Subchronic inhalation of mixtures of cigarette smoke constituents in Xpa-/-p53+/- knock-out mice: a comparison of intermittent with semi-continuous exposure to acetaldehyde, formaldehyde, and acrolein.

We investigated whether inhaling peak concentrations of aldehydes several times daily is more damaging than semi-continuously inhaling low-dose aldehydes. We exposed Xpa-/-p53+/- knock-out mice either intermittently or semi-continuously to mixed acetaldehyde, formaldehyde, and acrolein. The intermittent regimen entailed exposure to the aldehydes 7 min every 45 min, 12 times/day, 5 days/week, corresponding to concentrations inhaled by smokers. Semi-continuously exposed animals received half the dose of aldehydes in 8h/day, 5 days/week. Some mice in each group were sacrificed after 13 weeks of exposure; the rest breathed clean air until the end of 1 year. Mice injected intratracheally with benzo[a]pyrene formed a positive control group. The nasal cavity, lungs, and any macroscopically abnormal organs of all mice were analysed histopathologically. After 13 weeks of exposure, the subacute, overall, histopathological changes induced by the inhalation differed noticeably between the intermittently and semi-continuously treated Xpa-/-p53+/- knock-out mice. After 13 weeks of mixed aldehyde exposure, atrophy of the olfactory epithelium generally appeared, but disappeared after 1 year (adaptation and/or recovery). Respiratory epithelial metaplasia of the olfactory epithelium occurred at a higher incidence at 1 year. Except for a significantly greater number of tumours observed in knock-out mice compared to wild mice (semi-continuous aldehyde exposure and controls), no differences between the semi-continuous and intermittent exposure groups were observed.

Significance of ammonium compounds on nicotine exposure to cigarette smokers.

The tobacco industry publicly contends that ammonia compounds are solely used as tobacco additive for purposes of tobacco flavoring, process conditioning and reduction of its subjective harshness and irritation. However, neither objective scientific reports, nor the contents of a large number of internal tobacco company documents support this contention. The present review focuses on the hypothesis that addition of ammonium compounds to tobacco enhances global tobacco use due to smoke alkalization and enhanced free-nicotine nicotine exposure. Obviously, ammonia enhances the alkalinity of tobacco smoke. Consequently, the equilibrium shifts from non-volatile nicotine salts to the volatile free base that is more readily absorbed from the airways. The observed change in the kinetics of nicotine (i.e., shorter t(1/2) and higher c(max)) after ammoniation is, however, predominantly due to the higher concentration of nicotine in the smoke, rather than to an increase in the absorption rate of free-base nicotine in the respiratory tract. Although several findings support the hypothesis, additional studies are required and suggested to provide a proper, objective and independent scientific judgment about the effect of tobacco ammoniation on nicotine bioavailability. Scientific and public awareness of the effects of tobacco-specific ammonia compounds may stimulate global control, legislation and restriction of their use in cigarette manufacture.

Density of beta adrenoceptors in rat heart and lymphocytes 48 hours and 7 days after acute myocardial infarction.

Down regulation of the beta adrenoceptor is thought to play an important role in the diminished response to catecholamines in heart failure. beta Adrenoceptor densities were measured on membrane homogenates of rat right ventricle and lymphocytes 48 h or 7 d after experimental myocardial infarction, and in rats exposed to a continuous infusion of isoprenaline (400 micrograms.kg-1.h1). The performance of the rat hearts was also evaluated 48 h post infarction in an isolated retrograde perfused heart preparation. In contrast to a 60% down regulation in right ventricle and a 20% down regulation in lymphocyte membranes after isoprenaline infusion, there was no change in right ventricle and lymphocyte beta adrenoceptor densities after myocardial infarction. Left ventricular contractile performance was significantly depressed 48 h after myocardial infarction. Mean basal left ventricular pressure decreased from 108(SEM 3) to 63(4) mm Hg while the maximal response to dobutamine was decreased from 204(4) to 105(12) mm Hg (n = 8). No correlation was found between the receptor densities of right ventricular and lymphocyte membranes. We conclude that diminished response to beta sympathomimetics after myocardial infarction cannot be attributed to a loss of surface beta adrenoceptors, and that the lymphocyte beta adrenoceptor does not provide an adequate system to monitor small receptor changes on the myocardium.

Mepyramine but not cimetidine or clobenpropit blocks pertussis toxin-induced histamine sensitization in rats.

The effects of pertussis toxin (PT) and the role of histaminergic H(1), H(2) and H(3) receptor blockade on the actions of histamine on blood pressure, heart rate, blood gas values, and mortality were studied in anaesthetized rats. Four days after treatment with PT, histamine dose-dependently decreased mean arterial blood pressure (MAP) and PT enhanced the histamine-induced decrease in MAP. In the PT but not in the inactivated PT (IPT) or saline treated group three out of six animals died after the highest dose of histamine (300 mg kg(-1), i.v.) In order to determine the type of histamine receptor that mediates HS, 4 days after PT the selective antagonists mepyramine (H(1)), cimetidine (H(2)) and clobenpropit (H(3)) were administered 20 min before the challenge with histamine. Mepyramine completely inhibited both the enhanced histamine-induced decrease in MAP and mortality brought about by PT. Cimetidine and clobenpropit had no protective effects, but rather enhanced the histamine-induced mortality elicited by PT. The present study shows that PT caused HS in rats which is primarily mediated via H(1) and secondarily via H(2) and H(3) receptors. These results are considered to be a first step in the elucidation of the mechanism(s) of the HS test used in the quality control of acellular pertussis vaccine.

ACE inhibitor-induced angioedema. Incidence, prevention and management.

Available information from 1980 to 1997 on angiotensin converting enzyme (ACE) inhibitor-induced angioedema and its underlying mechanisms are summarised and discussed. The incidence of angioedema is low (0.1 to 0.2%) but can be considered as a potentially life-threatening adverse effect of ACE inhibitor therapy. This adverse effect of ACE inhibitors, irrespective of the chemical structure, can occur early in treatment as well as after prolonged exposure for up to several years. The estimate incidence is quite underestimated. The actual incidence can be far higher because of poorly recognised presentation of angioedema as a consequence of its late onset in combination with usually long term therapy. Also, a spontaneous reporting bias can contribute to an actual higher incidence of this phenomenon. The incidence can be even higher (up to 3-fold) in certain risk groups, for instance Black Americans. Treatment includes immediate withdrawal of the ACE inhibitor and acute symptomatic supportive therapy followed by immediate (and long term) alternative therapy with other classes of drugs to manage hypertension and/or heart failure. Preclinical and clinical studies for the elucidation of the underlying mechanism(s) of ACE inhibitor-associated angioedema have not generated definite conclusions. It is suggested that immunological processes and several mediator systems (bradykinin, histamine, substance P and prostaglandins) are involved in the pathogenesis of angioedema. A great part of all reviewed reports suggest a relationship between ACE inhibitor-induced angioedema and increased levels of (tissue) bradykinin. However, no conclusive evidence of the role of bradykinin in angioedema has been found and an exclusive role of bradykinin seems unlikely. So far, no clear-cut evidence for an immune-mediated pathogenesis has been found. In addition, ACE gene polymorphism and some enzyme deficiencies are proposed to be involved in ACE inhibitor-induced angioedema. Progress in pharmacogenetic and molecular biological research should throw more light on a possible genetic component in the pathogenesis of ACE inhibitor-associated angioedema.

Modulation by pertussis toxin of salbutamol- and arecoline-induced effects in the isolated heart and aorta of the rat.

The modulatory effects of pertussis toxin pretreatment on responses mediated via beta-adrenoceptors and muscarinic acetylcholine receptors were investigated in isolated rat hearts and aortic rings 4 days after in vivo administration of pertussis toxin. In isolated hearts, pertussis toxin increased heart weight and baseline coronary flow values but did not effect baseline left ventricular pressure values. In unpaced hearts, pertussis toxin inhibited the arecoline-induced cardiac standstill, while in paced hearts, the beta 2-adrenoceptor agonist salbutamol produced a dose-dependent vasodilation with similar characteristics in pertussis toxin and control preparations. Pertussis toxin had no effect on myocardial or aortic cyclic nucleotide levels and the myocardial beta-adrenoceptor density (Bmax) and dissociation constant (Kd). In precontracted aortic rings, pertussis toxin had no effect on the salbutamol or arecoline induced vasorelaxation. In summary, we demonstrated a reduced cholinergic responsiveness in isolated hearts but an intact beta 2-adrenoceptor pathway in isolated hearts as well as in isolated aortic rings after pertussis toxin pretreatment. In aortic rings no change in muscarinic acetylcholine receptor responsiveness occurred.

Effect of naloxone on blood pressure and survival in different shock models in rats.

The effect of naloxone on a number of experimental shock models, using the anaesthetized rat, was studied with special emphasis on mean arterial blood pressure (MABP) and chance of survival. Only a slight increase in MABP was noted in haemorrhagic shock models whereas survival was not affected. Naloxone was without effect in endotoxin shock (i.p. administration of endotoxin). In endotoxin shock (i.v. administration) naloxone increased MABP especially at a high dose of endotoxin. Although survival time was prolonged, the chance of permanent survival was not improved. Naloxone had practically no effect in anaphylactic shock and intestinal ischaemia shock. It is concluded that if naloxone has any effect it is relatively slight. However, this does not exclude the possibility that naloxone might still be considered as an adjunct to other forms of shock treatment at least in certain types of shock.

A study on possible modulating and direct effects of gamma2-MSH and ACTH-(1-24) on the cardiovascular system of the rat.

In conscious rats, gamma2-melanocyte-stimulating hormone (gamma2-MSH) dose-dependently increases blood pressure and heart rate, whereas adrenocorticotropin-(1-24) [ACTH-(1-24)] dose-dependently decreases blood pressure, an effect which was accompanied by a reflectory tachycardia. As the exact mechanism involved in these cardiovascular effects of the two melanocortins is as yet not known, we undertook a series of experiments to investigate the possibility that these peptides have modulating or direct effect on the cardiovascular system of the rat. In pithed rats gamma2-MSH, administered intravenously (i.v.) in doses of 5-200 nmol/kg, had no significant effect on systolic and diastolic blood pressure and on heart rate, whereas ACTH-(1-24), 5-500 nmol/kg, i.v., dose-dependently decreased blood pressure and increased heart rate. Infusion of gamma2-MSH, 10(-8) M, or ACTH-(1-24), 10(-6) M, in the isolated perfused rat heart did not significantly affect left ventricular pressure or coronary flow. Pretreatment with either gamma2-MSH or ACTH-(1-24) did not modify the responsiveness of the myocardium and coronary vasculature to salbutamol and phenylephrine. Neither gamma2-MSH nor ACTH-(1-24) did affect the vascular contractile machinery of skinned vascular smooth muscles of the rabbit with respect to Ca2+ handling in the cell, as measured by its sensitivity to exogenously applied Ca2+. Gamma2-MSH had no effect on blood pressure and heart rate in pithed rats in which postganglionic sympathetic outflow was stimulated by 1,1-dimethyl-4-phenylpiperazinium (DMPP), nor in pithed rats in which preganglionic sympathetic outflow was stimulated electrically. A dose of 15 nmol/kg ACTH-(1-24) had no significant influence on preganglionic outflow to the cardiac and vascular structures in pithed rats. These data show that gamma2-MSH does not exert its cardiovascular effects via a peripheral site of action at the level of the vascular system and the heart, nor directly on pre- or postganglionic sympathetic outflow. These results are in support for the notion that the peptide acts via a brain region localised outside the blood-brain barrier. The acute depressor effect of ACTH-(1-24), however, seems to be due to a direct effect on the vasculature in the periphery.

Vascular responses of isolated mesenteric resistance and basilar arteries from short- and long-term diabetic rats.

Vascular dysfunctions, e.g. alterations in the reactivity of blood vessels to neurotransmitters and hormones, are a well-established complication of diabetes mellitus. Whether these impairments are a consequence of direct postsynaptic deficits and/or indirect presynaptic deficits remains to be determined. To this end, we investigated the influence of the duration of diabetes on relaxation and contraction responses of isolated mesenteric resistance and equally-sized basilar arteries to postsynaptic activation by various vasoactive agents, using streptozotocin-induced diabetic rats and age-matched controls. Relaxation responses to vasodilator agents were studied in KCl-precontracted arteries. The duration of diabetes (4 or 40 weeks) did not affect the vasodilator responses to sodium nitroprusside or salbutamol in either artery. In mesenteric resistance vessels from short-term (4 weeks) and long-term (40 weeks) diabetic rats the vasoconstrictor responses to KCI, serotonin and vasopressin were the same as those in non-diabetic rats; however, the sensitivity (EC50) to noradrenaline was slightly but significantly enhanced after the long-term diabetic state. In contrast to the mesenteric arteries, noradrenaline did not cause contraction in basilar arteries taken from diabetic and control rats. Thus, there appear to be important differences in the reactivity to noradrenaline of the peripheral and cerebral vasculature. The basilar artery from short-term and long-term diabetic rats did not show different responsiveness to vasopressin whereas to serotonin a significant enhanced and decreased sensitivity (EC10 and EC50) was demonstrated in short-term and long-term diabetes, respectively. Our findings indicate that postsynaptic impairments do not play a major role in the alterations of vasoreactivity to vasodilators, noradrenaline or vasopressin seen in experimental diabetes. However, the duration of the diabetic state may have serious consequences for vasoreactivity of basilar arteries to serotonin and, therefore, warrants further investigations.

Plasma elimination of milrinone in rats in relation to its hemodynamic effects.

Milrinone (1,6-dihydro-2-methyl-6-oxo[3,4'-bipyridine]-5-carbonitrile) is a cardiotonic drug, currently under clinical investigation for the treatment of congestive heart failure. Its positive inotropic properties and its strong vasodilative action contribute to a favorable therapeutic effect. Plasma elimination of milrinone is generally by renal excretion of the unchanged drug. Since hemodynamic effects might influence the pharmacokinetics of renally eliminated drugs, we have investigated the plasma elimination of milrinone after different iv bolus doses of the compound in healthy rats. Half-times were 20.6 +/- 5.5 min (0.3 mg/kg milrinone), 17.0 +/- 1.8 min (1.0 mg/kg), 31.4 +/- 4.5 min (3.0 mg/kg), and 95.5 +/- 18.4 min (10.0 mg/kg). Clearances of milrinone showed a positive correlation with doses. Hemodynamic effects were dose dependent and (plasma) concentration dependent, and the maximum decrease in diastolic blood pressure was 54.5 +/- 0.5 mmHg. The half-effective plasma concentration of milrinone was 1.0 +/- 0.2 microM. The maximum increase in heart rate was 15%. We conclude that milrinone plasma elimination in rats is dose dependent, probably resulting from its strong vasodilator properties.

Effect of nitrite on blood pressure in anaesthetized and free-moving rats.

The effect of nitrite on blood pressure and heart rate was studied in anaesthetized (non-telemetric method) and free-moving rats (biotelemetry system). In anaesthetized rats, NaNO2 (10-1000 mumol/kg), infused over 5 min, induced a dose-related decrease in blood pressure. The maximal decrease in mean arterial blood pressure (MAP), caused by 1000 mumol/kg NaNO2 and measured 15 min after infusion was 55.9 +/- 3.2% (n = 3). After NaNO2 infusion, in the plasma, rapid conversion of nitrite into nitrate was observed. However, sodium nitrate (NaNO3, 100 mumol/kg) did not decrease blood pressure and there was no conversion of nitrate into nitrite. Free-moving rats received KNO2 which was added to drinking water (36 mmol/litre) for a period of 3 days. KNO2 decreased the MAP and increased the heart rate during the rat's activity phase at night but not during their resting phase in the day. An equal concentration of potassium (KCl, 36 mmol/litre added to drinking water) for 3 days did not decrease blood pressure. It is concluded that nitrite decreases blood pressure in rats, which probably induces, by renin-angiotensin system activation, hypertrophy of the adrenal zona glomerulosa.

Experimental study of the detrimental effect of dopamine/glucagon combination in d,l-propranolol intoxication.

1. Respiratory and cardiovascular failure are the principle toxic effects of beta-blocker overdose. Respiratory arrest is the primary cause of death in beta-blocker intoxicated rats. 2. The effect of glucagon, dopamine and the combination of glucagon/dopamine on respiratory and cardiovascular function and survival time in beta-blocker overdose was investigated in a model of acute d,l-propranolol (resp. 30 and 15 mg kg-1 h-1 in rat and rabbit) intoxication in spontaneously breathing rats and artificially ventilated rats and rabbits. 3. Glucagon (initial dose of 100 micrograms kg-1 (bolus), followed by 1 microgram kg-1 min-1), dopamine (25 micrograms kg-1 min-1) or the combination of glucagon/dopamine did not improve survival time (ST) in d,l-propranolol intoxicated spontaneously breathing rats and artificially ventilated rats and rabbits, although some haemodynamic variables i.e. heart rate (HR), mean arterial blood pressure (MAP), left ventricular pressure (LVPmax) and the differentiated left ventricular pressure (LVdp/dtmax) temporarily improved. 4. Survival time was considerably reduced in d,l-propranolol intoxicated spontaneously breathing and artificially ventilated rats treated with a combination of glucagon/dopamine, which induced a decrease in PaO2 and pH and an increase in PaCO2 partly due to ventilation/perfusion mismatch. 5. The combination of glucagon/dopamine should be used carefully in the treatment of beta-blocker overdose in man.

Reduced survival after isoprenaline/dopamine in d,l-propranolol intoxicated rats.

1. Respiratory and cardiovascular failure are principle toxic effects of beta-blocker overdose. Respiratory arrest is the primary cause of death in beta-blocker intoxicated rats. 2. The effect of beta-adrenoceptor agonists on respiratory and cardiovascular failure in beta-blocker overdose was investigated in a model of acute d,l-propranolol (30 mg kg-1 h-1) intoxication in spontaneously breathing rats. 3. Neither the aselective, hydrophilic beta-agonist isoprenaline (10, 25, 50 micrograms kg-1 min-1), nor the beta 1-selective, lipophilic beta-agonist flerobuterol (1, 3, 10 microgram kg-1 min-1) and the beta 2-selective, lipophilic beta-agonist clenbuterol (10, 25, 50 micrograms kg-1 min-1) had any beneficial effect on cardiovascular and respiratory variables or survival time in d,l-propranolol intoxicated spontaneously breathing rats. 4. Isoprenaline (10 micrograms kg-1 min-1) had no favourable effect on haemodynamic and respiratory variables in artificially ventilated d,l-propranolol intoxicated rats either. 5. Addition of dopamine to isoprenaline resulted in a significant reduction of survival time, primarily caused by a decreased in mean arterial blood pressure, in artificially ventilated d,l-propranolol intoxicated rats. Addition of glucagon to isoprenaline did not affect survival time. 6. Artificial ventilation is the most important supportive measure in d,l-propranolol intoxication in the rat.

Disturbance of cardiovascular circadian rhythms by pertussis vaccine in freely-moving rats.

Vaccination of young children with diphtheria, tetanus, poliomyelitis and pertussis (DTPoP) vaccine is effective in preventing outbreaks of whooping cough but adverse events sometimes occur. This pilot study shows that in freely-moving rats, multiple treatment with DTPoP (at day 0 and day 5, 6 ml/kg i.v.) increased heart rate (HR) for 5 days after the first treatment and decreased diastolic blood pressure (DBP) for at least 26 days after the first treatment and inhibited the circadian rhythm of HR and DBP for at least 10 days. DTPo vaccine, containing no pertussis vaccine, was free of such effects. Thus, in rats, the pertussis component of DTPoP acts on the cardiovascular system and disturbs its circadian rhythm. The contribution of these findings to clinical adverse effects is as yet unknown and needs further research.

The effect of compensation of acidosis on survival in endotoxin shock.

IP injection of 10 mg E. coli endotoxin in fasted female rats causes 100% mortality while hemodynamic effects are absent. A progressive fall in blood glucose to extremely low values with a concomitant rise in plasma lactate is recorded. Plasma pH falls below 7.00. Infusion of glucose or glucose and insulin does not prolong the survival time. An infusion of 5% NaHCO3 preventing the terminal acidosis has no effect on the survival time and dose not affect the blood glucose and plasma lactate concentrations. Artificial ventilation has no effect on survival time or on blood glucose and plasma lactate concentrations.

Modulation of antigen- and ischemia-induced effects by the platelet-activating factor antagonist WEB-2086 in isolated sensitized rat hearts.

The modulatory role of the platelet-activating factor (PAF) antagonist WEB-2086 (30 microM) on the response to antigen-induced (trinitrophenyl-haptenized ovalbumin) and global ischemia (30 and 60 min)-induced changes in the response to antigen was studied in isolated hearts from actively sensitized rats. In sensitized normoxic hearts, both antigen (0.8 mg) and PAF (100 pmol) induced a short-term increase followed by a long-term decrease in coronary flow (CF). The antigen- but not the PAF-evoked increase in CF was accompanied by a substantial release of histamine. WEB-2086 enhanced the vasodilator effect and abolished the vasoconstrictor effect of 100 pmol of PAF but neither modified the coronary vascular effects of antigen nor the antigen-induced histamine release. Ischemia for 60 min followed by 30 min of reperfusion increased the diastolic left ventricular pressure but a 30-min period of ischemia and reperfusion had no effect on baseline cardiac function. WEB-2086 had no effect on ischemia-induced changes in cardiac function. A 30-min period of global ischemia enhanced the antigen-induced decrease in CF and systolic left ventricular pressure (SLVP). A 60 min period, however, suppressed the antigen-induced effects on CF and SLVP as well as antigen-induced histamine release. WEB-2086 partly protected the heart against the enhanced antigen-induced decrease in CF and SLVP after a 30-min period of global ischemia but no modulatory role of WEB-2086 was observed after 60 min of global ischemia. Our conclusions are that (a) PAF is not involved in rat cardiac anaphylaxis since WEB-2086 was proven to be inactive; (b) cardiac ischemia and cardiac anaphylaxis have interrelated mechanism of action since ischemia changed the anaphylactic response, which indicates that coincidence of these two pathological events could influence the clinical outcome; and (c) PAF is possibly involved in rat cardiac ischemia since WEB-2086 partly protected the heart against the enhanced antigen-induced decrease in CF and SLVP after 30 min of ischemia and reperfusion.

Cardiovascular responses to the stereoisomers of dobutamine in isolated rat hearts 48 hours after acute myocardial infarction.

Effects of acute myocardial infarction (48 h) on cardiovascular responses to (+/-)-, (-)-, and (+)-dobutamine were studied in isolated perfused rat hearts. The effects of the racemate and the isomers on ventricular pressure were measured simultaneously in infarcted left ventricle and noninfarcted right ventricle. Administration of (+/-)-, (-)-, and (+)-dobutamine resulted in dose-dependent increases in inotropic parameters and coronary flow (CF) in both control and in infarcted hearts. As compared with the (+)-isomer, the racemate and the (-)-isomer in both control and infarcted hearts were approximately 1.5 and 15 times weaker with respect to inotropic parameters. For (+/-)-, (-)-, and (+)-dobutamine, there was no significant difference in pD2 values in any of the inotropic measurements between the infarcted group and the corresponding control group. The maximal obtainable responses were significantly lower in the infarcted groups as compared with their corresponding control group. In control hearts, effects of isoproterenol and methoxamine as compared with (+/-)-dobutamine were approximately 2 log units more and 2 log units less in potency, respectively. The inotropic effects of (-)-dobutamine but not those of methoxamine were completely antagonized by propranolol (0.3 microM). Although the results provide evidence for the existence of myocardial alpha 1-adrenoceptors, all forms of dobutamine exerted positive inotropic effects through activation of beta-adrenoceptors both in control and in infarcted in rat hearts.

Positive inotropic effects of milrinone, sulmazole and AR-L100 on isolated normal and infarcted hearts of the rat.

The recent development of new positive inotropic agents, such as milrinone, sulmazole and AR-L100 might provide new insights for the treatment of congestive heart failure. Although it has been reported that milrinone and sulmazole have cardiac phosphodiesterase III inhibiting properties, the pharmacological action of these drugs cannot be explained by these mechanisms alone. Despite the presence of cardiac phosphodiesterase III in the rat, the effect of milrinone on the rat heart has been reported to be small or even absent. In this study we have compared the effects of milrinone and sulmazole with these of AR-L100 on isolated hearts of normal rats and of rats with an experimentally induced myocardial infarction. A perfused heart preparation was used to assess the direct positive inotropic effect of milrinone, sulmazole and AR-L100 as well as their effect on isoprenaline-evoked increase of contractile force. The increase in left ventricular systolic pressure (LVP) in hearts of control animals amounted to 42.0 +/- 3.9 mm Hg, 18.2 +/- 2.4 mm Hg and 8.0 +/- 1.7 mm Hg for AR-L100, milrinone and sulmazole, respectively. The average initial LVP was 70.4 +/- 5.3 mm Hg. In infarcted hearts, the increase in LVP was 25.5 +/- 5.9 mm Hg, 12.6 +/- 2.3 mm Hg and 6.7 +/- 1.2 mm Hg for AR-L100, milrinone and sulmazole, respectively. In infarcted hearts, the average initial LVP was 38.6 +/- 1.6 mm Hg. These data show that these drugs have positive inotropic effects on rat hearts, although the effects of milrinone and AR-L100 on hearts from myocardial infarcted rats are smaller. However, interaction studies with isoprenaline showed a stronger potentiating effect of milrinone and sulmazole in infarcted hearts than in control hearts. Only in this respect sulmazole was more active than milrinone, while AR-L100 had no potentiating effect at all. These results suggest that milrinone and sulmazole are effective agents in conditions where higher levels of circulating catecholamines exist. Therefore, they might be particularly effective in the treatment of congestive heart failure.

Modulation of adrenoceptor-mediated cardiovascular effects by short-term in vivo infusion of isoproterenol in rats.

After a 16-h in vivo infusion period of isoproterenol (400 micrograms/kg/h) from a minipump implanted subcutaneously (s.c.) in rats, we observed an increase in heart weight due to tissue edema. In isolated perfused heart preparations, the EC50s of isoproterenol to induce positive inotropy and increase in coronary flow were increased approximately 7 and 4 times, respectively. Isoproterenol dose-response curves performed in trachea preparations, were shifted to the right by about fivefold as compared with the control group. In the presence of phentolamine, the isoproterenol induced maximal relaxation in the isolated aorta from isoproterenol-pretreated animals was reduced from 46.5 to 9.2% as compared with saline-pretreated rats. In the absence of phentolamine, the epinephrine (EPI) and norepinephrine (NE) cumulative dose-response curves in this preparation were not affected by isoproterenol pretreatment with respect to EC50 and maximal effect. However, in the presence of phentolamine, the contractile response to a supramaximal dose of NE (10 microM) amounted to 30 and 70% in the saline- and isoproterenol-pretreated rats, respectively. In the presence of both phentolamine and propranolol, a similar response of 70% was observed by this supramaximal dose of agonist in the saline-pretreated rats as well. In anesthetized rats, 120 min after removal of the minipumps, sodium nitroprusside induced increase in heart rate (HR) was reduced after isoproterenol pretreatment, whereas for salbutamol the decrease in diastolic blood pressure (DBP) was also reduced. As compared with salbutamol, a marked increase was observed in the ratio of mean arterial blood pressure (MAP) to HR for SNP after isoproterenol pretreatment. The phenylephrine-induced increase in MAP was increased after isoproterenol pretreatment. We conclude that in the pathogenesis of heart failure the beta-adrenoceptor-mediated effects of catecholamines are attenuated and alpha-adrenoceptor-mediated effects become progressively important.

Characterization and modulation of antigen-induced effects in isolated rat heart.

The response to antigen (trinitro-phenyl-haptenized ovalbumin) and the modulatory role of several antiallergic drugs was studied in isolated hearts from actively sensitized rats. Antigen induced a triphasic effect on coronary flow (CF) and left ventricular pressure (LVP) characterized by short-term increase (0-1.5 min = phase 1) and a severe decrease (1.5-7.5 min = phase 2) followed by a less pronounced long-lasting decrease (7.5- greater than 20 min = phase 3). The first phase was accompanied with a substantial release of 5-hydroxytryptamine (5-HT), histamine, and leukotrienes measured in cardiac effluents. The histamine2 (H2)-receptor antagonist cimetidine (60 microM) reversed the antigen-induced increase in CF to a decrease. In contrast, H1-receptor blockade by mepyramine (6 microM) had no effect. Methysergide (10 microM) and ketotifen (0.1 microM) evoked a mild suppression during all three phases. Indomethacin (10 microM) was almost inactive while tolfenamic acid (1 microM) was slightly active in this respect during phase 2. Addition of the 5-lipoxygenase inhibitor AA 861 (1 microM) resulted in complete suppression of the antigen-induced decrease in CF. The leukotriene antagonist FPL 55712 (5 and 50 nM) evoked a dose-dependent suppression with respect to the anaphylactic phases 2 and 3. A similar reduction was obtained with sodium cromoglycate (1 mM). AA 861, FPL 55712, and sodium cromoglycate also suppressed the antigen-induced decrease in LVP. The antigen-induced histamine release was not affected by the aforementioned drugs. Our results provide evidence that H2-receptor blockade during cardiac anaphylaxis enhances coronary constriction and may be detrimental in this condition. On the other hand, leukotriene antagonists and 5-lipoxygenase inhibitors may exert beneficial effects during cardiac anaphylaxis. Further experiments in this area are needed to clarify the precise role of mast cell-generated mediators in cardiac anaphylaxis possibly leading to new therapeutic approaches in this life-threatening disorder.