanged from a control value of 70 +/- 12 pg/ml to a level of 82 +/- 16 pg/ml (P greater than 0.05). Comparison of the two groups indicates that the natriuresis, diuresis, and plasma atrial natriuretic factor levels during volume expansion were significantly reduced in the rats with bilateral atrial appendectomy. No differences in mean arterial pressure and heart rate were observed between the two groups. These data demonstrate that removal of both atrial appendages in the rat attenuated the release of atrial natriuretic factor during volume expansion; and this effect, in turn, was associated with a reduction in the natriuretic and diuretic responses.

Effect of synthetic atrial natriuretic factor on aldosterone secretion in the rat.

Direct in vivo measurements of aldosterone secretion were made before and after infusion of synthetic rat atrial natriuretic factor (ANF) into anesthetized rats with markedly different levels of plasma renin activity. Infusion of ANF peptide at 350 ng . kg-1 . min-1 significantly decreased aldosterone secretion by 32% and plasma renin activity by 55% in rats that had been maintained on a normal-sodium diet. Similar reductions in aldosterone secretion and plasma renin activity were observed in hyperreninemic rats after chronic sodium restriction. Infusion of ANF at 350 ng . kg-1 . min-1 into anephric rats with low circulating levels of renin did not significantly decrease the secretion of aldosterone. Increasing the ANF peptide infusion dose fivefold in these anephric rats did result in a significant reduction in aldosterone secretion, but this higher dose also produced significant decreases in blood pressure not observed with the lower dose of ANF. These results demonstrate that infusion of synthetic ANF decreases the secretion rate of aldosterone in the rat, but the ability of ANF to decrease aldosterone secretion is attenuated when circulatory levels of renin and hence angiotensin II are very low. The data suggest that although ANF can exert a direct inhibitory effect on the adrenal glomerulosa in larger doses that also produce systemic cardiovascular effects, one physiological mechanism by which ANF suppresses aldosterone secretion may be related indirectly to the inhibition of renin release.

Renal mechanisms for suppression of renin secretion by atrial natriuretic factor.

The effects of synthetic atrial natriuretic factor on renin secretion were examined in anesthetized dogs with either a single filtering kidney or a single denervated nonfiltering kidney. In dogs with a single filtering kidney (Series 1, n = 6), a priming dose of atrial natriuretic factor (2 micrograms/kg, i.v.) followed by sustained intravenous infusions at doses of 200 and 400 ng/kg/min for 20 minutes each produced striking decrements (p less than 0.05) in renin secretion, from 1083 +/- 322 to 205 +/- 120 and 286 +/- 168 ng of angiotensin I per minute. This fall in renin secretion was associated with significant increases (p less than 0.05) in creatinine clearance, urine flow, sodium excretion, and the filtered load of sodium. Renal blood flow increased only transiently. In dogs with a single denervated nonfiltering kidney (Series 2, n = 6), infusion of atrial natriuretic factor at these doses also produced marked inhibition (p less than 0.05) of renin secretion, from 311 +/- 98 to 72 +/- 22 and 91 +/- 37 ng of angiotensin I per minute. Renal blood flow remained significantly elevated (p less than 0.05) throughout the infusion, in contrast to renal blood flow in Series I. Similar results were obtained in a third series of dogs (n = 6) with a single denervated nonfiltering kidney, during sustained intrarenal arterial infusions of atrial natriuretic factor. These results suggest that an increase in the sodium load delivered to the macula suppression of renin secretion by atrial natriuretic factor is mediated through its interactions with the two intrarenal receptor mechanisms, the renal vascular receptor and the macula densa.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of renal nerves in rats with low-sodium, one-kidney hypertension.

This study examined the role of the renal nerves in both the maintenance and developmental phases of hypertension produced by sodium restriction in one-kidney rats. Results indicate that mild hypertension is sustained through 6 wk after unilateral nephrectomy in rats fed a sodium-deficient diet, with the greatest increase in systolic blood pressure occurring within the first 2 wk. Six weeks after nephrectomy, renal denervation was performed in the sodium-restricted, hypertensive rats, and the blood pressure returned to normotensive levels. Plasma renin activity (PRA) was elevated fourfold after 6 wk of sodium restriction and was unchanged by renal denervation. In another series of experiments that examined the development of hypertension in this experimental model, contralateral renal denervation was performed at the time of nephrectomy, and this prevented the subsequent development of hypertension. PRA was significantly attenuated in these low-sodium, renal-denervated rats that failed to become hypertensive when compared with PRA in hypertensive low-sodium, sham-denervated rats. Kidney norepinephrine content was reduced by 96% after renal denervation in both phases of the hypertension. These data demonstrate that intact renal nerves are necessary for both the development and maintenance of mild hypertension after sodium restriction in one-kidney rats. The pressor contribution of the renal nerves to the hypertension in this experimental model appears to be related, at least in part, to the activation of the renin-angiotensin pressor mechanism.

Ganglionic blockade in conscious dogs with chronic caval constriction.

Chronic constriction of the thoracic inferior vena cava decreases venous return and cardiac output, increases the secretion of renin and aldosterone, and produces sodium retention with ascites and edema formation. The arterial pressure is maintained at normotensive levels in this caval model by an increase in total peripheral resistance. The objective of the present study was to compare renal and hemodynamic responses to ganglionic blockade in the conscious thoracic caval dog to responses obtained in another low-output model, the chronic sodium-deplete dog, and also to the responses obtained in the normal sodium-replete dog. The control base-line pressures averaged 103 +/- 2, 110 +/- 3, and 110 +/- 3 mmHg, respectively, in the sodium-replete, sodium-deplete, and thoracic caval dogs (P greater than 0.05). Ganglionic blockade in the conscious dog with caval constriction resulted in a sustained 20- to 30-mmHg fall in the arterial pressure; a sustained fall of 20 mmHg occurred in the sodium-deplete dogs. In contrast, ganglionic blockade failed to decrease the blood pressure at any time in the normal sodium-replete animals. Effective renal blood flow and creatinine clearance failed to demonstrate sustained changes after ganglionic blockade in any group of dogs; renal sodium excretion increased only in the normal sodium-replete dogs. These results suggest an enhanced contribution of the sympathetic nervous system to blood pressure maintenance in both the sodium-deplete and the caval dogs. Although the data fail to demonstrate an important contribution of the adrenergic system in the chronic sodium retention in these two experimental models, decreases in renal perfusion pressure may have blunted any potential natriuresis in these animals following ganglionic blockade.

Systemic and renal hemodynamic responses to vascular blockade of vasopressin in conscious dogs with ascites.

A role for arginine vasopressin has been implicated in the compensatory control of arterial blood pressure in several animal models with reported increases in plasma levels of arginine vasopressin. A threefold elevation in plasma vasopressin has been reported in conscious dogs following constriction of the inferior vena cava. In the present study, infusion of the arginine vasopressin antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid), 2-O-methyltyrosine] Arg8-vasopressin into conscious dogs with chronic caval constriction did not decrease mean arterial blood pressure. However, the dose of infused antagonist completely blocked the pressor response to 2 micrograms of exogenous vasopressin. Also the antagonist produced no effect on heart rate, plasma renin activity, or urinary volume and electrolyte excretions. A slight, transient increase (P less than or equal to 0.05) was observed in creatinine clearance and in PAH clearance following antagonist infusion, suggesting a possible decrease in renal vascular resistance. These data suggest that the direct vasoconstrictor actions of vasopressin contribute minimally, if at all, to blood pressure maintenance following chronic caval constriction. Alternatively, blockade of endogenous vasopressin receptors at the level of peripheral arterioles may have resulted in no depressor response due to a masking of this response by other compensatory hormonal and neural pressor systems.

Renal response to atrial natriuretic factor in conscious dogs with caval constriction.

Constriction of the thoracic inferior vena cava to decrease venous return and atrial filling markedly elevates plasma renin activity (PRA) and plasma aldosterone concentration (PAC) and produces chronic sodium retention and ascites in the dog. Infusion of a synthetic atrial natriuretic factor into conscious dogs with caval constriction and ascites at doses of 175 and 350 ng X kg-1 X min-1 for 30 min each produced striking increases (P less than 0.05) in creatinine clearance, diuresis, and kaliuresis but failed to increase urinary sodium excretion. Infusions of atrial natriuretic factor at these doses into conscious normal dogs, however, produced a striking increase in sodium excretion from 41 +/- 14 and 55 +/- 19 mu eq/min to 150 +/- 58 and 181 +/- 49 mu eq/min (P less than 0.05 for both values). Creatinine clearance and urine flow also increased in these normal dogs, but potassium excretion remained unchanged during the infusion periods. Atrial natriuretic factor produced parallel suppression (P less than 0.05) of the elevated levels of PRA and PAC in the caval dogs but failed to significantly decrease either PRA or PAC in the normal animals. Arterial pressure, heart rate, and PAH clearance were unchanged in both groups of dogs during infusion of atrial natriuretic factor. These results suggest that the pattern of renal electrolyte excretion elicited in response to the acute infusion of atrial natriuretic factor is dependent, at least partially, on the preexisting status of the renal tubules to facilitate sodium reabsorption and potassium excretion. The results also are consistent with the concept that atrial natriuretic factor might function to tonically inhibit the renin-angiotensin-aldosterone system.

Sodium and volume depletion activates neurogenic mechanisms in renal hypertensive dogs.

The acute response to ganglionic blockade (hexamethonium bromide, 30 mg/kg, i.v.) was used to evaluate the neurogenic contributions to mean arterial pressure maintenance in the conscious one-kidney, one clip hypertensive dog. Approximately 2 hours (112 minutes) after ganglionic blockade, captopril (10 mg/kg, i.v.) was given to block the renin-angiotensin system. Hypertensive animals were studied 3 days after clipping (group 2) or 2 to 4 weeks after clipping (groups 3 and 4). Groups 2 and 3 were fed a regular sodium diet, but group 4 animals were sodium and volume depleted. Normotensive control animals (group 1) were fed a regular sodium diet. On the day of the acute experiment the baseline blood pressures measured in group 2 (151 +/- 10 mm Hg, n = 5), group 3 (154 +/- 5 mm Hg, n = 7), and group 4 (160 +/- 8 mm Hg, n = 7) were not different (p greater than 0.05) from each other, but all were elevated (p less than 0.05) compared with the group 1 animals (106 +/- 3 mm Hg, n = 8). Also, there were no significant differences (p greater than 0.05) in the baseline plasma catecholamine levels among the three hypertensive groups. Ganglionic blockade produced a greater fall in blood pressure (p less than 0.05) in the sodium/volume-depleted dogs of group 4 (-35 mm Hg) than in group 1 (-10 mm Hg), group 2 (-3 mm Hg), or group 3 (-12 mm Hg) animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of meclofenamate on the renin response to aortic constriction in the rat.

This study examines the role of the renal prostaglandin system in stimulus-secretion coupling for renal baroreceptor-dependent renin release in the anesthetized rat. Changes in plasma renin activity (PRA) secondary to suprarenal aortic constriction were evaluated in groups of rats with a single denervated nonfiltering kidney (DNFK) with and without pretreatment with meclofenamate. Suprarenal aortic constriction was adjusted to reduce renal perfusion pressure to either 100 or 50 mmHg. In addition, similar experiments were performed in rats with a single intact filtering kidney. Inhibition of prostaglandin synthesis with meclofenamate failed to block or attenuate the increase in PRA in response to the decrement in renal perfusion pressure after both severe and mild aortic constriction for both the DNFK and the intact-kidney groups. The adequacy of prostaglandin inhibition was demonstrated by complete blockade with meclofenamate of the marked hypotensive and hyperreninemic responses to sodium arachidonate. The results in the DNFK indicate that in the rat, renal prostaglandins do not function as obligatory mediators of the isolated renal baroreceptor mechanism for the control of renin release. Also the findings in the intact filtering kidney suggest that prostaglandins are not essential in the renin response of other intrarenal receptor mechanisms that also are stimulated by a reduction in renal perfusion pressure.

Pathogenesis of one-kidney, one-clip hypertension in rats after renal denervation.

This study examines the role of the renal nerves in the chronic and early developmental stages of one-kidney, one-clip (1K-1C) Goldblatt hypertension. Groups of uninephrectomized Sprague-Dawley rats underwent renal artery constriction with a clip of an internal diameter of 0.23 mm (groups 1 and 3) or 0.40 mm (groups 2 and 4) to produce severe or moderate hypertension. Two weeks later, groups 1 and 2 were subjected to renal denervation and groups 3 and 4 were denervated 6 and 7 wk after clipping, respectively. In all four groups, hypertension remained unchanged during the subsequent 2 wk after denervation. To study further the effects of renal denervation during the early onset of hypertension, groups 5, 6, and 7 received the smaller (0.23 mm) clip after uninephrectomy. Groups 5 and 6 were renal denervated immediately before clipping; group 7 was not denervated. In groups 6 and 7 the renin-angiotensin system was blocked with a continuous infusion of the converting-enzyme inhibitor captopril for 24 h before and 15 days after clipping. In group 5, renal denervation did not prevent a prompt and severe rise in the systolic blood pressure. In groups 6 and 7, infusion of captopril prevented the hypertension only during the first 4 days after clipping; at no time was there a difference in the systolic blood pressure curves of groups 6 and 7 during or after captopril infusion. These data demonstrate that regardless of the severity and duration of hypertension, renal denervation failed to attenuate either the development or the maintenance of 1K-1C Goldblatt hypertension in the rat. Thus the present results fail to provide support for the concept that the renal nerves modulate the hypertension in this experimental model.

Effects of indomethacin in conscious dogs with experimental high-output heart failure.

The role of renal prostaglandins in the control of renin release and renal hemodynamic function (RHF) was studied in conscious dogs with a surgically created infrarenal aortocaval fistula, a model of high-output heart failure (HOHF). In series 1 during acute cardiac failure, indomethacin administration produced striking reductions in RHF but failed to alter the high level of plasma renin activity (PRA). In series 2, administration of indomethacin to dogs with chronic HOHF also resulted in pronounced decrements in RHF in spite of normal levels of PRA. Studies of individual animals with meclofenamate in both series 1 and 2 confirmed the findings with indomethacin with one exception; in one dog with chronic severe HOHF a very high level of PRA was present initially and fell 44% after meclofenamate. These observations indicate that in the acute and chronic phases of HOHF prostaglandins are involved in the maintenance of renal blood flow and glomerular filtration rate but do not play an essential role in the control of renin release.