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Biomedical subjects

J F Liard

Publications and source records attributed to J F Liard.

At least 19 recordsLinked to original sources
PubMed1992

Allosteric modifiers of hemoglobin: 2-[4-[[(3,5-disubstituted anilino)carbonyl]methyl]phenoxy]-2-methylpropionic acid derivatives that lower the oxygen affinity of hemoglobin in red cell suspensions, in whole blood, and in vivo in rats.

Two new potent allosteric effectors of hemoglobin, RSR-4 [2-[4-[[(3,5-dichloroanilino)carbonyl]-methyl]phenoxy]-2- methylpropionic acid] and RSR-13 [2-[4-[[(3,5-dimethlanilino)carbonyl]methyl]-phenoxy]-2-methylp rop ionic, are compared to the previously reported compounds L3,5 and L3,4,5 [Lalezari, I., Lalezari, P., Poyart, C., Marden, M., Kister, J., Bohn, B., Fermi, G., & Perutz, M. F. (1990) Biochemistry 29, 1515]. Unlike L3,5 and L3,4,5, RSR-4 and RSR-13 are less impeded by physiological concentrations of serum albumin. RSR-4 has also been shown to be more effective than L3,5 in shifting the allosteric equilibrium of bovine Hb toward the low-affinity T-state. X-ray crystal studies show that both RSR-4 and RSR-13 bind to only one pair of symmetry-related sites in the Hb central water cavity whereas previous studies on L3,5 and L3,4,5 demonstrated a second pair of symmetry-related binding sites near Arg 104 beta. Three major interactions between these allosteric effectors and Hb include the acid group with the guanidinium group of C-terminal Arg 141 alpha, the effector's amide oxygen with the ammonium ion of Lys 99 alpha, and the phi electrons of the halogenated or methylated aromatic ring and Asn 108 beta. No explanation has been found for the difference in number of binding sites observed for RSR-4 and RSR-13 (two sites) compared to L3,5 and L3,4,5 (four sites); also no correlation has been made between the number of binding sites and degree of allosteric shift in the oxygen equilibrium curve.(ABSTRACT TRUNCATED AT 250 WORDS)

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1992

cAMP and extrarenal vasopressin V2 receptors in dogs.

The effect of vasopressin analogues on plasma adenosine 3',5'-cyclic monophosphate (cAMP) concentration was examined in a group of five conscious dogs instrumented for the measurement of arterial pressure and cardiac output (electromagnetic flowmeter). These dogs were infused for 20 min with a selective antidiuretic (V2) agonist, desamino-8-D-arginine vasopressin (DDAVP, 10 ng.kg-1 x min-1). This infusion was repeated on another day in the presence of the combined V1-V2 antagonist d(CH2)5-D-Tyr(Et)-4-valine,8-arginine vasopressin. The dogs also received an infusion of the selective V1 agonist 2-phenylalanine,8-ornithine oxytocin (Phe-OrnOT) at a rate of 10 ng.kg-1 x min-1. The effect of these infusions was compared with those of an isotonic saline infusion. Plasma cAMP measured in the aorta remained unchanged during all infusions but that of the selective V2 agonist DDAVP alone, during which it increased significantly from 22.4 +/- 0.8 to 32.6 +/- 4.6 and 37.0 +/- 4.1 pmol/ml after 10 and 20 min, respectively. In the plasma sampled from the inferior vena cava caudal to the renal veins, cAMP increased during DDAVP infusion from 22.2 +/- 2.5 to 39.2 +/- 3.8 and 36.0 +/- 4.0 pmol/ml after 10 and 20 min, respectively. The infusion of DDAVP was later given to the same dogs under anesthesia after bilateral nephrectomy, which did not modify the effect of DDAVP on arterial plasma cAMP. In another group of four conscious dogs, infusion of DDAVP at the same rate did not induce significant changes in plasma catecholamines.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Reduced oxygen consumption induced by vasopressin in dogs depends on systemic administration.

1. Arginine vasopressin reduces whole-body oxygen consumption in conscious dogs. To determine whether this decrease could result from limited oxygen delivery, studies were performed in two groups of chronically instrumented dogs. 2. In the first group (n = 7), vasopressin was infused at a rate of 18.5 pmol min-1 kg-1 while the animals were breathing 10% oxygen. Hypoxaemia alone (arterial partial pressure of oxygen 4.67 kPa) decreased whole-body oxygen delivery by 30%. The fall in whole-body oxygen consumption induced by vasopressin during hypoxaemia was not different from that measured under normoxic conditions, even though whole-body oxygen delivery was more reduced. 3. In a second group of seven dogs, hindquarter blood flow (electromagnetic flowmeter on lower abdominal aorta) and oxygen consumption (blood flow multiplied by arteriovenous oxygen difference) were measured as infusions of vasopressin were given either systemically or into the lower abdominal aorta. Systemic vasopressin infusions at 0.92, 4.6 and 18.5 pmol min-1 kg-1 reduced hindquarter blood flow, oxygen delivery and oxygen consumption, but the decreases in blood flow and oxygen delivery were dose-related whereas that in oxygen consumption was not. Intra-arterial infusions of vasopressin that increased venous concentrations as much as or more than systemic infusion of 0.92 pmol of vasopressin min-1 kg-1 had no effect on oxygen consumption, even though the higher intra-arterial rate reduced blood flow and oxygen delivery as much as the systemic infusion. Thus systemic but not locally administered vasopressin reduced hindquarter oxygen consumption.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Interaction between V1 and V2 effects in hemodynamic response to vasopressin in dogs.

We investigated in conscious, chronically instrumented dogs whether actions mediated by V1 receptors affect cardiovascular effects elicited by V2-like receptors in response to vasopressin or vasopressin analogues. Infused arginine vasopressin (AVP) (220 pg.kg-1.min-1) did not have any significant effect on arterial pressure, cardiac output (CO), and heart rate (HR) when it was preceded by administration of a V1 receptor antagonist. However, when the same antagonist was administered 1 h after the start of the same infusion of AVP, CO, and HR increased significantly above control pre-AVP values, and total peripheral resistance (TPR) fell significantly below control. When a combined V1+V2 receptor antagonist was administered after 1 h of AVP infusion at the same rate, CO, HR, and TPR returned to, but not beyond, control values. When a selective V1 agonist was infused for 1 h, the administration of a V1 antagonist also returned hemodynamic values to, but not beyond, control. These results suggest that 1-h administration of AVP sensitized V2-like receptors to moderate levels of circulating AVP. In another set of experiments, the administration of a selective V1 agonist blunted significantly the CO and HR increase as well as the decrease in TPR normally associated with injection of a selective V2 agonist. However, administration of phenylephrine did not reduce these V2-mediated effects. We conclude that there are significant interactions between V1 and V2-like receptors in the cardiovascular system of conscious dogs, whereby V1 effects appear to 1) immediately antagonize the action of V2 agonists and 2) sensitize the organism to cardiovascular effects mediated by V2-like receptors after a prolonged exposure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Regional autoregulatory responses during infusion of vasoconstrictor agents in conscious dogs.

We investigated pressure-dependent autoregulatory responses in mesenteric, iliac, and renal vascular beds of conscious dogs during intravenous infusion of angiotensin II, phenylephrine, or arginine vasopressin at rates which increased arterial pressure by 20-40 mmHg. The arteries supplying these beds were instrumented with an electromagnetic flow probe, a nonoccluding catheter, and an electromagnetic flow probe, a nonoccluding catheter, and an occluder cuff connected with a servo-amplifier, which enabled us to return perfusion pressure to control levels during infusion of the vasoconstrictor agents. We attempted to differentiate between the increase in vascular resistance due to the direct effect of the vasoconstrictor agent and the increase induced by an autoregulatory response induced by elevations of aortic perfusion pressure. We measured a strong degree of autoregulation in the renal vascular bed with a fractional compensation value close to 1. Moderate autoregulation occurred in the mesenteric vascular bed, where the compensation was 0.4-0.5 with angiotensin II and phenylephrine and between 0.74 and 0.94 with vasopressin. No autoregulatory capacity could be demonstrated in the hindlimb. The findings indicate that, under conditions of increased systemic blood pressure, both the renal and the mesenteric vascular beds contribute to the increase in total peripheral resistance by pressure-dependent vasoconstrictor responses.

Angiotensin II↗
PubMed1990

Hemodynamics, fluid volume, and hormonal responses to chronic high-salt intake in dogs.

The sequential hemodynamics, fluid and electrolyte balances, and the hormonal responses to a 7-day high-salt (NaCl) intake were investigated in sodium-depleted conscious dogs (n = 6). Studies were carried out in metabolic cages mounted on sensitive load cells, which enabled continuous 24 h/day monitoring of total body weight (TBW) as an index of changes in body water. Beat-by-beat hemodynamics were determined 24 h/day. Water (700 ml/day iv) intake was maintained constant. Daily fluid and electrolyte balances and hormonal analyses were performed. An increase of daily salt intake from 8 to 120 meq increased TBW 251 +/- 44 g (P less than 0.05), which was sustained thereafter. Average 24-h mean arterial pressure (MAP) and heart rate (HR) remained unchanged. Average cardiac output (CO) increased 11% (P less than 0.05) above control values by day 2, while total peripheral resistance (TPR) decreased proportionally. CO and TPR returned to control values only when low salt was resumed. Blood volume (BV) was unchanged on day 2 as indicated by direct measurement of BV (51Cr-labeled red blood cells) or by analysis of plasma protein concentration. A 92-meq (P less than 0.05) sodium retention was observed initially, and plasma sodium concentration increased slightly. Plasma renin activity, angiotensin II, and aldosterone levels decreased significantly, whereas vasopressin and atrial natriuretic peptide levels remained unchanged. In summary, chronic high-salt intake resulted in a net retention of water and sodium with no changes in MAP, HR, or BV. The rise in CO was offset by a reduction in TPR, which appeared at least in part related to angiotensin II suppression.

Animals↗
PubMed1989

Vasopressin reduces oxygen uptake in intact dogs but not in sinoaortic-denervated dogs.

We have investigated the effect of infusions of arginine vasopressin on cardiac output and O2 uptake in the presence and in the absence of sinoaortic reflexes to better understand the mechanism of the exaggerated decrease in cardiac output elicited by vasopressin. Chronically instrumented dogs received, on separate days, 30-min infusions of vasopressin (0.2, 1, 5, 20, and 60 ng.kg-1.min-1), phenylephrine (1, 3, and 10 micrograms.kg-1.min-1), and angiotensin II (ANG II) (10, 20, and 50 ng.kg-1.min-1). These infusions all increased mean arterial pressure to a maximum of 63 +/- 8.2 mmHg during the highest phenylephrine infusion rate. Vasopressin reduced cardiac output (electromagnetic flowmeter) more than the other vasoconstrictors for equivalent increases in arterial pressure. Vasopressin also produced dose-dependent decreases in O2 uptake, measured by collection of expired air. Such decreases were not observed with the other two agents. On the contrary, ANG II and phenylephrine increased O2 uptake significantly when they decreased cardiac output the most. The decrease in O2 uptake induced by vasopressin was significantly correlated with the decrease in cardiac output. Pretreatment of the dogs with atropine prevented the decrease in O2 uptake and blunted the fall in cardiac output induced by vasopressin at a rate of 5 ng.kg-1.min-1. In dogs surgically deprived of sinoaortic receptors, vasopressin given at 1 and 5 ng.kg-1.min-1 failed to reduce O2 uptake and cardiac output significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1988

Characterization of acute hemodynamic effects of antidiuretic agonists in conscious dogs.

Conscious dogs instrumented for the measurement of arterial pressure and cardiac output (electromagnetic flowmeter) received intravenous injections of 4-valine-8-D-arginine vasopressin (VDAVP) and 1-deamino-8-D-arginine vasopressin (dDAVP), two specific antidiuretic agonists. Both agents led within minutes to dose-dependent increases in cardiac output and heart rate, as well as to decreases of total peripheral resistance and mean arterial pressure. Indomethacin did not affect the hemodynamic responses to VDAVP administration. The analog 8-arginine-9-desglycinamide vasopressin, which retains behavioral effects of vasopressin but is a weak antidiuretic agonist, showed only weak hemodynamic effects that were similar in nature to those of VDAVP and dDAVP. Thus, the capability to increase cardiac output and decrease peripheral resistance appeared to correlate best with the antidiuretic activity of the three vasopressin analogs tested. We also observed that pretreatment of dogs with a combined vasopressor (V1) and antidiuretic (V2) vasopressin antagonist completely prevented the increase in cardiac output that is normally associated with the infusion of arginine-vasopressin, 10 ng kg-1 min-1, after V1 blockade. Our results confirm the existence of powerful, dose-related hemodynamic effects of various antidiuretic agonists in conscious dogs; these effects being opposite to those normally elicited by arginine-vasopressin.

Animals↗
PubMed1986

Cardiovascular effects of vasopressin: some recent aspects.

We first discuss the question of direct versus indirect mechanisms in the vasoconstrictor effects induced by low plasma levels of arginine vasopressin (AVP). By infusing AVP directly into the arteries supplying various organs and tissues and measuring regional blood flows with radioactive microspheres in conscious dogs, it was determined that the increase in resistance measured after systemic administration of small amounts of AVP in the skeletal muscle, small intestine, colon, and abdominal fat results in large part from indirect mechanisms. Direct vasoconstrictor effects of AVP at these plasma concentrations were limited to the skin, the pancreas, and the compact bones. We then consider the question of cardiovascular effects of AVP from its antidiuretic activity. In the presence of a vascular antagonist, AVP decreased peripheral resistance and increased cardiac output in conscious dogs. An analog with selective antidiuretic activity, VDAVP, produced the same effects as the combination of vasopressin plus vascular antagonist. These data indicate that vasopressin, by its antidiuretic activity, produces cardiovascular effects that are opposed to many of those produced by its vasoconstrictor action. Studies in 48-h dehydrated dogs showed that part of the hemodynamic response to blockade of the vasoconstrictor action of vasopressin under these conditions is caused by unmasking cardiovascular effects linked to the antidiuretic activity of the arginine vasopressin molecule.

Animals↗
PubMed1979

Effects of propranolol in chronic two-kidney Goldblatt hypertension in rats.

Propranolol administered subcutaneously in a dise of 30 mg/kg twice a day for 3 weeks did not significantly lower systolic tail blood pressure (STBP) in chronic two-kidney Goldblatt hypertension in rats. Plasma renin activity (PRA) measured at the end of the treatment was not significantly different in propranolol treated and dextrose treated rats, although there was marked bradycardia in propranolol treated rats. However, 3 out of 10 propranolol treated hypertensive rats had pressures in the normotensive range during the last week of therapy. PRA values in these three rats were significantly lower than those in dextrose treated hypertensive rats. STBP on day 20 showed a positive correlation with PRA in both propranolol (r = 0.90, p less than 0.01) and dextrose (r = 0.85, p less than 0.01) treated hypertensive rats. Hypertension was associated with an increase in heart weight, which was significantly blunted but not abolished by propranolol treatment. Thus, propranolol did not decrease blood pressure in most rats with chronic two-kidney Goldblatt hypertension; when it did lower blood pressure, its antihypertensive effect appeared related to its renin suppression effect. Furthermore, propranolol mitigated hypertension induced cardiac hypertrophy, independently of its antihypertensive effect.

Animals↗
PubMed1976

Haemodynamics and body fluid volumes in response to fluid loading in conscious dogs: non-excretory renal influences.

1. Twelve conscious, chronically instrumented dogs were subjected to rapid loading with sodium chloride solution (150 mmol/1; saline) before and 1 day after bilateral nephrectomy (six dogs) or ureterocaval anastomosis (six dogs). Measurements were performed up to 3 h after the fluid load and included cardiac output with an electromagnetic flowmeter, mean arterial pressure and right atrial pressure with chronically implanted catheters, interstitial fluid pressure with a plastic capsule, heart rate, extracellular fluid volume, erythrocyte volume, plasma volume, plasma protein concentration and other variables. 2. The increase in cardiac output in response to saline load was significantly prolonged in the anephric dogs compared with those with uretero-caval anastomosis; mean arterial pressure, right atrial pressure and heart-rate changes were similar in both groups. 3. Plasma volume appeared to increase more in the anephric dogs than in those with uretero-caval anastomosis during the first hour after the infusion, although conflicting results were obtained with different estimates of plasma volume changes. Interstitial fluid pressure increased significantly less in the anephric dogs in the early stages of the fluid load. 4. Effective vascular compliance (the ratio of the change in blood volume to the change in right atrial pressure) appeared increased in the anephric dogs. On the other hand, the change in cardiac output for a given change in right atrial pressure was found to increase after bilateral nephrectomy. 5. It is suggested that the prolonged increase in cardiac output observed in anephric dogs was not the consequence of preferential plasma volume expansion nor of decreased venous compliance, but may reflect an alteration in the cardiac function curve.

Animals↗