Electrophysiologic effects of chronic amiodarone therapy and hypothyroidism, alone and in combination, on guinea pig ventricular myocytes.
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Amiodarone is a widely used antiarrhythmic drug, the mechanisms of action of which remain incompletely understood. Indirect evidence suggests that the class III properties of amiodarone may be mediated by cardiac antithyroid effects. We sought to determine whether the effects of chronic amiodarone on repolarization in guinea pig hearts can be attributed to an antithyroid action by studying the changes in dofetilide-sensitive rapid (IKr) and dofetilide-resistant slow (IKs) delayed rectifier currents, inward rectifier K+ current (IK1), and action potentials of ventricular myocytes from five groups of guinea pigs: control, hypothyroid, amiodarone-treated for 7 days, hypothyroid plus amiodarone, and vehicle (dimethyl sulfoxide) treated. IKs was reduced by amiodarone (to 61% of control, P <.05, at 50 mV) but was more strongly reduced by hypothyroidism (to 35% of control, P <.01, 50 mV). Amiodarone significantly reduced IKr and IK1 (by 55 and 64% at 10 mV and -50 mV, respectively), which were unaffected by hypothyroidism. Amiodarone alone and hypothyroidism alone had similar action potential-prolonging actions. Hypothyroid animals treated with amiodarone showed a combination of ionic effects (strong IKs reduction, similar to hypothyroidism alone; reduced IKr and IK1, similar to amiodarone alone), along with action potential prolongation significantly greater than that caused by either intervention alone. We conclude that chronic amiodarone and hypothyroidism have different effects on ionic currents and that their combination prolongs action potential duration to a greater extent than either alone in guinea pig hearts, suggesting that the class III actions of amiodarone are not mediated by a cardiac hypothyroid state. (+info)
Central administration of [Phe1psi(CH2-NH)Gly2]nociceptin(1-13)-NH2 and orphanin FQ/nociceptin (OFQ/N) produce similar cardiovascular and renal responses in conscious rats.
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In vitro studies have shown that [Phe1Psi(CH2-NH)Gly2]OFQ/N(1-13)-NH2 (referred to as [FG]OFQ/N(1-13)-NH2) is the first selective antagonist to prevent the binding of the endogenous ligand orphanin FQ/Nociceptin (OFQ/N) at the orphan opioid-like receptor. In the present study, we examined the potential changes in cardiovascular and renal function produced by the i.c.v. injection of [FG]OFQ/N(1-13)-NH2 in conscious Sprague-Dawley rats. In conscious rats, i.c.v. injection of [FG]OFQ/N(1-13)-NH2 produced a marked and sustained decrease in heart rate, mean arterial pressure, and urinary sodium excretion and a profound increase in urine flow rate (i.e., a water diuresis). The cardiovascular and renal excretory responses produced by i.c.v. [FG]OFQ/N(1-13)-NH2 were dose dependent and were similar in pattern but of longer duration than responses evoked by i.c.v. OFQ/N. In other animals, the i.c.v. injection of OFQ/N(1-13)-NH2, a potential metabolite of [FG]OFQ/N(1-13)-NH2, produced changes in cardiovascular and renal function that were comparable to those evoked by i.c.v. [FG]OFQ/N(1-13)-NH2. In contrast, OFQ/N(2-17), a fragment of OFQ/N [OFQ/N(1-17)], was inactive when administered centrally. Finally, studies were performed to determine whether [FG]OFQ/N(1-13)-NH2 may be an antagonist at the orphan opioid-like receptor receptor when administered centrally at a dose that alone was inactive. In these studies, i.c.v. pretreatment of animals with low-dose [FG]OFQ/N(1-13)-NH2 failed to prevent the cardiovascular and renal excretory response to i.c.v. OFQ/N. Although [FG]OFQ/N(1-13)-NH2 is reported to be an antagonist of the OFQ/N receptor in vitro, these findings indicate that this compound has agonist activity similar to that of the endogenous ligand OFQ/N when administered centrally in vivo. (+info)
Human endothelin-1 clearance kinetics revealed by a radiotracer technique.
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Levels of endothelin-1 (ET-1) are elevated in many disease states, although its total body kinetics of elimination are poorly understood. Therefore, it remains uncertain whether the presence of elevated levels of ET-1 in the setting of disease are secondary to changes in production or clearance or some combination thereof. Using a 125I-labeled ET-1 infusion technique, the volume of distribution and kinetics of clearance of endothelin were described in five normal volunteers. Heart rate, blood pressure, right atrial pressure, and arterial blood samples for the counting of 125I and the measurement of ET-1 were obtained at multiple time points before and up to 45 h after the start of the infusion. The radiotracer infusion had no effect on heart rate, blood pressure, right atrial pressure, or endogenous ET-1 levels. ET-1 clearance was best described by a three-compartment model, which revealed that ET-1 has a much longer terminal half-life and volume of distribution than was previously reported. This suggests extensive uptake of ET-1 in various organ systems and slow clearance. These new findings have important implications for the understanding of the pathophysiology of ET-1 in disease states as well as for the understanding and development of ET-1 receptor blockers and endothelin-converting enzyme inhibitors. (+info)
The rostral ventrolateral medulla mediates the sympathoactivation produced by chemical stimulation of the rat nasal mucosa.
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1. We sought to outline the brainstem circuit responsible for the increase in sympathetic tone caused by chemical stimulation of the nasal passages with ammonia vapour. Experiments were performed in alpha-chloralose-anaesthetized, paralysed and artificially ventilated rats. 2. Stimulation of the nasal mucosa increased splanchnic sympathetic nerve discharge (SND), elevated arterial blood pressure (ABP), raised heart rate slightly and inhibited phrenic nerve discharge. 3. Bilateral injections of the broad-spectrum excitatory amino acid receptor antagonist kynurenate (Kyn) into the rostral part of the ventrolateral medulla (RVLM; rostral C1 area) greatly reduced the effects of nasal mucosa stimulation on SND (-80 %). These injections had no effect on resting ABP, resting SND or the sympathetic baroreflex. 4. Bilateral injections of Kyn into the ventrolateral medulla at the level of the obex (caudal C1 area) or into the nucleus tractus solitarii (NTS) greatly attenuated the baroreflex and significantly increased the baseline levels of both SND and ABP. However they did not reduce the effect of nasal mucosa stimulation on SND. 5. Single-unit recordings were made from 39 putative sympathoexcitatory neurons within the rostral C1 area. Most neurons (24 of 39) were activated by nasal mucosa stimulation (+65.8 % rise in discharge rate). Responding neurons had a wide range of conduction velocities and included slow-conducting neurons identified previously as C1 cells. The remaining putative sympathoexcitatory neurons were either unaffected (n = 8 neurons) or inhibited (n = 7) during nasal stimulation. We also recorded from ten respiratory-related neurons, all of which were silenced by nasal stimulation. 6. In conclusion, the sympathoexcitatory response to nasal stimulation is largely due to activation of bulbospinal presympathetic neurons within the RVLM. We suggest that these neurons receive convergent and directionally opposite polysynaptic inputs from arterial baroreceptors and trigeminal afferents. These inputs are integrated within the rostral C1 area as opposed to the NTS or the caudal C1 area. (+info)
Preserved arterial flow secures hepatic oxygenation during haemorrhage in the pig.
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1. This study examined the extent of liver perfusion and its oxygenation during progressive haemorrhage. We examined hepatic arterial flow and hepatic oxygenation following the reduced portal flow during haemorrhage in 18 pigs. The hepatic surface oxygenation was assessed by near-infrared spectroscopy and the hepatic metabolism of oxygen, lactate and catecholamines determined the adequacy of the hepatic flow. 2. Stepwise haemorrhage until circulatory collapse resulted in proportional reductions in cardiac output and in arterial, central venous and pulmonary wedge pressures. While heart rate increased, pulmonary arterial pressure remained stable. In addition, renal blood flow decreased, renal vascular resistance increased and there was elevated noradrenaline spill-over. Further, renal surface oxygenation was lowered from the onset of haemorrhage. 3. Similarly, the portal blood flow was reduced in response to haemorrhage, and, as for the renal flow, the reduced splanchnic blood flow was associated with an elevated noradrenaline spill-over. In contrast, hepatic arterial blood flow was only slightly reduced by haemorrhage, and surface oxygenation did not change. The hepatic oxygen uptake was maintained until the blood loss represented more than 30 % of the estimated blood volume. At 30 % reduced blood volume, hepatic catecholamine uptake was reduced, and the lactate uptake approached zero. 4. Subsequent reduction of cardiac output and portal blood flow elicited a selective dilatation of the hepatic arterial vascular bed. Due to this dilatation liver blood flow and hepatic cell oxygenation and metabolism were preserved prior to circulatory collapse. (+info)
Left ventricular function in chronic renal failure.
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Left ventricular function was studied in 14 patients with end-stage chronic renal failure using non-invasive methods (echocardiography and systolic time intervals). Patients were divided into 3 groups. Group 1 consisted of 5 patients who were normotensive at the time of study and group 2 of 7 patients who were hypertensive when studied. Group 3 consisted of 2 patients: one was receiving propranolol and the other, studied 302 days after renal transplantation, was receiving digitalis for recurrent episodes of cardiac failure. All except the patient receiving propranolol had normal left ventricular function in systole with normal measurements of fractional fibre shortening (% delta S, EF) and normal measurements relating to the velocity of ventricular contraction (mean Vcf, mean velocity of posterior wall motion). Stroke volume and cardiac output were normal in some patients but were increased in patients with fluid overload. Early diastolic compliance of the left ventricle seemed to be normal except in the patient with recurrent cardiac failure. The study provided no evidence for the existence of a specific uraemic cardiomyopathy. (+info)
Haemodynamic adaptation at rest and during exercise to long-term antihypertensive treatment with combination of beta-receptor blocking and vasodilator agent.
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Systemic and pulmonary haemodynamics were studied at rest in the supine and upright position, and during exercise in the sitting position at 75 and 150 Watt, in 13 hypertensive men aged 50-8 +/- 8-7 years before and after 13 months treatment with oral oxprenolol (120 to 160 mg t.i.d.) supplemented by oral hydrallazine (50 to 75 mg t.i.d.) during the last 6 months. Pressures were recorded by means of catheters inserted percutaneously into the pulmonary and brachial artery; cardiac output was determined according to Fick. Treatment resulted in a significant reduction of systemic systolic, diastolic, and mean pressures at rest in the supine position and during exercise, and of systolic pressures in the upright posture. Pulmonary systolic and mean pressures increased slightly at rest in the supine position and during exercise, and no changes occurred at rest in the upright position. The left ventricular filling pressure was unchanged at rest both in the supine and upright position; it increased slightly during exercise. The haemodynamic changes by which systemic pressure was reduced were those typical of beta-adrenergic blockade: reduction of cardiac output resulting from a decrease of both heart rate and stroke volume, while the total systemic vascular resistance was unchanged at rest in the supine position but increased in the upright posture and during exercise. The A-V O2 difference increased remarkably. This long-term observation again suggests that the acute haemodynamic effects of an antihypertensive regimen can be modified during long-term application. It did not give evidence of a readjustment of the vascular resistance occurring, at least not in the upright position and during exercise, as has been suggested for long-term beta-adrenergic blockade. (+info)
Heart rate--left ventricular ejection time relations. Variations during postural change and cardiovascular challenges.
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Regression equations for heart rate (HR)--ejection time (LVET) relations provide the appropriate factors for predicting or correcting left ventricular ejection time at any HR. We investigated HR-LVET regressions under different conditions common to both physiological and clinical studies of LVET which had been selected because of predictably different physiological responses. Ten normal subjects were studied during both supine and sitting rest and during isometric handgrip (IHG) in both supine and sitting postures and 10 during head-up tilt. Unexpectedly, as compared with pre-exercise rest on a bicycle ergometer, the slope for the resting state on a chair was slightly flatter, and LVET values were uniformly higher throughout the range of HRs measured. Differences among HR-LVET slopes and intercepts appeared to reflect the established behaviour of stroke volume and ejection rate under the conditions studied. Differences observed among intercepts, especially in supine vs. upright postures, are substantial and require that the appropriate intercept be applied in predicting LVET at a given HR. differences among slopes, while not statistically significant, may, under practical conditions, lead to unacceptable error if the appropriate slope factor is not used in correcting LVET for HR. (+info)