Kaluresis independent K homeostasis in dogs: activity after ureter ligation and pancreatectomy

In ureter ligated dogs intravenous administration of KCl stimulates both insulin secretion and activity of a kaluresis independent K homeostatic mechanism (K transfer capacity) that retards the development of hyperkalemia by transferring K to intracellular fluid. If the preparation is K loaded by infusion with 2 mEq KCl/kg/hr until prelethal ECG changes of hyperkalemic cardiotoxicity appear, about 50% of administered K is transferred. An increased proportion--70%--is transferred if the animal is K loaded 70 minutes after pancreatectomy--when serum immunoreactive insulin is fixed at less than 4 uU/ml. That proportion (70%) is unchanged by simultaneous adrenalectomy, but is reduced to less than 40% by propranolol blockade of B receptors. Increased post pancreatectomy K transfer capacity apparently involves K transfer mediated by B receptors that are activated by an extra-adrenomedullary B agonist(s). Findings also indicate that residual post pancreatectomy insulin biological activity mediates K transfer.     

Effect of alpha-adrenergic blockade on the cardiovascular responses to hypoxemia and hypercapnic acidosis in conscious dogs

In order to evaluate the role of the alpha-adrenergic system in the systemic and renal hemodynamic changes of the acute combined blood gas derangement, seven conscious mongrel dogs in careful sodium balance (80 mEq/day for 4 days) were evaluated. Each animal was evaluated during combined acute hypoxemia (PaO2 = 35 +/- 1 mm Hg) and hypercapnic acidosis (PaCO2 = 56 +/- 2 mm Hg; pH = 7.18 +/- 0.01) with (i) vehicle (D5W) alone and (ii) alpha 1-adrenergic blockade with prazosin, 0.1 mg/kg iv. Mean arterial pressure increased during the combined blood gas derangement with vehicle. In contrast, mean arterial pressure fell during combined acute hypoxemia and hypercapnic acidosis with alpha 1-adrenergic blockade. The mechanism for abrogation of the rise in mean arterial pressure during the combined blood gas derangement by alpha 1-adrenergic blockade appeared to be through attenuation of the rise in cardiac output rather than an exaggerated fall in total peripheral resistance. These observations suggest that the alpha-adrenergic system is important in circulatory homeostasis during the combined blood gas derangement.     

Insulin and beta receptor modulation of K homeostasis in nephrectomized dogs with hyperkalemia

In nephrectomized dogs infused with 2 mEq KCl/kg/hr a homeostatic mechanism retards the development of hyperkalemia by transferring about 70% of the K load to intracellular fluid. beta Adrenergic receptor activity is importantly involved in the transfer process; halting it with propranolol reduces the proportion transferred to less than 35%. The addition of pancreatectomy increases the involvement of beta receptor activity; propranolol treatment now reduces the proportion transferred to less than 20%. Insulin treatment, on the other hand, not only improves transfer of a K load, it also alters the response to propranolol. Nephrectomized dogs treated with 2 U insulin/kg/hr deposit some 80% of the infused K in intracellular fluid. After beta receptor blockade, nearly 90% is transferred. The results suggest that in the K homeostatic mechanism of nephrectomized dogs, insulin and beta receptors may be reciprocally related. K transfer mediated by beta receptors improves after pancreatectomy, and insulin mediated K transfer improves after beta receptors are inactivated.     

Cardiac sensitivity to hyperkalemia in adrenalectomized dogs.

In dogs with bilateral adrenalectomy loaded with K by infusion of 2 mEq KCI/kg/hr there is a marked increase of cardiac sensitivity to hyperkalemia. Typical ECG changes begin at lower serum K levels (5-6 mEq/l) and the prelethal arrhythmias that signal the imminent onset of fatal when mean serum K is 7.6 mEq/l, 2.9 mEq/l above the average pre-infusion level. In control dogs, ECG changes start above 8 mEq K/liter, and prelethal arrhythmias appear between 9.5 and 10.2 mEq/l, a mean increase of 5.6 mEq/l above the average preinfusion level.     

In situ demonstration of angiotensin-dependent and independent pathways for hyperaldosteronism during chronic extracellular fluid volume depletion.

In wild-type mice, 2-wk administration of losartan, an angiotensin (Ang) II type 1 (AT1) receptor antagonist, along with dietary sodium restriction, resulted in an elevation of plasma aldosterone greater than that seen with sodium restriction alone (2.75 +/- 0.35 vs. 1.38 +/- 0.16 ng/ml, P < 0.01). Plasma potassium increased in sodium-restricted, losartan-treated mice (6.0 +/- 0.2 mEq/liter), while potassium remained unchanged in mice with sodium restriction alone. To study the effect of Ang II on glomerulosa cells that may operate independently of plasma potassium in situ, we used chimeric mice made of cells with or without the intact AT1A gene (Agtr1a). When animals were fed a normal diet or chronically infused with Ang II, the aldosterone synthase mRNA was detectable only in Agtr1a+/+ but not Agtr1a-/- zona glomerulosa cells. After 2 wk of sodium restriction, plasma aldosterone increased (1.51 +/- 0.27 ng/ml) and potassium remained on average at 4.5 +/- 0.2 mEq/liter, with aldosterone synthase mRNA expressed intensively in Agtr1a+/+, but not detectable in Agtr1a-/- cells. Simultaneous sodium restriction and losartan treatment caused increases in plasma potassium (5.5 +/- 0.1 mEq/liter) and aldosterone (1.84 +/- 0.38 ng/ml), with both Agtr1a-/- and Agtr1a+/+ cells intensively expressing aldosterone synthase mRNA. Thus, aldosterone production is regulated by Ang II in the adrenal gland during chronic alterations in extracellular fluid volume when plasma potassium is maintained within the normal range. In the light of a previous observation that dietary potassium restriction superimposed on sodium restriction abolished secondary hyperaldosteronism in angiotensinogen null-mutant mice, the present findings demonstrate that when the renin-Ang system is compromised, plasma potassium acts as an effective alternative mechanism for the volume homeostasis through its capacity to induce hyperaldosteronism.     

High calcium intake does not prevent stress-salt hypertension in dogs

Avoidance conditioning sessions and isotonic saline (1.3 L/day) were administered to dogs for 12 days under conditions of a low (0.1%) or high (1.5%) calcium diet. Twenty-four-hour mean arterial pressure increased comparably during the stress-salt conditioning periods on both the low (systolic: +16 +/- 5 mm Hg; diastolic: +6 +/- 2 mm Hg) and high (systolic: +17 +/- 4 mm Hg; diastolic: +11 +/- 4 mm Hg) calcium diets. Urine volume, sodium excretion, and serum calcium levels on the high calcium diet were not significantly different from those on the low calcium diet. In a second experiment, calcium was infused continuously for six days into the arterial circulation of normotensive or stress-salt hypertensive dogs at a rate of 0.12-0.23 mEq/min. Although serum calcium levels increased by up to 50% under these conditions, there were no significant effects on 24-hour levels of arterial pressure. In contrast to the protective effect of augmented potassium intake, these findings indicate that calcium intake does not influence the development of stress-salt hypertension in dogs.     

An anesthetic technic in dogs for studying the arrhythmogenic effects of acute coronary occlusion

Intramuscular injection of levomepromazine (0.5 mg/kg) 30 min before intravenous injection of 10 mg/kg pentobarbital sodium induces a good surgical anaesthesia in dogs artificially ventilated with 50% N2O and 50% O2 and given 0.01 mg/kg atropine and 0.1 mg/kg pancuronium intravenously before left thoracotomy. This protocol is suitable for the study of the arrhythmogenic effects of acute one-stage coronary artery ligation in anaesthetized dogs. In fact, minor interference with the autonomic nervous system appears to be involved since heart rate is maintained slow and mean aortic pressure is kept within normal limits, as pH, PaO2, anc PaCO2 during subsequent periods. Acute circumflex coronary arterio-venous pedicle ligation close to the left main trunk division resulted in this model in a high incidence of ventricular fibrillation (10 out of 15 dogs) early (7 +/- 4 min) after occlusion. Specific interventions aimed at reducing the incidence of early post-ischemic life-threatening ventricular arrhythmias might be tested in this model.     

Maternal dehydration: impact on ovine amniotic fluid volume and composition

Maternal dehydration consistent with mild water deprivation or moderate exercise results in maternal and fetal plasma hyperosmolality and increased plasma arginine vasopressin (AVP). Previous studies have demonstrated a reduction in fetal urine and lung fluid production in response to maternal dehydration or exogenous fetal AVP. As fetal urine and perhaps lung liquid combine to produce amniotic fluid, maternal dehydration may affect the amniotic fluid volume and/or composition. In the present study, six chronically-prepared pregnant ewes with singleton fetuses (128 +/- 1 day) were water deprived for 54 h to determine the effect on amniotic fluid. Maternal plasma osmolality (306.5 +/- 0.9 to 315.6 +/- 1.9 mOsm/kg) and AVP (1.9 +/- 0.2 to 22.2 +/- 3.2 pg/ml) significantly increased during dehydration. Similarly, fetal plasma osmolality (300.0 +/- 0.9 to 312.7 +/- 1.7 mOsm/kg) and AVP (1.4 +/- 0.1 to 10.4 +/- 2.4 pg/ml) increased in parallel to maternal values. Amniotic fluid osmolality (276.8 +/- 5.7 to 311.6 +/- 6.5 mOsm/kg) and sodium (139.8 +/- 4.8 to 154.0 +/- 5.4 mEq/l) and potassium (9.1 +/- 1.3 to 13.9 +/- 2.4 mEq/l) concentrations increased while a significant (35%) reduction in amniotic fluid volume occurred (871 +/- 106 to 520 +/- 107 ml). These results indicate that maternal dehydration may have marked effects on maternal-fetal-amniotic fluid dynamics, possibly contributing to the development of oligohydramnios.     

Hemodynamic actions of endothelin in conscious and anesthetized dogs

The newly described endogenous peptide, endothelin, was administered to five chronically instrumented conditioned dogs. Endothelin produced significant and simultaneous increases in both heart rate (HR) and mean arterial pressure (MAP) in conscious dogs. Endothelin also produced significant increases in MAP in anesthetized animals. Ganglionic suppression induced by hexamethonium (10 mg/kg) and atropine (0.1 mg/kg) blocked HR responses and markedly inhibited the pressor responses to endothelin in conscious animals. These results suggest that endothelin in part acts to elevate blood pressure and heart rate through modification of autonomic nervous system tone. When endothelin and angiotensin II were administered in mole equivalent doses, angiotensin II produced a pressor response of greater magnitude than did endothelin in conscious animals.     

Volume expansion during acute angiotensin II receptor (AT(1)) blockade and NOS inhibition in conscious dogs

The responses to AT(1)-receptor blockade (candesartan 1 mg/kg) and to concomitant volume expansion (saline 35 ml/kg for 90 min) with and without nitric oxide synthase (NOS) inhibition (N(G)-nitro-L-arginine methyl ester 30 microg small middle dot kg(-1) small middle dot min(-1)) were investigated in separate experiments in normal dogs. AT(1) blockade decreased arterial pressure (106 +/- 4 to 96 +/- 5 mmHg) and increased glomerular filtration rate (GFR) by 17% and sodium excretion threefold. NOS inhibition increased arterial pressure (103 +/- 3 to 116 +/- 3 mmHg) and decreased GFR by 21% and reduced sodium excretion by some 80%. Volume expansion increased arterial pressure significantly in all series involving this procedure, most pronounced during combined AT(1) blockade and NOS inhibition (21 +/- 4 mmHg). Volume expansion during AT(1) blockade elicited marked natriuresis (26 +/- 11 to 274 +/- 55 micromol/min) that was severely reduced by concomitant NOS inhibition (10 +/- 3 to 45 +/- 11 micromol/min), but still much larger than that seen with volume expansion during NOS inhibition alone (2 +/- 1 to 23 +/- 7 micromol/min). Volume expansion during AT(1) blockade increased GFR (+30%), less so during combined AT(1) blockade and NOS inhibition (+13%), but it did not increase GFR significantly (P = 0.07) during NOS inhibition alone. Plasma ANG II increased greater than sevenfold with AT(1) blockade and doubled with NOS inhibition (paired t-test, P < 0.05), whereas it decreased by 50-80% during volume expansion irrespective of pretreatment, i.e., during NOS inhibition, volume expansion did not generate subnormal plasma ANG II concentrations. In conclusion, 1) acute AT(1) blockade leads to hyperfiltration, natriuresis, and hyperresponsiveness to volume expansion, 2) these responses are >85% inhibitable by unspecific NOS inhibition, and 3) NOS inhibition alone is followed by increases in plasma ANG II, hypofiltration, and severe antinatriuresis that may be counterbalanced but not overwhelmed by volume expansion. Thus NOS inhibition virtually abolishes the volume expansion natriuresis, at least in part, due to the lack of appropriate inhibition of the renin-angiotensin-aldosterone system.     

Acetazolamide impairment of the transfer of infused K from extracellular to intracellular fluid.

In intact dogs K loaded by infusion with 2 mEq KC1/kg/hr, treatment with acetazolamide produces both a profound kaluresis and a marked impairment of the animal's ability to transfer the infused K to intracellular fluid. The impairment is unrelated to kaluresis, since it is substantially the same in nephrectomized animals. Neither does the impairment stem fromacetazolamide induced acid- osis - there is a similar fall of blood pH in untreated control animals in which there is brisk transmembrane K transfer of infused K; and the $\text{ability}$ to transfer K is relatively unimpaired in nephrectomized dogs rendered acidotic by HCl administration. Acetazolamide is an effective therapeutic and prophylactic agent in the treatment of hypokalemic periodic paralysis; the results of the present investigation suggest a possible explanation of its therapeutic efficacy.     

Effect of human epidermal growth factor (hEGF) on splanchnic circulation in dogs

The effect of intravenous administration of human epidermal growth factor on the splanchnic blood flows was examined in anesthetized dogs, using an ultrasonic transit-time volume flow meter. Human epidermal growth factor (0.1, 0.5 and 1 microgram/kg) significantly increased blood flows in the portal vein (36.9 +/- 7.4% at 1 microgram/kg) and the superior mesenteric artery (49.0 +/- 16.8% at 1 microgram/kg). Systemic blood pressure monitored simultaneously was significantly decreased (8.4 +/- 1.2% at 1 microgram/kg). This study is the first to demonstrate that intravenous administration of epidermal growth factor increases the portal venous blood flow.     

Alpha-adrenoceptor-mediated coronary vasoconstriction is augmented during exercise in experimental diabetes mellitus.

This study tested whether alpha-adrenoceptor-mediated coronary vasoconstriction is augmented during exercise in diabetes mellitus. Experiments were conducted in dogs instrumented with catheters in the aorta and coronary sinus and with a flow transducer around the circumflex coronary artery. Diabetes was induced with alloxan monohydrate (n = 8, 40 mg/kg i.v.). Arterial plasma glucose concentration increased from 4.7 +/- 0.2 mM in nondiabetic, control dogs (n = 8) to 21.4 +/- 1.9 mM 1 wk after alloxan injection. Coronary blood flow, myocardial oxygen consumption (MVo(2)), aortic pressure, and heart rate were measured at rest and during graded treadmill exercise before and after infusion of the alpha-adrenoceptor antagonist phentolamine (1 mg/kg iv). In untreated diabetic dogs, exercise increased MVo(2) 2.7-fold, coronary blood flow 2.2-fold, and heart rate 2.3-fold. Coronary venous Po(2) fell as MVo(2) increased during exercise. After alpha-adrenoceptor blockade, exercise increased MVo(2) 3.1-fold, coronary blood flow 2.7-fold, and heart rate 2.1-fold. Relative to untreated diabetic dogs, alpha-adrenoceptor blockade significantly decreased the slope of the relationship between coronary venous Po(2) and MVo(2). The difference between the untreated and phentolamine-treated slopes was greater in the diabetic dogs than in the nondiabetic dogs. In addition, the decrease in coronary blood flow to intracoronary norepinephrine infusion was significantly augmented in anesthetized, open-chest, beta-adrenoceptor-blocked diabetic dogs compared with the nondiabetic dogs. These findings demonstrate that alpha-adrenoceptor-mediated coronary vasoconstriction is augmented in alloxan-induced diabetic dogs during physiological increases in MVo(2).     

K(ATP) channels mediate the beneficial effects of chronic ethanol ingestion

Chronic ingestion of low doses of ethanol protects the myocardium from ischemic injury by activating adenosine receptors and protein kinase C. We tested the hypothesis that ATP-dependent potassium (K(ATP)) channels mediate these beneficial effects. Dogs were fed with ethanol (1.5 g/kg) or water mixed with dry food twice per day for 12 wk. After they were acutely instrumented for measurement of hemodynamics, dogs received saline (vehicle) or glyburide (0.1 mg/kg iv) and were subjected to 60 min of coronary artery occlusion followed by 3 h of reperfusion. Infarct size (through triphenyltetrazolium chloride staining) was significantly (P < 0.05) reduced to 14 +/- 1% of the left ventricular area at risk in ethanol-pretreated dogs compared with controls (25 +/- 2%). Glyburide alone did not affect infarct size (25 +/- 3%) but abolished the protective effects of ethanol pretreatment (28 +/- 3%). No differences in hemodynamics or coronary collateral blood flow (through radioactive microspheres) were observed among groups. The results indicate that K(ATP) channels mediate the protective effects of chronic consumption of ethanol.     

Heart rate response to onset of exercise: evidence for enhanced cardiac sympathetic activity in animals susceptible to ventricular fibrillation

A large heart rate (HR) increase at the onset of exercise has been linked to an increased risk for adverse cardiovascular events, including cardiac death. However, the relationship between changes in cardiac autonomic regulation induced by exercise onset and the confirmed susceptibility to ventricular fibrillation (VF) has not been established. Therefore, a retrospective analysis of the HR response to exercise onset was made in mongrel dogs with healed myocardial infarctions that were either susceptible (S, n = 131) or resistant (R, n = 114) to VF (induced by a 2-min occlusion of the left circumflex artery during the last minute of exercise). The ECG was recorded, and time series analysis of HR variability (vagal activity index, the 0.24-1.04-Hz frequency component of R-R interval variability) was measured before and 30, 60, and 120 s after the onset of exercise (treadmill running). Exercise elicited significantly (ANOVA, P < 0.0001) greater increases in HR in susceptible dogs at all three times (e.g., at 60 s: R, 46.8 +/- 2.3 vs. S, 57.1 +/- 2.2 beats/min). However, the vagal activity index decreased to a similar extent in both groups of dogs (at 60 s: R, -2.8 +/- 0.1 vs. S, -3.0 +/- 0.2 ln ms2). Beta-adrenoceptor blockade (BB, propranolol 1.0 mg/kg iv) reduced the HR increase and eliminated the differences noted between the groups [at 60 s: R (n = 26), 40.4 +/- 3.2 vs. S (n = 31), 37.5 +/- 2.4 beats/min]. After BB, exercise once again elicited similar declines in vagal activity in both groups (at 60 s: R, -3.6 +/- 0.5 vs. S, -3.2 +/- 0.4 ln ms2). When considered together, these data suggest that at the onset of exercise HR increases to a greater extent in animals prone to VF compared with dogs resistant to this malignant arrhythmia due to an enhanced cardiac sympathetic activation in the susceptible dogs.     

Importance of calcium in citric acid-induced airway constriction

In previous studies, a 5-min inhalational challenge with 10% citric acid aerosol (0.52 M) elicited bronchoconstriction in Basenji-Greyhound (BG) dogs with hyperreactive airways but not in mongrel dogs. This response was independent of vagal reflexes because it was not attenuated by atropine. Citric acid might elicit bronchoconstriction because of acidity, calcium chelation, or some other effect of the citrate molecule. To assess these factors, barbiturate-anesthetized BG dogs were challenged (5 min) with aerosols of 10% acetic acid or a citric acid (0.48 M)/Na3citrate (0.04 M) mixture of equivalent pH, 6% Na2-ethylenediaminetetraacetic acid (EDTA), or 6% CaNa2EDTA. Each challenge was delivered in a separate week. The acidity alone was not an adequate stimulus, since pulmonary resistance (RL) was unaltered by 10% acetic acid, although markedly increased by the citric acid-Na3citrate mixture [2.2 +/- 0.4 (SE) cmH2O X l-1 X s prechallenge, 10.0 +/- 2.2 postchallenge]. Aerosols of Na2EDTA provoked a similar increase in RL (2.1 +/- 0.4 cmH2O X l-1 X s prechallenge, 9.0 +/- 1.8 postchallenge). Neither effect was attenuated by intravenous atropine (0.2 mg/kg). CaNa2EDTA caused no changes in RL. We conclude that it is the calcium chelating action of citric acid rather than its acidity that is responsible for bronchoconstriction in BG dogs with hyperreactive airways.     

Possible sensory receptor of nonadrenergic inhibitory nervous system

To determine the sensory receptor of the nonadrenergic inhibitory nervous system (NAIS), 22 cats were anesthetized and serotonin was continuously administered (50-250 micrograms.kg-1.min-1 iv) to increase pulmonary resistance (RL) to 377 +/- 57% (SE) of the control value. We then 1) mechanically irritated the trachea, 2) intravenously administered capsaicin (5 micrograms/kg), or 3) induced hypoxia (arterial PO2 30-40 Torr) to stimulate irritant and bronchial C-fiber receptors, pulmonary C-fiber receptors, or the carotid body (chemoreceptors), respectively. After treatment with atropine (3 mg/kg iv) and propranolol (2 mg/kg iv), the serotonin-induced change in RL was reduced by 58.6 +/- 14.3% by mechanical irritation and 63.3 +/- 12.1% by intravenous capsaicin. However, hypoxia produced no dilatation of the airways. In further experiments, we employed capsaicin inhalation to stimulate bronchial C-fiber receptors. Inhaled capsaicin (0.1%, for 5 breaths) also reduced RL by 79.2 +/- 9.2% of the elevated value, after atropine and propranolol. Treatment with a ganglionic blocking agent, hexamethonium (2 mg/kg iv), abolished bronchodilator responses, implying that a reflex pathway through vagal nerves is involved in this phenomenon. These results suggest that pulmonary and bronchial C-fiber receptors may be involved as sensory receptors in NAIS reflex bronchodilatation.     

Mechanism for the increase in plasma renin activity by pentobarbital anesthesia

The mechanism by which pentobarbital anesthesia causes increases in plasma renin activity (PRA) was examined in dogs infused with either propranolol or indomethacin, an inhibitor of prostaglandin synthetase. Infusion of propranolol at 1 mg/kg, (I.V.) followed by 0.6–0.7 mg/kg/hr decreased PRA from 6.98±2.49 ng/m1/hr during control periods to 1.58±0.79 ng/m1/hr 30 minutes after the injection of propranolol (P<0.025). Subsequent induction of anesthesia with sodium pentobarbital caused PRA to rise to 3.87±0.93 ng/m1/hr in 30 minutes. (P<0.01). Plasma potassium concentration decreased from 4.6±0.2 mEq/L to reach 4.0±0.1 mEq/L 30 minutes after induction of anesthesia (P<0.005). Infusion of indomethacin at 5 mg/kg, (I.V.) followed by 1.5 ? 3.1 mg/kg/hr into conscious dogs did not decrease PRA. In contrast to the report by Montgomery et al (Fed. Proc. 36: 989, 1977), we found that the increase in PRA after pentobarbital anesthesia could not be blocked by indomethacin. PRA was 5.3±1.2 ng/m1/hr(M ± SEM) during control periods and was 4.7±1.4 ng/m1/hr 30 minutes after the infusion of indomethacin (P<0.1). PRA increased to 10.9±2.3 ng/m1/hr, 9.2±2.2 ng/m1/hr, and 7.7±1.7 ng/m1/hr at 5, 15 and 30 minutes, respectively, after the administration of pentobarbital (P<0.005, P<0.025, P<0.05). PRA declined to 4.2±1.3 ng/m1/hr 60 minutes after pentobarbital anesthesia (P<0.1). It is concluded that the mechanism by which pentobarbital causes increases in PRA is independent of prostaglandins.     

Effect of antibodies to the neuropeptide GRP on distention-induced gastric acid secretion in the rat

The present study examined and compared the effects of muscarinic blockade, beta-adrenergic blockade and immunoneutralization of the neuropeptide gastrin-releasing peptide (GRP) on distention-induced gastric acid secretion and gastrin release. In response to distention of rat stomachs with 0.9% NaCl, acid output rose from 3.5 +/- 0.5 mumol H+/30 min to 15.4 +/- 2.5 mumol H+/30 min (P less than 0.01). Intravenous administration of 4 mg/kg propranolol did not affect the acid secretory response to distention, however both 2 mg/kg atropine and 6 mg/kg pirenzepine significantly decreased gastric acid secretion by 44.8 +/- 7.8% and 40.9 +/- 5.7% (P less than 0.05), respectively. When specific antibodies to GRP were infused intravenously, the acid secretory response to distention was nearly abolished, decreasing to 5.1 +/- 0.8 mumol H+/30 min (P less than 0.01). In contrast to the effects on acid secretion, GRP antiserum did not significantly alter the gastrin release observed following distention. Results of these studies indicate that, under the conditions of these experiments, the acid secretory response to gastric distention may be independent of its effect on gastrin release. Although distention-induced gastric acid secretion may be partially governed by muscarinic pathways, the acid secretory response to distention in the rat appears to involve GRP-containing neurons.     

ETA-receptor blockade impairs vasoconstriction after hemorrhage in xenon-anesthetized dogs treated with an AT1-receptor antagonist

The effects of endothelin receptor subtype A (ETA) blockade on hemodynamics and hormonal adaptation during hemorrhage were studied in xenon/remifentanil-anesthetized dogs (n=6) pretreated with an angiotensin II type 1 (AT1)-receptor blocker. Controls: after a baseline awake period, anesthesia was induced in the dogs with propofol and maintained with xenon/remifentanil (baseline anesthesia). Sixty minutes later, 20 mL x kg(-1) of blood was withdrawn within 5 min and the dogs observed for another hour (hemorrhage). AT1 group followed the same protocol as controls except the AT1-receptor blocker losartan (i.v. 100 microg x kg(-1) x min(-1)) was started at the beginning of the experiment. AT1+ETA group was the same as AT1 group but with the addition of the ETA-receptor blocker atrasentan (i.v. 1 mg x kg(-1), then 0.01 mg x kg(-1) x min(-1)). In controls, mean arterial pressure (MAP) remained unchanged during baseline anesthesia, whereas systemic vascular resistance (SVR) increased from 3282+/-281 to 7321+/-803 dyn.s.cm-5, heart rate (HR) decreased from 86+/-4 to 40+/-3 beats x min(-1), and cardiac output (CO) decreased from 2.3+/-0.2 to 0.9+/-0.1 L x min(-1) (p<0.05), with no further changes after hemorrhage. In AT1-inhibited dogs, MAP (71+/-6 mm Hg) and SVR (5939+/-611 dyn x s x cm(-5)) were lower during baseline anesthesia and after hemorrhage, but greater than those in AT1+ETA (66+/-7 mm Hg, 5034+/-658 dyn x s x cm(-5)) (p<0.05). HR and CO were not different between groups. Plasma concentration of vasopressin was highest with AT1+ETA inhibition after hemorrhage. Combined AT1+ETA-receptor blockade impaired vasoconstriction more than did AT1-receptor blockade alone, both during baseline xenon anesthesia and after hemorrhage. Even a large increase in vasoconstrictor hormones could not prevent the decrease in blood pressure and the smaller increase in SVR. Thus, endothelin is an important vasoconstrictor during hemorrhage, and both endothelin and angiotensin II are essential hormones for cardiovascular stabilization after hemorrhage.