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.     

Regional blood flow in response to exercise in conscious dogs

Summary Regional blood flow was measured with the microsphere method in conscious dogs under resting conditions and during moderate exercise on the treadmill.With respect to total organ blood flow, exercise induced a marked increase in blood flow to the calf muscles and to the myocardium, and a significant decrease in the arterial blood supply to the liver. Slight changes in blood flow to the other organs under study (various skeletal muscles, skin, brain, kidneys, intestine) were not significant.Study of the blood flow distribution within the myocardium showed a slight decrease of the ratio of subendocardial to subepicardial blood flow in the left ventricular free wall in response to exercise, and within the brain there was a relative increase in the blood flow to the cerebellum.     

Renal prostaglandin E2 secretion and excretion in conscious dogs.

Renal prostaglandin E2 (PGE2) secretion and excretion rates were determined in nine conscious dogs. Renal venous (RV) and urine PGE2 concentrations were measured by radioimmunoassay. In 21 controls tests RV PGE2 ranged from 37 to 215 pg/ml, with a mean concentration of 97 +/- 11 pg/ml. Basal left kidney PGE2 secretion was 317 +/- 42 pg.g-1.mm-1. Urine PGE2 concentration averaged 8,320 +/- 1,510 pg/ml with a PGE2 excretion rate of 3,260 +/- 480 pg/min from both kidneys. Indomethacin (2 mg/kg) reduced RV and urine PGE2 concentrations by 60 and 77%, respectively. Meclofenamate (2 mg/kg) decreased RV and urine PGE2 concentrations by 36 and 48%, respectively. PG inhibition had no significant influence on blood pressure or renal blood flow (RBF). PG inhibition reduced urine flow rate and increased urine osmolality. Indomethacin had no effect on urine sodium concentration or sodium excretion; meclofenamate increased urine sodium concentration and slightly diminished sodium excretion. These data demonstrate that PGE2 is released from the kidney in a conscious animal and that both indomethacin and meclofenamate significantly reduce the renal secretion and excretion of PGE2. In a normal, conscious animal prostaglandins do not control blood pressure or RBF but are involved in the excretion of water.     

Angiotensin II in the renal excretory response to behavioral stress in conscious dogs

The effects of inhibition of the renin-angiotensin system on the decreased renal excretion of sodium and water resulting from behavioral stress (shock avoidance) were examined in conscious saline-infused (4-5 ml/min) dogs. During saline infusion alone in six dogs, avoidance decreased sodium excretion (64% from 329 mueq/min) and urine flow (63% from 1.9 ml/min). During converting enzyme inhibition with captopril in the same dogs, the decreases in sodium excretion (35% from 464 mueq/min) and urine flow (35% from 2.6 ml/min) during avoidance were attenuated. Similarly, in six other dogs, avoidance decreased sodium excretion (41% from 361 mueq/min) and urine flow (43% from 2.1 ml/min) with saline infusion alone. During angiotension II (ANG II) receptor antagonism with saralasin, decreases in sodium excretion (29% from 417 mueq/min) and urine flow (27% from 2.2 ml/min) were attenuated. These mean changes in excretion during inhibition of the renin-angiotensin system were significantly (P less than 0.05) less than during saline alone. Whereas decreases in fractional sodium and water excretion were attenuated by renin-angiotensin inhibition, decreases in glomerular filtration rate and effective renal blood flow and increases in mean arterial pressure were not affected. These results indicate that ANG II contributes to the renal excretory response to avoidance.     

Investigation of kinetics of integrated metabolic response to adrenergic blockade in conscious dogs

We have used multiple isotope infusions to study the integrated response of glucose, fat, and protein metabolism to combined alpha + beta-adrenergic blockade in conscious, unstressed, fasting (15 h) dogs. The response to the blocking agents was evaluated both with and without control of the glucoregulatory hormones. The hormones were controlled at the basal level by infusions of somatostatin and metyrapone to block their secretion, and by the infusion of insulin, glucagon, growth hormone, and cortisol at physiological rates. We found that adrenergic blockade markedly inhibited lipolysis, as reflected by falls in glycerol and plasma FFA appearance. The decrease in fat mobilization after blockade resulted in a proportionate shift from fat as an energy substrate toward carbohydrate. Glucose production and oxidation were both enhanced after blockade. The source of the increased glucose production was presumably hepatic glycogen because urea production was presumably hepatic glycogen because urea production was unaffected and glycerol uptake was decreased. These results are consistent with the interpretation that basal adrenergic activity plays an important role in the mobilization of fat in fasting dogs. A secondary consequence of that action is apparently a diminution of glucose production and oxidation, although the mechanism responsible for the latter response is not clear.     

Renal nerve blunts natriuretic and diuretic response to atrial natriuretic peptide in conscious rabbits

The contribution of the renal nerve to the natriuretic and diuretic responses to rat atrial natriuretic peptide (rAMP) was investigated in conscious rabbits with unilateral renal denervation. Renal nerve activity (RNA) was measured at the contralateral innervated kidney. Catheters were bilaterally implanted into the ureters. Urine samples were collected from each kidney by gravity drainage at 10-min clearance intervals. In rabbits with all baroreflexes intact, infusion of rANP at 0.3 micrograms/(kg.min) for 30 min decreased mean arterial pressure by 8 +/- 4 mmHg and increased RNA by 53 +/- 13%. After sinoaortic baroreceptor denervation (SAD), hypotensive response to infusion of rANP was greater than that in intact rabbits, while RNA did not change. After SAD plus vagotomy, infusion of rANP lowered mean arterial pressure by 21 +/- 4 mmHg and RNA by 19 +/- 6%. In the denervated kidney, infusion of rANP increased Na+ excretion by 16.1 +/- 4.5 from 3.5 +/- 1.0 muEq/min and water excretion by 0.17 +/- 0.05 from 0.08 +/- 0.02 ml/min. In the contralateral innervated kidney, infusion of rANP increased the amount of Na+ and water excretion by 4.5 +/- 3.2 muEq/min and 0.07 +/- 0.04 ml/min, which were significantly less than those in the denervated kidney. These results indicate that infusion of rANP increases RNA, due to baroreceptor reflexes, and that this increase in RNA blunts natriuretic and diuretic action of rANP.     

The response of adipose tissue blood flow to insulin-induced hypoglycemia in conscious dogs and rats

A comparative study, focusing on the modification of regional blood flow in adipose tissue during insulin-induced hypoglycemia, was performed on dogs and rats at room temperature (22°C) and on rats at thermoneutrality (28–32°C). Insulin dosages of 3 IU/kg in rats and 0.75 IU/kg in dogs were found to cause changes of comparable amplitude and kinetics in plasma glucose and catecholamine levels in both species. At thermoneutrality, hypoglycemia induced an increase in blood supply to adipose tissue in both species: in dogs, blood flow density was markedly increased from the periphery (+75% in subcutaneous region) to the deeper locations (+550% in perirenal region); in rats, the increase of fractional cardiac output was especially pronounced in brown adipose tissue. By contrast, in rats acclimated at room temperature, hypoglycemia induced a decrease of fractional cardiac output to white adipose tissue and even more markedly, to brown adipose tissue (–45%). These results strongly suggest that, in rats at ambient temperature below thermoneutrality, thermoregulatory heat production is shut off during hypoglycemia.     

Sympathetic effects on cerebral and ocular blood flow in rabbits pretreated with indomethacin

The effects of unilateral stimulation of the cervical sympathetic chain on cerebral and ocular blood flow was investigated in 8 rabbits anesthetized with pentobarbital sodium and pretreated with indomethacin in order to inhibit the formation of prostaglandins. Blood flow determinations were made with the labelled microsphere method during normotension and acute arterial hypertension. Hypertension was induced by ligation of the thoracic aorta. Evans blue was given as a tracer for protein leakage during hypertension. Sympathetic stimulation had no significant effect on the blood flow in the brain under the two conditions studied. In the uvea marked effects of sympathetic stimulation were obtained at normotension as well as at hypertension. There were no indications of breakdown of the blood-brain barrier or the blood-aqueous barrier. Thus, there was no evidence for any prostaglandin-mediated inhibition of sympathetic effects in the brain or the eye.     

Renal dysgenesis in a monozygotic twin: association with in utero exposure to indomethacin

We report oligohydramnios and renal dysgenesis in one of identical twins, which might have resulted from in utero exposure to early, prolonged high-dose indomethacin. The proposita was the second of twin girls born at 36 weeks of gestation. Pregnancy was complicated initially by polyhydramnios in both amniotic sacs and premature uterine contractions. After administration of indomethacin and terbutaline from 16 to 30 weeks' gestation, serial prenatal ultrasound examinations ultimately showed oligohydramnios in twin B and resolution of polyhydramnios in twin A. On day 5 twin B developed hematuria, hypertension, renal failure, hyponatremia, hyperkalemia, metabolic acidosis, sodium wasting and severe, transient inability to excrete potassium. Renal sonography showed enlarged, hyperechoic kidneys with almost no corticomedullary differentiation. Renal biopsy revealed immature glomeruli, dilated Bowman's spaces, dilated tubules, and interstitial fibrosis. The liver was histologically normal. Indomethacin may induce oligohydramnios and transient renal insufficiency in humans and renal dysgenesis in fetal monkeys; it might have induced the abnormalities in this patient.     

Pitfalls in acid/base experiments with conscious dogs

Arterial pH and blood gases were measured at intervals in conscious dogs after their first human contact of the day. Blood was sampled through an indwelling catheter in the aorta without disturbing the animals. It appeared that in the first 90 min arterial PO₂, oxygen saturation and haemoglobin concentration significantly declined. PCO₂ and pH changed less consistently when the acid/base status of the dogs was normal, but when a non-respiratory acidosis was present there was a significant decrease in pH and a significant increase in PCO₂. Arterial pH and blood gases were also measured before and after feeding the animals. It appeared that an appreciable metabolic alkalosis developed within 2 h after a meal. The alkaline tide was accompanied by a trend to higher values for PCO₂. It is concluded that, after a period of seclusion, renewed human contact causes behavioural changes in a dog, which may result in appreciable transitory changes in arterial pH and blood gas values. Blood sampling from conscious dogs should therefore take place after a proper period of habituation; preferably, a few samples should be taken at intervals to check that a steady state has been reached. If possible, blood should be collected before feeding; in any case the relationship in time of blood sampling to feeding should be constant throughout.     

Tolerance to haemorrhage during vasopressin antagonism and/or captopril treatment in conscious sheep

The effect of separate and combined blockade of vasopressin (AVP) V₁-receptors and angiotensin II formation on resistance to a slow venous haemorrhage (0.7 ml kg^-1 min^-1) was studied in six conscious adult sheep by bleeding to the point of an abrupt fall in the mean systemic arterial pressure (MSAP). Intravenous administration of the V₁-receptor antagonist [d(CH₂)₅Tyr(Me)AVP] (10 μg kg^-1) and/or the angiotensin I converting enzyme inhibitor captopril (20 mg+1 mg h^-1) did not cause any significant haemodynamic changes in the normovolaemic animal. The volume of haemorrhage necessary to induce acute hypotension (MSAP < 50 mmHg) was significantly smaller after AVP blockade alone (13.8±0.7 ml kg^-1; P < 0.01) but not after captopril treatment (14.7±1.6 ml kg^-1; n.s.) compared to control animals receiving no drug treatment (16.8±0.6 ml kg^-1). The combined treatment with the AVP antagonist and captopril caused a further decrease in tolerance to haemorrhage (9.4±1.2 ml kg^-1; P < 0.001). Blockade of AVP V₁-receptors was associated with an attenuated increase in systemic vascular resistance immediately after the end of haemorrhage, concomitant with an accentuated lowering of the central venous pressure. In contrast, captopril treatment decreased the degree of vasoconstriction mainly during the second half of the post-haemorrhage observation period of 1 hour. It is concluded that both AVP and angiotensin II contribute to the maintenance of the MSAP during haemorrhage in conscious sheep. During the spontaneous recovery after hypotensive blood loss, a vasoconstrictor effect of AVP is evident mainly during the initial 15 min, whereas at later stages angiotensin II appears to be of relatively greater importance.     

Evaluation of a neurogenic rapid coronary dilatation during an excitatory response in conscious dogs

Summary The regional distribution of the peripheral vascular resistance was studied in normotensive and hypertensive Wistar rats. Two models of experimental hypertension were investigated: (I) in 32 animals the right renal artery was constricted by a silver clip (two-kidney Goldblatt hypertension); (II) in 46 animals the left kidney was removed and the right renal artery was clipped as in the first group (one-kidney Goldblatt hypertension). The normotensive control group comprised 61 untreated animals of the same strain and age. The distribution of cardiac output to 14 tissues was determined by means of the particle distribution technique.The resistance was increased in all regions investigated, a decreased or unchanged resistance was not observed. For most of the investigated tissues the regional resistance was increased exactly in proportion to the total peripheral resistance (TPR). Exceptions to this were found in 2 regions where the change of local resistance deviated from that of TPR: the splanchnic area and the skeletal muscle. In both cases the 2 models differed from each other. In the two-kidney model the increase of resistance in the splanchnic circulation was more intense than in other organs. In contrast, in the one-kidney model the local change of resistance was less than that of TPR. The change of rkeletal muscle resistance was not significantly different from the change of TPR in the two-kidney model, while in the one-kidney model the increase of local resistance was significantly higher than that of TPR.It is concluded that the etiology of the abnormal resistance is different in the 2 models investigated and that known extrinsinc pressor factors may play a role in the two-kidney, but not in the one-kidney Goldblatt hypertension.