Ouabain inhibits renin release by a direct renal haemodynamic effect.

The effect of intrarenal infusion of ouabain (90 micrograms/kg) on renin release was examined in the anaesthetized dog. Ouabain reduced cortical Na-K-ATPase activity to 23% and outer medullary activity to 18% of the control level. During renal arterial constriction to a perfusion pressure below the autoregulatory range, renin release rose from 1.2 +/- 0.4 to 47.4 +/- 6.9 micrograms/min (P less than 0.001). This response was abolished by ouabain. When superimposed on renal arterial constriction, beta-adrenergic stimulation enhanced renin release from 25.6 +/- 10.7 to 56.9 +/- 9.5 micrograms/min (P = 0.02) at a urinary sodium excretion of 2 +/- 1 mumol/min. After ouabain, the corresponding increment substantially decreased since release rose from 5.6 +/- 2.0 to 19.9 +/- 5.3 micrograms/min only (P = 0.02), at a urinary sodium excretion of 140 +/- 67 mumol/min. When glomerular filtration was reduced to zero by ureteral occlusion in one series, renin release increased to 22.6 +/- 5.1 but was reduced (P less than 0.05) by ouabain to 13.5 +/- 5.5 micrograms/min and superimposed isoproterenol had no effect. According to these observations, ouabain inhibits renin release by a direct effect on the afferent arteriole through constriction of the autoregulating renin-secreting segment.

Effect upon longitudinal growth of femur by intramedullary nailing in rats.

In an experimental study using rats it was found that intramedullary nailing through the distal femoral growth plate resulted in a significant retardation of longitudinal growth. Drilling only and pin removal after 7 weeks also gave significant inhibition of growth after 14 weeks, while drilling only with immediate removal of the pin gave no growth disturbance during the first 7 weeks. The investigation indicates that damage to the central portion of the epiphyseal growth plate in rats leads to inhibition of longitudinal growth.

Conditions for augmentation of renin release by theophylline.

Isoproterenol, dopamine, glucagon and dibutyryl cyclic AMP (DB-cAMP) increase renin release at low but not at control blood pressure. These findings suggest that autoregulated afferent arteriolar dilation is a prerequisite of renin release mediated by intracellular generation of cyclic AMP. To examine this hypothesis further the effects on renin release of theophylline, which would maintain high intracellular concentration of cAMP by inhibiting phosphodiesterase, were studied in anesthetized dogs. After inhibiting beta-adrenergic stimulation with propranolol, theophylline increased renin release significantly from 0.7 +/- 0.2 to 1.8 +/- 0.7 micrograms/min at control blood pressure and from 23 +/- 4 to 41 +/- 5 micrograms/min at a renal perfusion pressure of about 50 mmHg. The greater effect at low blood pressure occurred despite adjustment of the infusion rate of theophylline to keep arterial plasma concentration of theophylline unaltered. Isoproterenol infusion at low blood pressure raised renin release from 41 +/- 11 to 76 +/- 19 micrograms/min before and 54 +/- 13 to 108 +/- 31 micrograms/min during continuous infusion of theophylline. The renin release response to infusion of theophylline at low blood pressure was not enhanced by DB-cAMP infusion. We conclude that arteriolar dilation provides a condition for stimulation of renin release during the theophylline infusion. Theophylline infusion may augment the effect of isoproterenol on renin release by delaying the intracellular degradation of cAMP.

Mechanism of renin release during renal nerve stimulation in dogs.

During renal nerve stimulation, a predominant vasoconstrictory effect on small arteries would lower blood pressure in the afferent arterioles and induce arteriolar dilation and renin release by the autoregulation mechanism. This hypothesis was examined in anaesthetized dogs by stimulating renal nerves at 4 Hz which permitted continuous reduction of renal blood flow (RBF) by 30-40%; renin release increased almost equally at control and low blood pressure, and in the non-filtering kidney during ureteral occlusion. Examinations of the relationship between RBF and arterial perfusion pressure during mechanical constriction of the renal artery showed that the lowest autoregulating pressure was 25-35 mmHg higher during nerve stimulation than in control experiments, consistent with the hypothesis of arteriolar dilation. Phenoxybenzamine, an inhibitor of alpha-adrenoceptors, abolished vasoconstriction and the effect of nerve stimulation on renin release at control blood pressure; renin release rose from 0.9 +/- 0.4 to 17 +/- 5 microgram/min before, and from 1.7 +/- 0.5 to 4.6 +/- 1.4 microgram/min after phenoxybenzamine infusion. At pressures below the range of autoregulation, phenoxybenzamine did not alter renin release response to nerve stimulation. Propranolol, a Beta-adrenergic inhibitor, attenuated the effect of nerve stimulation on renin release both at control and low blood pressure. We conclude that during renal nerve stimulation (1) renin release is caused by beta-adrenergic stimulation provided the afferent arterioles are dilated and (2) that alpha-adrenergic stimulation dilated the afferent arterioles as a consequence of a predominant vasoconstrictory effect on small arteries. Hence, by inhibiting the beta-adrenergic effect by propranolol, renin release does not increase during renal nerve stimulation. Phenoxybenzamine prevents renin release at control blood pressure because afferent arterioles are not dilated during nerve stimulation. In contrast, phenoxybenzamine does not reduce renin release during nerve stimulation at low blood pressure because afferent arterioles are dilated by the autoregulating mechanism.

Conditions for humoral alpha-adrenoceptor stimulation of renin release in anaesthetized dogs.

To examine whether an alpha-adrenergic agonist, methoxamine, influences renin release solely by its haemodynamic effect, experiments were performed in anaesthetized dogs with denervated kidneys. Methoxamine was infused intrarenally at rates which reduced renal blood flow (RBF) by 30-40%. At control blood pressure, renin release rose during infusion of methoxamine from 1.4 +/- 0.7 to 31 +/- 11 microgram/min. A beta-adrenergic stimulator, isoproterenol, did not increase renin release significantly when administered alone into the renal artery, but doubled the effect of methoxamine infusion: at control blood pressure renin release rose from 0.5 +/- 0.3 to 71 +/- 17 microgram/min during combined infusion of isoproterenol and methoxamine. Mechanical constriction of the renal artery left RBF unaltered down to a renal perfusion pressure of 90 +/- 4 mmHg during methoxamine infusion, whereas the lowest autoregulating pressure in control experiments averaged 60 +/- 5 mmHg. At renal infusion pressure below the range of autoregulation, renin release was not further increased by intrarenal infusion of methoxamine. Isoproterenol infusion at low renal perfusion pressure doubled renin release, which was not significantly altered by additional infusion of methoxamine. The stimulatory effect of methoxamine on renin release at control blood pressure could be diminished but not prevented by infusing 2.9% NaCl intravenously in large amounts. These data indicate that methoxamine induces autoregulated dilation of afferent arterioles by disproportionate vasoconstriction on pre-afferent arteries. Thereby afferent arterioles are conditioned for stimulation of renin release by isoproterenol.

Conditions for stimulation of renin release by cyclic AMP in anaesthetized dogs.

Cyclic AMP (cAMP) is the intracellular mediator of beta-adrenergic stimulation in most tissues. Stimulation of beta-adrenoceptors increases renin release much more at low than at control arterial perfusion pressure. If beta-adrenergic stimulation is mediated by cAMP, this nucleotide should also potentiate renin release at low perfusion pressure. In anaesthetized, propranolol treated dogs, the dibutyryl derivative of cAMP (DB-cAMP), which penetrates cell membranes more readily than cAMP, increased renin release significantly during renal arterial constriction at a perfusion pressure below the range of autoregulation, but no significant effect was observed at control blood pressure. A dose-response relationship could be demonstrated in propranolol treated dogs by administering DB-cAMP at 10, 100 and 1000 micrograms/min at low but not at control blood pressure. Since sodium excretion increased, stimulation of a macula densa mechanism is unlikely, whereas arteriolar dilation, caused by autoregulation at low blood pressure, may condition the juxtaglomerular apparatus for renin release. Infusion of cAMP had no effect on renin release either at control or low blood pressure, whereas 5'AMP exerted a marked inhibitory effect at low blood pressure. We conclude that infusion of DB-cAMP rather than cAMP stimulates renin release at low but not at control blood pressure and that this effect is not mediated by beta-adrenergic receptors; cAMP may be an intracellular mediator of renin release.

Mechanism of renin release during acute ureteral constriction in dogs.

The relationship between renal arterial pressure and renin release was examined in anesthetized dogs during complete or partial ureteral constriction. During complete ureteral occlusion ureteral pressure rose to 95+/-4 mm Hg and renin release increased from 1.7+/-0.7 to 22.3+/-3.1 mug/min; renal blood flow (RBF) was not significantly changed. Renin release was not further increased during subsequent renal arterial constriction; RBF fell in proportion to perfusion pressure, indicating maximum autoregulated arteriolar dilation. During partial ureteral constriction to a ureteral pressure of 65+/-6 mm Hg, renin release was moderately raised but release mechanisms became fully stimulated when renal arterial pressure was reduced to 104+/-3 mm Hg. By further constricted of the renal artery, RBF fell in proportion to perfusion pressure and renin release remained high and constant. In control experiments without ureteral constriction, renal arterial pressure had to be reduced to below 65+/-8 mm Hg to fully stimulate renin release (22.0+/-3.8 mug/ml which is not different from 22.3+/-3.1 mug/min during ureteral occlusion). During partial ureteral constriction, saline infusion (0.9% NaCl at 40 ml/min) raised urine flow, sodium excretion, renal pelvic pressure, and renin release. Thus, the stimulatory effect on renin release of a rise in ureteral pressure exceeded the inhibitory effect of increased sodium excretion. This observation, together with maximum renin release coinciding with complete arteriolar dilation during various combinations of renal arterial and ureteral constriction, is compatible with the conclusion that arteriolar dilation is predominating stimulus to renin release during ureteral constriction.

Tibial shaft fractures treated with intramedullary nailing.

A series of 132 patients with 139 tibial shaft fractures treated with intramedullary nailing is presented. Nailing was performed either primarily or secondarily and reaming was performed in most cases. A rigid fixation was secured in most patients. At followup of 124 patients the results were good or fair in 96% (107 had good results, 12 had fair results). Only one patient had a lasting poor result, while 4 patients had uneventful healing and ultimately good result after renailing.

Segmental tibial shaft fractures.

A series of 54 cases with multiple fractures of the tibia is reported. Sixty-eight per cent of the group were pedestrians hit by a car. Fifty-two per cent were open fractures. Osteosynthesis was performed in 33 cases, whereas 21 were treated conservatively. Plate osteosynthesis was accomplished in 23 cases, seven had intramedullary nailing, and two were treated by Hoffman's external fixation device. Only one patient sustained a severe complication, viz., deep wound infection and osteomyelitis; however, even this infection was transient. All fractures healed except those sustained by two patients who died within 3 months; these deaths were, however, without any causal relationship to the osteosynthesis. One patient had a traumatic vascular lesion concomitant with the fracture, and his leg was amputated 3 days after the injury. Another patient had his leg amputated 1 year after his accident, in this case also because of injury to the vessels and nerves. It was concluded from the present series that segmental or multiple tibial shaft fractures do not entail more complications nor do they exhibit a slower rate of union than simple tibial shaft fractures if the treatssue injury.

Influence of ethacrynic acid on intrarenal renin release mechanisms.

Ethacrynic acid infused i.v. in anesthetized dogs after inhibiting sympathetic mechanisms of renin release increased renal blood flow rate (RBF) by 54% and practically abolished autoregulation of RBF; renin release increased from 0.8 +/- 0.9 (mean +/- SEM) to 16.4 +/- 3.7 mug/min (P less than 0.05). Without infusion of ethacrynic acid; constriction of the renal artery to a pressure below the range of autoregulation reduced renovascular resistance markedly and renin release rose to 27.2 +/- 5.5 mug/min (P less than 0.05). During arterial constriction, ethacrynic acid had no additional effect on renovascular resistance or renin release averaging 28.4 +/- 6.7 mug/min. Infusion of ethacrynic acid and saline at control pressure increased sodium excretion to about one-half of the filtrate and reduced rein release which did not, however, return to control. Infusion of hypertonic saline during autoregulated vasodilatation induced by arterial constriction had a similar effect, but again renin release continued to exceed control. We propose that ethacrynic acid increases renin release through a hemodynamic mechanism triggered by afferent arteriolar dilation and inhibits renin release by greatly increasing the delivery of sodium to the distal convoluted tubules.