Cardiac Output Rate Research Articles

Role of protein kinase D1 in vasoconstriction and haemodynamics in rats

AimsProtein kinase D (PKD), once considered an effector of protein kinase C (PKC), now plays many pathophysiological roles in various tissues. However, little is known about role of PKD in vascular function. We investigated the role of PKD in contraction of rat aorta and human aortic smooth muscle cells (HASMCs) and in haemodynamics in rats. Methods and resultsIsometric tension of rat aortic was measured to examine norepinephrine-induced contraction in the presence of PKD, PKC and Rho-kinase inhibitors. Phosphorylation of PKD1, myosin targeting subunit-1 (MYPT1), myosin light chain (MLC), CPI-17 and heat-shock protein 27 (HSP27), and actin polymerization were measured in the aorta. Phosphorylation of MYPT1 and MLC was also measured in HASMCs knocked down with specific siRNAs of PKD 1, 2 and 3. Intracellular calcium concentrations and cell shortening were measured in HASMCs.Norepinephrine-induced aortic contraction was accompanied by increased phosphorylation of PKD1, MYPT1 and MLC and actin polymerization, all of which were attenuated with PKD inhibitor CRT0066101. PKD1 phosphorylation was not inhibited by PKC inhibitor, chelerythrine or Rho kinase inhibitor, fasudil. In HASMCs, the phosphorylation of MYPT1 and MLC was attenuated by PKD1, but not PKD2, 3 knockdown. In HASMCs, CRT0066101 inhibited norepinephrine-induced cell shortening without affecting calcium concentration. Administration of CRT0066101 decreased systemic vascular resistance and blood pressure without affecting cardiac output in rats. ConclusionsPKD1 may play roles in aorta contraction and haemodynamics via phosphorylation of MYPT1 and actin polymerization in a calcium-independent manner.

Myocardial stretch-induced compliance is abrogated under ischemic conditions and restored by cGMP/PKG-related pathways.

Introduction: Management of acute myocardial infarction (MI) mandates careful optimization of volemia, which can be challenging due to the inherent risk of congestion. Increased myocardial compliance in response to stretching, known as stretch-induced compliance (SIC), has been recently characterized and partly ascribed to cGMP/cGMP-dependent protein kinase (PKG)-related pathways. We hypothesized that SIC would be impaired in MI but restored by activation of PKG, thereby enabling a better response to volume loading in MI. Methods: We conducted experiments in ex vivo rabbit right ventricular papillary muscles under ischemic and non-ischemic conditions as well as pressure-volume hemodynamic evaluations in experimental in vivo MI induced by left anterior descending artery ligation in rats. Results: Acutely stretching muscles ex vivo yielded increased compliance over the next 15min, but not under ischemic conditions. PKG agonists, but not PKC agonists, were able to partially restore SIC in ischemic muscles. A similar effect was observed with phosphodiesterase-5 inhibitor (PDE5i) sildenafil, which was amplified by joint B-type natriuretic peptide or nitric oxide donor administration. In vivo translation revealed that volume loading after MI only increased cardiac output in rats infused with PDE5i. Contrarily to vehicle, sildenafil-treated rats showed a clear increase in myocardial compliance upon volume loading. Discussion: Our results suggest that ischemia impairs the adaptive myocardial response to acute stretching and that this may be partly prevented by pharmacological manipulation of the cGMP/PKG pathway, namely, with PDE5i. Further studies are warranted to further elucidate the potential of this intervention in the clinical setting of acute myocardial ischemia.

Expressions of SERCA2a and miR-25-3p/5p in myocardium of rats with heart failure and therapeutic effects of Xiefei Lishui recipe

To investigate the expressions of sarcoplasmic reticulum calcium ATPase 2a (SERCA2a) mRNA and miR-25-3p/5p in myocardium of rats with heart failure and the therapeutic effects of Xiefei Lishui recipe(Traditional Chinese Medicine). SD rats were randomly divided into five groups:control group, model group, Traditional Chinese Medicine group(TCM group), captopril group and digoxin group(n=10). Heart failure rat model was induced by intraperitoneal injections of doxorubicin(6 injections within 2 weeks; total dose:15 mg/kg). Five weeks after the first injection, Distilled water(10 ml/(kg·d)), TCM(22 g/(kg·d)), captopril(19 mg/(kg·d)),and digoxin(32μg/(kg·d))were administrated by gastrogavage for 35 days,respectively. Myocardial expressions of SERCA2a mRNA and miR-25-3p/5p were detected;myocardial activities of SERCA2a were measured; cardiac output(CO) and left ventricular ejection fraction(LVEF) and plasma level of B-type natriuretic peptide (BNP) were measured. Myocardial mRNA expression of SERCA2a was significantly down-regulated in rats with heart failure which could be significantly up-regulated by TCM or captopril or digoxin,while expressions of miR-25-3p and miR-25-5p in myocardium were significantly up-regulated which could be significantly down-regulated by TCM or captopril. SERCA2a activity, CO and LVEF in rats with heart failure were decreased significantly which could be significantly increased by TCM,while plasma level of BNP was increased significantly which could be significantly decreased by TCM or captopril or digoxin. CO in rats with heart failure could be signifi-cantly increased by captopril or digoxin. In rats with heart failure, myocardial mRNA expression of SERCA2a was downregulated, expression of miR-25-3p and miR-25-5p in myocardium was upregulated. Xiefei Lishui recipecan upregulate myocardial mRNA expression of SERCA2a, downregulate expression of miR-25-3p and miR-25-5p in myocardium and improve cardiac function.

E0127 Determination of pulmonary artery pressure and cardiac output in rat

ObjectiveTo establish a method for determination of pulmonary artery pressure and cardiac output in rat.Methods20 Sprgue—Dawely rats were randomly assigned into two groups: control group and pulmonary arterial hypertension (PAH)...

Determination of acute and chronic effects of cadmium on the cardiovascular system of rats

In this study, the systemic hemodynamics induced by acute and chronic cadmium (Cd+2) intoxication in the cardiovascular system of rats using thoracic electrical bioimpedance were examined and the acute and chronic effects of Cd+2 intoxication on the activities of antioxidant enzymes and malondialdehyde (MDA) were compared. Also, in this study, ultrastructural changes in the heart and aorta of rats were evaluated. Thirty-eight male Wistar albino rats were randomly divided into control, acute, and chronic groups. Chronic group was administered by oral gavage an aqueous solution of CdCl2 for 60 days, at dose of 15 mg Cd+2/kg/day. Acute group was administered by oral gavage an aqueous solution of CdCl2 with a single dose of 15 mg Cd+2/kg. Cadmium increased the stroke volume and cardiac output of rats in the chronic group, but did not change the heart rate significantly. Antioxidant enzymes activities and MDA level significantly increased in the chronic group. In ultrastructural examination, there were widespread degenerative changes in heart muscle cells of the chronic group but endothelial cells and smooth muscle cells in the aorta tissue samples had normal morphological features in all groups. All of the findings indicate that Cd+2 toxication can cause deformation in heart muscle cells due to an increase in free radicals and lipid peroxidation. Also, this study has confirmed that a long-term-Cd+2 exposure increased stroke volume (SV) and cardiac output (CO), but did not change the heart rate (HR).

Cardiac Output (CO), Stroke Volume (SV) and Heart Rate (HR) in exercising rats

Exercise requires augmented blood flow to skeletal muscle. Increased blood flow is delivered by redistribution of blood flow and by increased CO caused by increases in both SV and HR. The purpose of this study was to determine the effects of two different levels of exercise on volumetric CO, SV and HR in untrained rats. Male Sprague Dawley rats exposed to a Columbus Instruments 5/6 treadmill and trained to run for brief period of time. Animals were instrumented with a 2.5SL transit time flow probe (Transonic Systems Inc.) on the ascending aorta for determination of CO. After a recovery period of at least 1 week, rats were again exposed to the treadmill. On the day of testing, animals were attached to the flow meter by a thether. 15 min. of homecage baseline CO were determined using IOX software (1000Hz, 1 min. averages). Animals were transferred to the treadmill and allowed to acclimate for 15 min. Subjects then were exercised at 15 or 30 m/min for 10 min. After a 15 min rest, the animals were exposed to the alternate level of exercise. All values are expressed as χ±sem. Under homecage baseline conditions, CO = 74±7 ml/m, HR=392±23 bpm, and SV=181±17 μl/m. With onset of exercising at 15m/min all parameters increased to an initial peak then dropped slightly over the remaining exercise period. Average hemodynamic values were: CO 107±11, HR=504±19 and SV=198±16. At 30 m/min all parameters increased and remained level throughout the exercise at: CO=123±11, HR=540±16 and SV=213±15. These studies demonstrate that increasing levels of treadmill exercise are maintained by increasing levels of CO in the rat. Both SV and HR are instrumental in achieving this increase.

Measurement of Cardiac Output in Rats: Using Extracorporeal AV Loop with Ultrasound Dilution Technology – A Validation Study

Measurement of Cardiac Output in Rats: Using Extracorporeal AV Loop with Ultrasound Dilution Technology – A Validation Study

Dose‐independent pharmacokinetics of torasemide after intravenous and oral administration to rats

After intravenous (at doses of 1, 2, 5, and 10 mg/kg) and oral (at doses of 1, 5, and 10 mg/kg) administration of torasemide, the pharmacokinetic parameters were dose-independent. Hence, the extent of absolute oral bioavailability (F) was also independent of oral doses; the values were 95.6, 98.8, and 97.3% for oral doses of 1, 5, and 10 mg/kg, respectively. The high F values indicated that the first-pass (gastric, intestinal, and hepatic) effects of torasemide in rats could be almost negligible. After intravenous administration, the total body clearances of torasemide were extensively slower than the reported cardiac output in rats and hepatic extraction ratio was only 3-4% suggesting almost negligible first-pass effects of torasemide in the heart, lung, and liver in rats. Based on in vitro rat tissue homogenate studies, the tissues studied also showed negligible metabolic activities for torasemide. Equilibrium of torasemide between plasma and blood cells of rat blood reached fast and plasma-to-blood cells concentration ratio was independent of initial blood concentrations of torasemide, 1, 5, and 10 microg/ml; the mean value was 0.279. Protein binding of torasemide to fresh rat plasma was 93.9 +/- 1.53% using an equilibrium dialysis technique.

Pharmacokinetics of DA‐8159, a New Erectogenic, after Intravenous and Oral Administration to Rats: Hepatic and Intestinal First‐Pass Effects

The purposes of this study were to report dose‐independent (after intravenous administration) and dose‐dependent (after oral administration) area under the curve of plasma concentration versus time from time zero to time infinity (AUC), and gastric, intestinal, and/or hepatic first‐pass effects (after intravenous, intraportal, intragastric, and intraduodenal administration) of DA‐8159 [5‐[2‐propyloxy‐5‐(1‐methyl‐2‐pyrollidinylethylamidosulfonyl)phenyl]‐1‐methyl‐3‐propyl‐1,6‐dihydro‐7H‐pyrazolo(4,3‐d)pyrimidine‐7‐one], a new erectogenic, in rats. After intravenous administration at doses of 5, 10, and 30mg/kg, the AUCs and time‐averaged total body clearances (CLs) were dose‐independent. However, the AUCs were dose‐dependent after oral administration at doses of 20, 30, 50, and 100mg/kg. This result could be due to saturation of first‐pass effects at high doses. The extent of absolute oral bioavailability (F) of DA‐8159 was 38.0% at a dose of 30mg/kg. Considering almost complete absorption of DA‐8159 from rat gastrointestinal tract (∼99% of oral dose of 30mg/kg), the low F could be due to considerable hepatic, gastric, and/or intestinal first‐pass effects. After intravenous administration at three doses, the CLs were considerably slower than the reported cardiac output in rats, suggesting almost negligible first‐pass effect of DA‐8159 in the heart and lung. The AUCs were not significantly different between intragastric and intraduodenal administration of DA‐8159 at a dose of 30mg/kg (131 and 127 μg · min/mL), suggesting that gastric first‐pass effect of DA‐8159 was almost negligible in rats. However, the values were significantly smaller than that after intraportal administration (311 μg · min/mL), indicating considerable intestinal first‐pass effect of DA‐8159 in rats of ∼58% of the oral dose. Approximately 23% of DA‐8159 at a dose of 30mg/kg absorbed into the portal vein was eliminated by the liver (hepatic first‐pass effect) based on AUC difference between intravenous and intraportal administration (the value, 23%, was equivalent to ∼9.6% of oral dose). The low F of DA‐8159 after oral administration at a dose of 30mg/kg to rats was mainly due to considerable intestinal (∼58%) first‐pass effects. © 2003 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2185–2195, 2003

Dose-independent pharmacokinetics of a candidate for diabetic neuropathy, SR-4668, after intravenous and oral administration to rats: Intestinal first-pass effect

Dose-independent pharmacokinetic parameters of SR-4668 were observed after intravenous (i.v.) administrations at doses of 25, 50, and 75mg/kg and oral administrations at doses of 50, 100, and 150mg/kg to rats. The hepatic, gastric, and intestinal first-pass effects of SR-4668 were also measured after i.v., intraportal (i.p.), intraduodenal (i.d.), and intragastric (i.g.) administrations at a dose of 50mg/kg to rats. Although a considerable amount of orally administered SR-4668 was absorbed, the F was low—only 33%. This indicates considerable first-pass (gastric, intestinal, and/or hepatic) effects of SR-4668 in rats. After i.v. administrations, the total body clearances of SR-4668 were considerably slower than the reported cardiac output in rats, suggesting that the first-pass effects of SR-4668 in the lung and heart could be negligible, if any, in rats. The AUCs of SR-4668 were comparable between i.v. and i.p. administrations, suggesting that the hepatic first-pass effect of SR-4668 was not considerable in rats. The AUCs were also comparable between i.d. and i.g. administrations, suggesting that gastric first-pass effect was almost negligible in rats. However, the AUC after an i.d. administration was significantly smaller (approximately 55% decrease) than that after an i.p. administration, suggesting that the intestinal first-pass effect was approximately 55% of oral dose. The rests of the orally administered dose could be mainly due to degradation of SR-4668 in gastric juices; 77.3–95.6% of the spiked amount of SR-4668 were recovered after 4-h incubation in five human gastric juices. The above data suggested that the low F of SR-4668 could be mainly due to considerable intestinal first-pass effect in rats.

Dose-Independent Pharmacokinetics of a New Neuroprotective Agent for Ischemia-Reperfusion Damage, KR-31543, after Intravenous and Oral Administration to Rats: Hepatic and Intestinal First-Pass Effects

The purpose of this study was to report dose-independent pharmacokinetics of KR-31543, a new neuroprotective agent for ischemia-reperfusion damage, after intravenous (iv) and oral (po) administration and first-pass effects after iv, intraportal, intragastric, and intraduodenal administration in rats. After iv (10, 20, and 50 mg/kg) and oral (10, 20, and 50 mg/kg) administration, the pharmacokinetic parameters of KR-31543 were dose independent. The extent of absolute oral bioavailability (F) was 27.4% at 20 mg/kg. Considering the amount of unabsorbed KR-31543 from the gastrointestinal tract at 24 h (4.11%), the low F value could be due to the hepatic, gastric, and/or intestinal first-pass effects. After iv administration of three doses, the total body clearances were considerably slower than the reported cardiac output in rats, suggesting almost negligible first-pass effect in the heart and lung in rats. The areas under the plasma concentration–time curves from time zero to time infinity (AUCs) were not significantly different between intragastric and intraduodenal administration of KR-31543 (20 mg/kg), suggesting that the gastric first-pass effect of KR-31543 was almost negligible in rats. However, the values were significantly smaller (305 and 318 μg · min/mL) than that after intraportal administration (494 μg · min/mL), indicating a considerable intestinal first-pass effect of KR-31543 in rats; that is, ∼40% of the oral dose. Approximately 50% of KR-31543 absorbed into the portal vein was eliminated by the liver (hepatic first-pass effect) based on iv and intraportal administration (the value, 50%, was equivalent to ∼30% of the oral dose). The low F value of KR-31543 after oral administration of 20 mg/kg to rats was mainly due to considerable intestinal (∼40%) and hepatic (∼30%) first-pass effects.

An alternative thermodilution method to measure cardiac output in a rat model of stagnant hypoxia.

Rats are often used to study hemodynamics in animal research. We have established an alternative method to measure cardiac output in a conscious rat using a thermodilution technique via a left ventricular injection. The validity of this method was evaluated in conscious rats and compared with the results obtained using the radiolabeled microspheres (reference sample method). Using 20 male Sprague-Dawley rats, a baseline cardiac index was measured by thermodilution to determine the baseline cardiac index and to evaluate between animal variability. The baseline cardiac index was compared to the reference sample method with 6 rats. Following baseline measurements, an intra-atrial balloon was inflated in a stepwise manner to create 2 to 3 different cardiac outputs, and the cardiac index was computed. For each measurement, the cardiac index was first measured by thermodilution and immediately followed by the reference sample method. A total of 21 measurements were obtained, and the results were analyzed by a Bland-Altman plot and the correlation coefficient was calculated. Although the agreement between the two methods was poor, both methods had a good correlation (r2 = 0.59). With the thermodilution technique, we demonstrated a small coefficient of variation in each measurement, with a low intra-animal and inter-animal variability. As there is no gold standard method to measure cardiac output in rats, we believe that left ventricular thermodilution is a reliable method, and overcomes several technical difficulties such as heat loss, one of the significant limitations of the conventional thermodilution method (via right atrial injection). This new thermodilution technique (via the left ventricle) is therefore an attractive alternative method to measure cardiac output in rats.

Cardiac output in rats of different ages during blockade of α1 and β-adrenoceptorsand β-adrenoceptors

In acute experiments on rats of different ages (21, 30, 42 and 70 days), the α1-adrenoblocker prazosin increased the heart rate (HR), and the β-blocker propranolol (Obsidan) infused after prazosin reduced this parameter. Prazosin decreased both stroke volume and cardiac output, blockade of β-adrenoceptors further decreased these parameters. It is concluded that both α1- and β-adrenoceptors are involved in the sympathetic regulation of cardiac output in developing animals.

Pharmacokinetics of a new reversible proton pump inhibitor, YH1885, after intravenous and oral administrations to rats and dogs: hepatic first-pass effect in rats.

The pharmacokinetics of YH1885 were evaluated after intravenous (iv) and oral administrations of the drug to rats and dogs. The reason for the low extent of bioavailability (F) of YH1885 after oral administration of the drug to rats and the absorption of the drug from various rat gastrointestinal (GI) segments were also investigated. After iv administration of YH1885, 5-20 mg kg(-1), to rats, the pharmacokinetic parameters of YH1885 seem to be independent of the drug at the dose ranges studied. After oral administration of YH1885, 50-200 mg kg(-1), to rats, the area under the plasma concentration-time curve from time zero to 12 or 24 h (AUC(0-12 h) or AUC(0-24 h)) was proportional to the oral dose of the drug, 50-100 mg kg(-1), however, the AUC(0-24 h) value at 200 mg kg(-1) increased with less proportion to the dose increase (324, 689, and 815 microg x min mL(-1) for 50, 100, and 200 mg kg(-1), respectively) due to the poor water solubility of the drug. This was proved by the considerable increase in the percentages of the oral dose remaining in the entire GI tract as unchanged YH1885 at 24 h (11.8, 15.3, and 42.8% for 50, 100, and 200 mg kg(-1), respectively). The F value after oral administration of YH1885 to rats was relatively low; the value was approximately 40% at the oral dose of 50 and 100 mg kg(-1). The reason for the low F in rats was investigated. The liver showed the highest metabolic activity for YH1885 based on an in vitro rat tissue homogenate study; hence, the liver first-pass effect was estimated. The value of AUC after intraportal administration of the drug, 5 mg kg(-1), was approximately 70% (116 versus 163 microg x min mL(-1)) of that after iv administration of the drug, 5 mg kg(-1), to rats; the liver first-pass effect of YH1885 in rats was estimated to be approximately 30%. The total body clearance of YH1885 after iv administration of the drug, 5-20 mg kg(-1), to rats were considerably lower than the cardiac output of rats, indicating that the lung and/or heart first-pass effect of YH1885 could be negligible in rats. After oral administration of YH1885, 50 and 100 mg kg(-1), to rats, the F value was approximately 40%, and approximately 15% of the oral dose was recovered from the entire GI tract as unchanged YH1885 at 24 h, and 30% of the oral dose disappeared with the liver first-pass effect. Therefore, the remainder, approximately 15% of the oral dose, could have disappeared with the small intestine first-pass effect and/or degradation of the drug in the GI tract. YH1885 was absorbed from ileum, duodenum, and jejunum of rat, however, YH1885 was under the detection limit in plasma when the drug was instilled into the rat stomach and large intestine. After iv administration of YH1885, 5-20 mg kg(-1), to dogs, the pharmacokinetic parameters of YH1885 also seemed to be independent of the drug at the dose ranges studied. However, after oral administration of YH1885, 0.5 and 2 g per whole body weight, to dogs, the AUC(0-10 h) values were not significantly different (96.8 versus 98.2 microg x min mL(-1)) and this could be due to the poor water-solubility of the drug. YH1885 was not detected in the urine after both iv and oral administration of the drug to both rats and dogs.

Central circulation in rats with different tolerance to acute blood loss

Study of the dynamics of cardiac output in rats with different tolerance to acute massive blood loss showed that the pumping ability of the heart remains intact during the entire posthemorrhagic period in all high-resistant and in 65% low-resistant rats. In 35% rats that were low-resistant to blood loss, the cardiac output deficiency syndrome developed after cessation of bleeding against the background fall in arterial pressure and a decrease in the hepatic blood flow, which are the signs of rapid variant of the dysfunction produced by acute blood loss.

Liver and gastrointestinal first-pass effects of azosemide in rats.

Since considerable first-pass effects of azosemide have been reported after oral administration of the drug to rats and man, first-pass effects of azosemide were evaluated after intravenous, intraportal and oral administration, and intraduodenal instillation of the drug, to rats. The total body clearances of azosemide after intravenous (5 mg kg-1) and intraportal (5 and 10 mg kg-1) administration of the drug to rats were considerably smaller than the cardiac output of rats suggesting that the lung or heart first-pass effect (or both) of azosemide after oral administration of the drug to rats was negligible. The total area under the plasma concentration-time curve from time zero to time infinity (AUC) after intraportal administration (5 mg kg-1) of the drug was significantly lower than that after intravenous administration (5 mg kg-1) of the drug (1000 vs 1270 micrograms min mL-1) suggesting that the liver first-pass effect of azosemide was approximately 20% in rats. The AUC from time 0 to 8 h (AUC0-8 h) after oral administration (5 mg kg-1) of the drug was considerably smaller than that after intraportal administration (5 mg kg-1) of the drug (27.1 vs 1580 micrograms min mL-1) suggesting that there are considerable gastrointestinal first-pass effects of azosemide after oral administration of azosemide to rats. Although the AUC0-8 h after oral administration (5 mg kg-1) of azosemide was approximately 15% lower than that after intraduodenal instillation (5 mg kg-1) of the drug (27.1 vs 32.0 micrograms min mL-1), the difference was not significant, suggesting that the gastric first-pass effect of azosemide was not considerable in rats. Azosemide was stable in human gastric juices and pH solutions ranging from 2 to 13. Almost complete absorption of azosemide from whole gastrointestinal tract was observed after oral administration of the drug to rats. The above data indicated that most of the orally administered azosemide disappeared (mainly due to metabolism) following intestinal first-pass in rats.

Validity of thermal dilution technique for measurement of cardiac output in rats.

The validity of the thermal dilution technique for the measurement of cardiac output was verified in experiments on a circulation model and on anesthetized rats under open- and closed-chest conditions. In the circulation model thermal dilution was compared with direct (Fdir) and electromagnetic (F(elm)) flowmetry. Flow values measured in the circulation model with the thermal dilution (Fth) technique correspond well with direct flowmetry (Fth = 0.92 Fdir + 7.0; r = 0.888) and with electromagnetic flowmetry (Fth = 0.95 F(elm) + 1.2; r = 0.990). In the anesthetized rat cardiac output was determined with thermal dilution and simultaneously with Fick's method and/or with electromagnetic flowmetry. Fick's method and electromagnetic flowmetry resulted in identical cardiac output values (COFick = 0.95 COelm; r = 0.865), whereas the thermal dilution technique yielded unequivocally higher values. The extent of overestimation is much more pronounced at low cardiac output than at a high output. The study clearly demonstrates that this overestimation is due to heat diffusion, which is obviously of greater significance in small animals than in large animals or humans. Therefore, the thermal dilution technique is not appropriate for the measurement of cardiac output in the rat.

Stress and cocaine elicit similar cardiac output responses in individual rats.

Cocaine use and behavioral stress elicit variable cardiovascular responses in individuals. In the present study, we examined the effects of cocaine or stress on arterial pressure, heart rate, and cardiac output in conscious rats. Rats were instrumented for determination of ascending aortic blood flow as an index of cardiac output using pulsed Doppler flow-metry. Cocaine administration elicited consistent decreases in cardiac output in some rats, whereas others had increases. In contrast, the pressor and heart rate responses were similar in these two groups of animals. Air jet stress also elicited a decrease in cardiac output only in a subset of conscious rats, yet produced equivalent pressor responses in all rats. Cardiac output responses to cocaine and air jet stress were closely correlated in individual rats, indicating that these stimuli evoke similar hemodynamic responses in individual rats. These observations suggest that the rat may provide a model for understanding differential cardiovascular sensitivity to cocaine and/or stress in humans.

Distribution of cardiac output during diurnal changes of activity in rats

Rat locomotor and feeding behavior varies on a diurnal basis; at night the animals actively forage and eat, whereas during the day they are more inactive and somnolent. At night, cardiac output is higher, presumably for enhanced perfusion of the active muscles to support increased metabolism and for enhanced perfusion of the digestive organs to support increased digestion and nutrient absorption. Conversely, it is hypothesized that during the daytime, blood flow to these two tissues is relatively low. The purpose of this study was to test these hypotheses by measuring cardiac output and the distribution of cardiac output in rats at various times in the diurnal cycle (8:00 A.M., 4:00 P.M., and 8:00 P.M.). The radiolabeled microsphere technique was used to measure cardiac output and distribution of blood flow to the tissues. Distribution of the total cardiac output was accounted for by complete dissection, weighing, and counting of organs and carcass. Cardiac output at 8:00 P.M. (136 +/- 9 ml/min) was elevated 13% (P less than 0.05) over that at 4:00 P.M. The proportion of the cardiac output distributed to the skeletal muscles (4:00 P.M.: 25%; 8:00 P.M.: 27%) and to the digestive tract (4:00 P.M.: 14%; 8:00 P.M.: 14%) did not change between the two time periods. Thus total muscle blood flow increased (P less than 0.05) from 31 +/- 2 at 4:00 P.M. to 36 +/- 4 ml/min at 8:00 P.M.; the only digestive organ to show a significant increase in blood flow from 4:00 P.M. to 8:00 P.M. was the stomach (133 +/- 17 to 166 +/- 19 ml/min, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of Pentaerythritol Tetranitrate following Intra-Arterial and Oral Dosing in the Rat

The pharmacokinetics of pentaerythritol tetranitrate (2,2-bis(hydroxymethyl)-1, 3-propanediol tetranitrate, 1) were studied in rats following a single intra-arterial or oral dose (2mg/kg) of the 14C-labeled drug. Blood levels of the tetranitrate and its metabolites were determined using a thin-layer radiochromatographic procedure. The apparent systemic clearance of 1 was 0.61 ∓ 0.16 L/min/kg (mean ∓ SD, n=6) which exceeded the value of normal cardiac output in rats. The steady-state volume of distribution was 4.2 ∓ 1.1 L/kg (n=6), and the elimination half-life was estimated at 5.8 ∓ 0.6min (n=6). Blood levels of 1 were only detectable (higher than 4.0ng/mL) in three of the six rats examined after the oral dose. The trinitrate derivative (2, 2-bis(hydroxymethyl)-1, 3-propanediol trinitrate, 2) the active metabolite of 1, was not detectable following oral dosing with the tetranitrate. The oral bioavailability of 1 was in the range of 0–8%. in spite of the low water solubility of 1 (i.e., 1 μg/mL), a rather high fraction of the radioactive oral dose [25.7 ∓ 10.3% (n=4) versus 62.4 ± 14.5% (n=4) from the intraarterial dose] was recovered in the urine. A significant portion of the intra-arterial dose (32.7 ∓ 11.0%, n=4) was eliminated in feces, indicating enterohepatic recycling of radioactivity. Analysis of the metabolite pattern in urine indicated extensive metabolism of 1, 2, and the dinitrate derivative 3 (2,2-bis(hydroxymethyl)-1, 3-propanediol dinitrate). Less than 0.2% of the dose was recovered as unchanged drug and 2 following either route of administration.