Mol Kg-1 Min-1 Research Articles

The cardiovascular actions of dopexamine hydrochloride, an agonist at dopamine receptors and beta 2-adrenoceptors in the dog.

The receptor pharmacology of the cardiovascular effects of dopexamine hydrochloride in the anaesthetized dog (given by i.v. infusion of 3 X 10(-9)-10(-7) mol kg-1 min-1) has been analysed by the use of selective receptor antagonists and of ganglionic blockade. The increases in cardiac output, contractility, and rate were antagonized by the beta 2-adrenoceptor antagonist, ICI 118551. Renal blood flow rose secondary to reduction in renal vascular resistance and this was antagonized by SCH 23390, a highly selective DA1-receptor antagonist. Peripheral vasodilation and reduction of blood pressure were mediated by a combination of DA1- and DA2-receptor and beta 2-adrenoceptor stimulation. In a separate group of dogs, the cardiac stimulant effects of dopexamine HCl were partially reflex and were reduced by ganglion block, revealing responses due to stimulation of cardiac beta 2-adrenoceptors. Thus the beta 2-adrenoceptor agonist action of dopexamine HCl is not only partly responsible for afterload reduction but also leads to direct cardiac stimulation. From its cardiovascular profile, dopexamine HCl is likely to be of use in acute treatment of heart failure.

Vascular pharmacology of methylene blue in vitro and in vivo: a comparison with NG‐nitro‐l‐arginine and diphenyleneiodonium

1. The vascular effects of the soluble guanylyl cyclase inhibitor, methylene blue as well as the nitric oxide (NO) synthase inhibitors, NG-nitro-L-arginine (L-NOARG) and diphenyleneiodonium (DPI) were studied in rat isolated aortic rings and conscious, unrestrained rats. 2. Acetylcholine (ACh) and sodium nitroprusside (SNP) caused concentration-dependent relaxation of preconstricted aortic rings. Both methylene blue (1 x 10(-5) M) and L-NOARG (3 x 10(-5) M) abolished ACh-induced relaxation; however, methylene blue but not L-NOARG shifted the concentration-response curve of SNP to the right. 3. In conscious rats, i.v. infusion of methylene blue (1.1 x 10(-5) mol kg-1 min-1), at a concentration which reduced the aortic tissue level of cyclic GMP by 50%, did not significantly alter mean arterial pressure (MAP) and heart rate (HR). In contrast, i.v. bolus injection of L-NOARG (1.5 x 10(-4) mol kg-1) markedly increased MAP and decreased HR. 4. Both ACh and SNP dose-dependently decreased MAP in conscious rats. Methylene blue did not alter the magnitude or duration of ACh- or SNP-induced depressor responses. L-NOARG, on the other hand, significantly though incompletely, reduced the magnitude and duration of the depressor response to ACh but not SNP. The depressor response to ACh or SNP was not altered by pretreatment with indomethacin (1.4 x 10(-5) mol kg-1) or capsaicin (3.3 x 10(-4) mol kg-1). 5. NG-nitro-L-arginine methyl ester (L-NAME) also caused dose-dependent increases in MAP in conscious rats. Both methylene blue and DPI (1 x 10-5 mol kg-1) selectively shifted the dose-pressor response curve of L-NAME to the right.6. These results suggest that: (1) the inhibition of endogenous NO biosynthesis does not necessarily lead to pressor response in vivo, (2) L-NOARG may not produce pressor response solely via the inhibition of endogenous endothelial NO biosynthesis, and (3) the depressor responses to ACh and SNP may not involve the release of NO or prostanoids or afferent nerve transmitters.

Reversal of established responses to endothelin‐1 in vivo and in vitro by the endothelin receptor antagonists, BQ‐123 and PD 145065

1. Endothelin-1 binds almost irreversibly to its receptors and causes prolonged vasoconstrictions. Here we have studied the reversal of established responses to ET-1 in vivo and in vitro by BQ-123, an ETA receptor-selective antagonist, and/or PD 145065, an ETA/ETB receptor non-selective antagonist. 2. In anaesthetized rats pretreated with hexamethonium, infusion of ET-1 (10(-11) mol kg-1 min-1) increased the mean arterial pressure (MAP) from 93 +/- 1.5 mmHg to 137 +/- 2.4 mmHg after 70 min (n = 29). While the ET-1 infusion was continued an additional infusion of BQ-123 caused a gradual dose-dependent reduction in the pressor effect of ET-1. For instance, after a 60 min infusion of BQ-123 (10(-8) mol kg-1 min-1) the MAP was decreased by 29.3 +/- 4.3 mmHg (n = 4). 3. PD 145065 was a much weaker antagonist of the established pressor effects of ET-1. At 10(-8) mol kg-1 min-1 it had no significant effect and even at 10(-7) mol kg-1 min-1 the elevated blood pressure was only reduced by 11.8 +/- 8.0 mmHg (n = 5) after 60 min. Co-infusion of BQ-123 and PD 145065 caused smaller reductions in the established response to ET-1 than infusion of BQ-123 alone. 4. Sustained contractions of rat aortic rings induced by ET-1 (3 x 10(-9) M) and mediated by ETA receptors were slowly reversed by addition of BQ-123 (10(-5) M) or PD 145065 (10(-5) M). For instance,after 40 min the elevated tone was reduced 85.8 +/- 5.6% (n = 6) by PD 145065, and 77.1 +/- 6.7% (n = 6)by BQ-123. Thus, on the rat aortic rings in vitro both antagonists were equally effective against established responses to ET-1.5. ET-1 increased the perfusion pressure of the rat isolated perfused kidney by 138.1 +/- 7.6 mmHg(n = 14). Subsequent co-infusion of BQ-123 or PD 145065 reversed this increase with PD 145065 being more active. For instance, PD 145065 (10-6 M) reversed the increase in perfusion pressure by 56.9 +/- 8.8% (n = 5) and BQ-123 (10-6 M) reversed it by 22.8 +/- 8.0% (n = 5). This fits well with the vasoconstriction induced by ET-1 in the rat kidney being mediated by ETA and ETB receptors.6. Thus, sustained vasoconstrictions to ET-1 in vitro, mediated by either ETA or ETB receptors, may be reversed slowly by the subsequent application of receptor antagonists. Similarly, endothelin antagonists reverse the pressor effects of ET-1 in vivo although co-antagonism of ETA and ETB receptors or the co-administration of an ETA receptor antagonist, BQ-123, and a mixed antagonist, PD 145065 produces less reversal than the application of an ETA receptor-selective antagonist. This may be because PD 145065 also reduces vasodilatations induced by ET-1 in vivo, or could suggest that because of its peptide structure PD 145065 affects the elimination of ET-1.

EXERCISE IN THE TERRESTRIAL CHRISTMAS ISLAND RED CRAB GECARCOIDEA NATALIS - ENERGETICS OF LOCOMOTION

The respiratory and circulatory physiology of exercising Christmas Island red crabs Gecarcoidea natalis were investigated with respect to their annual breeding migration. Red crabs were allowed to walk for up to 45 min. During this exercise period, the functioning of the circulatory system in gas transport and the energy status of the red crabs were quantified. Energy production during exercise required both aerobic and anaerobic contributions. The aerobic scope of G. natalis was low, with only a doubling of the resting rate of oxygen consumption (resting M(dot)O2=95±15 µmol kg-1 min-1). Maximal O2 consumption was attained within the first 5 min of exercise and the level remained stable thereafter. The anaerobic contribution to energy production was directly related to the speed of locomotion. l-lactate levels in blood and leg muscle were similar throughout the exercise period; blood lactate concentration was 33.39±2.29 mmol l-1 after 45 min of exercise. Heart rate in resting animals was 56±7 beats min-1. At the onset of exercise, heart rate also doubled, but without a significant increase in cardiac output. Increased O2 delivery was facilitated by increased extraction from the blood. During the 45 min of exercise, glucose levels increased rapidly in the muscle tissue (from 2.30±0.54 to 8.78±1.20 mmol l-1) and subsequently in the blood (from 1.22±0.26 to 2.12±0.17 mmol l-1), fuelling increased glycolysis during locomotion. The energy production from stored glucose/glycogen was sufficient to support the energetic needs of locomotion, since the energy charge remained stable at 0.82. Haemolymph l-lactate levels in crabs sampled in the field after migration were high compared with levels in many crustacean species but equivalent to l-lactate levels in laboratory animals exercised for less than 10 min. During their migration, therefore, the red crabs avoid exceptional l-lactate build-up in the blood by either walking very slowly or intermittently. However, G. natalis are exceptionally well adapted to cope with exhaustive locomotion and the resultant severe metabolic acidosis.

Endothelin and endothelium‐derived relaxing factor control of basal renovascular tone in hydronephrotic rat kidneys.

1. In order to investigate the control of renal vascular tone by endothelin (ET) and endothelium-derived relaxing factor (EDRF) under basal conditions, we infused intravenously anti-ET-1/3 antibodies (a-ET-1/3) and NG-nitro-L-arginine methyl ester (L-NAME) in split hydronephrotic rat kidneys. 2. A 25 min I.V. infusion of a-ET-1/3 (4.0 x 10(-13) mol kg-1 min-1) induced a time-dependent vasodilatation of arcuate (16.5%) and interlobular arteries (18.6%) as well as an increase of glomerular blood flow (GBF) by 32%. 3. Inhibition of EDRF synthesis by L-NAME produced a marked vasoconstriction of arcuate arteries (17.1%) and efferent (20.1%) arterioles and a decrease of GBF by 43%. 4. Co-infusion of a-ET-1/3 and L-NAME induced efferent vasoconstriction by 19.5%, whereas preglomerular vessel diameters remained unchanged. 5. The specificity of a-ET-1/3 effects was confirmed by simultaneous I.V. application of a-ET-1/3 and ET-1 (160 ng I.V.) which produced no significant vascular effects. Injection of ET-1 alone constricted arcuate arteries and decreased glomerular blood flow by 25%. 6. Experiments in normal rat kidneys with a-ET-1/3 I.V. revealed an increase of renal blood flow by 21%. 7. Our results demonstrate a physiological control of basal vascular tone in larger preglomerular arterioles by ET and EDRF. Efferent arteriolar tone is predominantly controlled by EDRF.

Impaired Glucose Tolerance in Obesity is Associated with Insensitivity to Insulin in Multiple Aspects of Metabolism as Assessed by a Low Dose Incremental Insulin Infusion Technique

To determine whether Impaired Glucose Tolerance gives rise to additional defects in insulin action in lipid and ketone metabolism, thirty-two obese subjects were studied by low-dose incremental insulin infusion. Sixteen had Impaired Glucose Tolerance and 16 had normal glucose tolerance. Body mass index was 36.9-80.9 kg m-2 and was similar in each group. In patients with Impaired Glucose Tolerance, plasma insulin was higher in the fasted state (logarithmic mean 14.5 (9.8-21.6) (-SD(-)+SD) vs 9.6 (6.4-14.5) mU l-1, p less than 0.01) and during the infusion (p less than 0.001). The metabolic clearance rate for insulin at the highest infusion rate was lower (14.2 +/- 0.8 (+/- SE) vs 18.9 +/- 2.1 ml kg-1 min-1, p less than 0.05) in these subjects. Basal hepatic glucose production was higher in subjects with Impaired Glucose Tolerance (6.3 +/- 0.4 vs 4.5 +/- 0.6 mol kg-1 min-1, p less than 0.02) and remained elevated during infusion (p less than 0.01). Glucose disposal per unit circulating insulin at the maximal infusion rate was approximately half in subjects with Impaired Glucose Tolerance (0.022 +/- 0.010 vs 0.047 +/- 0.017 ml kg-1 min-1 mU-1 l, p less than 0.01). When simultaneous insulin and metabolite concentrations during the infusion are plotted as dose-response relationships, a difference in relative sensitivity to insulin in Impaired Glucose Tolerance over subjects with normal glucose tolerance is suggested for non-esterified fatty acids 0.72 (95% CI 0.62-0.84) and glycerol 1.85 (1.37-2.49).(ABSTRACT TRUNCATED AT 250 WORDS)

Renal vascular effects of leukotriene C4 in the isolated perfused kidney of the rat.

1 The vascular effects of leukotriene C4 (LTC4) were investigated in the isolated perfused kidney of the rat. 2 LTC4 (6.4 X 10(-10) to 3.2 X 10(-8) mol kg-1 min-1 given over 5 min) resulted in a prompt, dose-dependent increase in renal vascular resistance in a recirculating system, which lasted for more than 60 min. 3 LTC4 was 10 to 20 fold and 1000 to 2000 fold, respectively, less active on a molar basis than noradrenaline and angiotensin II in eliciting renal vasoconstriction. 4 The vascular response to LTC4 was blocked dose-dependently by FPL 55712, an antagonist of slow reacting substance of anaphylaxis. OKY 1581, a specific thromboxane synthetase inhibitor, and indomethacin, a cyclo-oxygenase inhibitor, did not influence the LTC4 response. 5 LTC4 given in a single-pass perfusion system resulted in a short lasting response with baseline values for renal vascular resistance reached after 4 min. 6 These results show that LTC4 is a short acting renal vasoconstrictor with less potency than noradrenaline and angiotensin II. Its pressor effects seem to be mediated by specific leukotriene receptors and independent of cyclo-oxygenase products. The long-lasting effect in the recirculating arrangement, in contrast to the single pass system, is compatible with formation of active metabolite(s).

Cardiovascular studies with SK&F 93319, an antagonist of histamine at both H1- and H2-receptors.

Cardiovascular studies have been made in anaesthetized cats with SK&F 93319, an antagonist of histamine at both H1- and H2-receptors. SK&F 93319, 8 X 10(-8) and 4 X 10(-7) mol kg-1 min-1 antagonized depressor responses to injections of histamine and the maximum displacement of histamine dose-response curves exceeded that which can be obtained with either an H1-receptor antagonist or an H2-receptor antagonist alone. SK&F 93319, 8 X 10(-8) and 4 X 10(-7) mol kg-1 min-1, also caused dose-dependent antagonism of histamine-induced falls in blood pressure and total peripheral resistance during intravenous infusions of histamine. SK&F 93319 inhibited depressor responses to intravenous injections of 2-(2-aminoethyl)pyridine, dimaprit and impromidine. The displacement of the 2-(2-aminoethyl)pyridine dose-response curve was similar to the displacement of histamine dose-response curves. SK&F 93319 caused greater displacement of dimaprit or impromidine dose-response curves than of histamine or 2-(2-aminoethyl)pyridine dose-response curves. SK&F 93319 was an effective antagonist of histamine, 2-(2-aminoethyl)pyridine or dimaprit-induced vasodilatation in femoral and gastric vasculature. SK&F 93319 has been shown to be an effective antagonist of vascular responses to histamine in anaesthetized cats. SK&F 93319 appeared to be more effective as an H2-receptor antagonist than as an H1-receptor antagonist in these vascular studies.

Dose-dependent, and long-lasting, effects of repeated intravenous injections of calcium on the canine secretin-stimulated pancreatic juice secretion.

The effects of repeated intravenous calcium administration on pancreatic juice secretion were investigated in four Thomas fistula dogs. During stimulation by 1.0 U kg-1h-1 GIH secretin, three Ca doses were administered: 2, 4 and 8 mu mol kg-1 min-1 during 1 h, saline being used in control tests; one dose only was tested per day. It was found that Ca administration induced both acute and long-lasting effects. Acute effects were characterized by an increased response to secretin stimulation. Fluid, HCO3(-), protein and Ca outputs increased significantly in a dose-dependent manner, the increase of protein output being the most dramatic. Long-lasting effects, until now unrecognized, were characterized by a progressive increase of protein secretion during the first hour of secretin stimulation. This increase kept going during the 3 months of repeated calcium injections. Although protein plugs were observed in the juice, sometimes stopping the flow of juice, no pancreatic lesion was found. A second protocol showed that, after discontinuing calcium injections, the long-lasting effects decreased progressively, but protein hypersecretion was still significant 3.5 months later. The importance of these findings regarding chronic pancreatitis due to hyperparathyroidism is discussed.

Reduction by Cimetidine of Acute Gastric Hemorrhage Caused by Reinfusion of Blood After Exposure to Exogenous Acid During Gastric Ischemia in Rats

The present study has been made in anesthetized rats to characterize conditions of exposure to acid and extent of ischemia which determine the development of gastric hemorrhage. Gastric hemorrhage occurred in rats subjected to shock during exposure of the gastric lumen to acid after the reinfusion of withdrawn blood. When the acid concentration was constant, bleeding was dependent on the degree of shock. When hemorrhage shock was constant, bleeding from the stomach appeared pH dependent, although this did not quite achieve statistical significance. Cimetidine 2 x 10(-6) mol kg-1 min-1 (30 mg kg-1 hr-1) and 1 x 10(-5) mol kg-1 min-1 (150 mg kg-1 hr-1) significantly reduced gastric hemorrhage whether given prophylactically before gastric injury or therapeutically after completion of gastric injury. Because protection can be demonstrated against an injury involving exogenous acid and after the injury has been established, it is probable that the effectiveness of cimetidine in these studies is independent of its antisecretory effects.

Histamine receptors in peripheral vascular beds in the cat.

1. The vasodilator activity of histamine has been studied in anaesthetized cats. 2. Histamine causes dose-dependent vasodilatation in the vasculature of the hind-limb and mesentery, perfused with blood at constant flow. 3. Experiments using the selective antagonists mepyramine and metiamide indicate the involvement of both H1- and H2-receptors in the vasodilator responses to histamine. Mepyramine (2.5 X 10(-6) mol/kg), causes displacement of the histamine dose-response curve. This displacement is maximum with a dose-ratio of about 10. Further dose-dependent displacement of the dose-response curve occurred after metiamide (4 X 10(-7) mol kg-1 min-1 and 2 X 10(-6) mol kg-1 min-1), although these doses of metiamide had no effect on histamine responses in the absence of mepyramine. 4. Vasodilator responses could also be elicited by the selective H1-receptor agonists, 2-methylhistamine, 2-(2-aminoethyl)pyridine and 2-(2-aminoethyl)thiazole and the selective H2-receptor agonist, 4-methylhistamine. 5. The selectivity of mepyramine and metiamide as histamine receptor antagonists was confirmed by their failure to reduce the vasodilator responses to acetylcholine, isoprenaline and bradykinin.

An analysis of the depressor responses to histamine in the cat and dog: involvement of both H1- and H2-receptors.

1 The depressor responses to histamine, in anaesthetized cats and dogs, have been shown to involve both histamine H1- and H2-receptors. 2 In both species, histamine caused dose-dependent falls in blood pressure. The dose-response curve could be displaced to the right by administration of mepyramine 2.5 times 10(-6) mol/kg i.v. The displacement was maximal with a dose-ratio of less than ten. 3 Metiamide alone, up to 2 times 10(-6) mol kg-1 min-1, had no significant effect on the histamine dose-response curve. 4 When administered in the presence of mepyramine, metiamide, 4 times 10(-7) and 2 times 10(-6) mol kg-1 min-1, caused dose-dependent displacements to the right, of the histamine dose-response curve greater than could be achieved with mepyramine alone. 5 The results indicate the presence of both histamine H1- and H2-receptors in the cardiovascular system of the cat and dog. Both receptors produce a common response, i.e. a fall in blood pressure.