Cardiac excitation-contraction coupling in the portal hypertensive rat.

Basal contractility and responses to beta-adrenoceptor activation are compromised in hearts from rats with chronic portal vein stenosis. Here we report the effect of partial ligation of the portal vein on myocardial G protein expression, beta-adrenoceptor-G protein coupling, and excitation-contraction coupling (ECC). Contractility (dT/dt) was reduced 30-50% in right and left ventricles, but the rate of relaxation (-dT/dt) was unaffected. Isoproterenol-induced positive inotropism was diminished, but there was no difference in ED(50). The concentration-dependent increase in -dT/dt was unaffected. G(s)alpha and G(i)alpha expression, cholera toxin- and pertussis toxin-induced ADP-ribosylation, and formation of the agonist-receptor-G(s) complex were unaffected by portal vein stenosis. Of the components of ECC examined, the caffeine-sensitive sarcoplasmic reticulum Ca(2+) pool was reduced 35%, although the Ca(2+) uptake and release processes were unchanged; the apparent density of L-type Ca(2+) channels decreased 60% with no change in affinity; the dihydropyridine Ca(2+) channel agonist BAY K 8644 produced relative changes in dT/dt that were similar in both groups, suggesting normal function in the remaining Ca(2+) channels; and Na(+)/Ca(2+) exchange was reduced 50% in the portal vein stenosis group. These data suggest that the effect of portal vein stenosis on the myocardium is the result of alterations to ECC.

Cardiac impairment and nitric oxide synthase activity in the chronic portal vein-stenosed rat.

Decreased cardiac contractility and beta-adrenergic responses have been observed in the chronic portal vein-stenosed (PVS) rat. Because nitric oxide (NO) may be increased in PVS and has been recognized as a negative inotropic agent, we investigated the induction of NO synthase (NOS2) and/or changes in constitutive NOS (NOS3) as factors in the cardiac dysfunction of the PVS rat. Ten to twelve days after portal vein stenosis or sham operation, cardiac function was evaluated in paced left ventricular papillary muscles (LVPM) and right ventricular strips (RV). To determine if NO modulation of contractile function was altered in PVS, we examined the increase in developed tension produced by the effect of Nomega-nitro-L-arginine (L-NNA) on the myocardial force-frequency relationship. Cardiac tissue NOS2 and NOS3 activities were assayed, Western blot analyses of NOS2 and NOS3 expression were performed, and circulating nitrate-nitrite (NOX) levels (an indicator of in vivo NOS activity) were assayed. Basal LVPM and RV contractile indexes were significantly reduced in PVS (30-50%), without a change in the relaxation rate. No between-group differences in the cardiac NOS2 or NOS3 enzymatic activities of PVS and sham-operated (SO) rats were observed. Western blots revealed no cardiac NOS2 expression in either SO or PVS rats. In contrast, NOS3 was expressed in both SO and PVS rats, but there was no quantitative difference in expression between the two groups. Changes in the cardiac force-frequency relationship (staircase effect) after L-NNA were consistent with NOS3 modulation of contractile function in both SO and PVS rats, but there was no between-group difference in the modulation. Circulating NOX concentrations did not differ between SO and PVS rats. In conclusion, protein expression data, enzymatic assays, end-product assays, and functional data indicate that between-group differences in NOS2 and NOS3 activity are not responsible for the cardiac impairment that has been observed in the chronic PVS rat.

Superior mesenteric artery blood flow and indomethacin-induced intestinal injury and inflammation.

Intestinal injury caused by nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with increased mucosal permeability, microvascular injury, focal intravascular thrombus formation, fibrin deposition, and neutrophil infiltration. Ulcerations and adhesions are also prominent feature of this injury. Although NSAID-induced inhibition of prostaglandin formation has been suggested to produce ischemic injury and inflammation, no studies have directly assessed intestinal blood flow in experimental NSAID-induced enteropathy. This study tested the hypothesis that indomethacin-induced small bowel injury and inflammation result from intestinal ischemia. With the use of pulsed Doppler flowmetry, superior mesenteric artery blood flow was continuously monitored in conscious rats after doses of indomethacin known to promote acute and then chronic small bowel inflammation (7.5 mg/kg, 2 sc doses spaced 24 h apart). After 72 h, rats were anesthetized and a section of small bowel was removed for histology and intestinal myeloperoxidase activity measurements. Mean arterial blood pressure was not affected until 32 h after indomethacin, when it decreased 20% (P < 0.05) to P < 0.01). Sustained blood flow changes first occurred at 20 h, when an increase of 15% (P < 0.01) was observed, whereas flow resistance decreased. Flow resistance continued to decrease for the remainder of the 72-h period, and there was an accompanying blood flow increase to +40% (P < 0.05 to P < 0.01). Intestinal ulcers developed in 86% of indomethacin-treated rats. Adhesions, dilation, and thickening of the distal jejunum and proximal ileum were observed in most indomethacin-treated rats. Histological grading of intestinal injury yielded scores of 7.1 +/- 1.2 and zero for indomethacin-treated and vehicle-injected rats, respectively (P < 0.01). Myeloperoxidase activity was greater in indomethacin-treated rats (6.7 +/- 1.9 vs. 1.8 +/- 0.3 U/cm, P < 0.05). These results suggest that indomethacin-induced enteropathy is associated with an increase, not a decrease, in superior mesenteric artery blood flow. Therefore, ischemia dose not appear to be a mechanism by which subcutaneous indomethacin administration produces small intestinal injury and inflammation.

Vagal and sympathetic components of the heart rate reflex in chronic portal vein stenosis.

The effects of portal hypertension and portosystemic shunting on autonomic components of the heart rate (HR) baroreflex and on skeletal muscle blood flow changes were investigated using the chronic portal vein-stenosed rat. Phenylephrine- and sodium nitroprusside-induced changes in mean arterial pressure (MAP), HR, and skeletal muscle conductance (SMC) were assessed before and after muscarinic or beta-adrenoceptor blockade. Stenosed rats had lower MAP than sham-operated rats (90 +/- 3 vs. 81 +/- 2 mmHg, P < 0.05), and their portal pressure was higher (7.4 +/- 0.5 vs. 13.9 +/- 1.0 mmHg, P < 0.005). Phenylephrine pressor responses were reduced in stenosed animals, their associated bradycardic responses were enhanced [-1.912 +/- 0.109 vs. -1.427 +/- 0.148 beats per minute (bpm)/mmHg, P < 0.01], and their SMC responses were diminished. Methylatropine abolished bradycardic responses and enhanced pressor responses without affecting SMC. After propranolol, reflex bradycardic responses in stenosed rats were less than in shams (-0.492 +/- 0.085 vs. -0.738 +/- 0.058 bpm/mmHg, P < 0.01), and their pressor and SMC responses became indistinguishable from shams. In contrast, tachycardic responses to nitroprusside-induced hypotension before propranolol were impaired in stenosed rats (-1.492 +/- 0.114 vs. -2.225 +/- 0.347 bpm/mmHg, P < 0.05), and their SMC responses were reduced. Muscarinic blockade did not affect HR or SMC responses to hypotension in either stenosed or sham rats. beta-Adrenoceptor blockade, however, prevented hypotension-induced tachycardia, enhanced nitroprusside depressor responses, and eliminated the between-group differences in SMC responses. These studies indicate that increased gain of the parasympathetic limb of the cardiac baroreflex was responsible for attenuated pressor responses to phenylephrine in portal vein-stenosed animals and that beta-adrenoceptors contributed to skeletal muscle vascular hyporesponsiveness to phenylephrine in portal-vein stenosed animals. Altered beta-adrenoceptor function also appears to contribute to impaired chronotropic and skeletal muscle conductance responses to hypotension.

Pharmacologic therapy of angina pectoris.

The primary drugs utilized in the treatment of angina pectoris include organic nitrates, beta-adrenoceptor antagonists, Ca2+ antagonists, and the antithrombotic agents aspirin and heparin. Not all of these drugs are useful in every form of angina, and treatment is symptomatic rather than curative. In stable effort angina, beta-blockers, Ca2+ antagonists, and organic nitrates provide relief from angina pain and improve exercise tolerance primarily through their ability to decrease oxygen demand. The antiplatelet action of aspirin may decrease the incidence of myocardial infarction in these patients. Ca2+ channel blockers and organic nitrates are the drugs of choice for variant angina. These vasodilators restore blood flow by relieving the coronary vasospasm that triggers the ischemic episode. In unstable angina, aspirin and heparin reduce the risk of myocardial infarction, and aspirin increases survival. Heparin and nitrates alleviate angina pain, and under some circumstances beta-blockers and Ca2+ antagonists have a role in the relief of pain.

Cardiac beta-adrenoceptor-effector coupling in portal vein-stenosed rats.

Cardiac beta-adrenergic signal transduction was examined in chronic portal vein-stenosed rats. Basal tension and maximum rate of tension development were significantly depressed in left ventricular papillary muscles (0.21 +/- 0.03 N/cm2 and 8.2 +/- 1.7 N.s-1.cm-2, respectively) compared with sham-operated controls (0.51 +/- 0.05 N/cm2 and 19.9 +/- 4.4 N.s-1.cm-2, respectively). The positive inotropic response to isoproterenol was also attenuated. Adenosine 3',5'-cyclic monophosphate formation was decreased significantly when GTP (-41.9%), isoproterenol with GTP (-45.3%), or guanosine 5'-O-(3-thiotriphosphate) (-52.4%) was used to stimulate adenylyl cyclase, but not when Mn2+ or forskolin was used. Beta-Adrenoceptor density (sham operated 24.6 +/- 2.0 fmol/mg; portal vein stenosed 26.4 +/- 2.1 fmol/mg) and the apparent dissociation constant (sham operated 0.26 +/- 0.04 nM; portal vein stenosed 0.29 +/- 0.04 nM) were unaffected. Portal venous hypertension did not alter beta-adrenergic receptor affinity for isoproterenol. However, it was necessary for isoproterenol to occupy three times the number of receptors in papillary muscles from stenosed animals to produce an equal increase in force generation. These data suggest that although portal vein stenosis does not alter cardiac beta-adrenoceptor density or affinity for ligands, transduction of the signal between the receptor and adenylyl cyclase is adversely influenced and may be responsible for the diminished responsiveness of beta-adrenoceptors in the myocardium.

Preservation of pulmonary function by an outer membrane protein F vaccine. A study in rats with chronic pulmonary infection caused by Pseudomonas aeruginosa.

This study investigated the ability of a protein F vaccine to reduce macroscopic evidence of lung damage and preserve pulmonary function in immunized animals in a rat model of chronic pulmonary infection caused by Pseudomonas aeruginosa. Other membrane protein F of P aeruginosa was purified by extraction from polyacrylamide gels of cell envelope proteins of the PAO1 immunotype 7 strain. Rats were immunized intramuscularly with either 25 micrograms of the purified protein F or bovine serum albumin on days 0 and 14 and then challenged on day 28 via intratracheal inoculation of agar beads containing cells of an immunotype 3 clinical isolate of P aeruginosa. Also, included was a noninfected control group which received only sterile agar beads. On day 35, the lungs were excised, pulmonary compliance measured, and the lungs examined macroscopically for the presence and severity of lesions. The protein F-immunized rats had a significant (p < 0.01) reduction in the number of severe pulmonary lesions as compared with bovine serum albumin-immunized rats. Lung compliance (CL) was significantly (p < 0.001) reduced in rats which were immunized with bovine serum albumin (n = 17, CL = 0.12 +/- 0.008), whereas CL of protein F-immunized rats (n = 12, CL = 0.17 +/- 0.006) was similar to that of noninfected control rats (n = 5, CL = 0.15 +/- 0.008). This study demonstrated that a protein F vaccine has the ability to decrease macroscopic lung lesions from infection and preserve pulmonary function in actively immunized rats upon subsequent challenge with P aeruginosa in this model of chronic lung infection.

Cardiac performance in the portal vein-stenosed rat.

Patient studies and experimental models suggest that impaired cardiac function might contribute to the altered pressor responses and compromised reflex responses to hypotension observed in liver disease. To elucidate the role that portosystemic shunting plays in cardiac impairment, right atrial chronotropic and right ventricular inotropic responses to a beta-adrenoceptor agonist were compared using isolated cardiac tissues from sham-operated and chronic portal vein-stenosed rats. Maximal chronotropic responses of sinoatrial tissue from portal vein-stenosed rats to isoproterenol were reduced 18% (P less than 0.05) with no change in sensitivity [mean effective dose (ED50)]. Basal indexes of contraction were diminished 48% (P less than 0.0025) and 60% (P less than 0.0005) for developed tension and change in force over change in time (dF/dt), respectively, in ventricular tissue from portal vein-stenosed animals. In addition, the maximal response for isoproterenol-induced ventricular contraction was smaller in portal hypertensive animals (-44%, P less than 0.0005, and -52%, P less than 0.01 for developed tension and dF/dt, respectively), but no changes in isoproterenol ED50 values were found. These results indicate that portal venous hypertension with extensive portosystemic shunting leads to impairment of basal myocardial contraction and decreased chronotropic and inotropic responsiveness to beta-adrenoceptor agonists.

Role of extracellular Ca2+ in diaphragmatic contraction: effects of ouabain, monensin, and ryanodine.

The effects of zero extracellular Ca2+ on the contractility of rat diaphragmatic strips in vitro were studied in conjunction with various pharmacological agents known to influence the intracellular Ca2+ concentration: the Na+ ionophore, monensin, and the Na(+)-K+ pump inhibitor, ouabain, which enhance [Ca2+]i, caffeine, which induces Ca2+ release from the sarcoplasmic reticulum (SR), and ryanodine, which prevents Ca2+ retention by the SR. The effect of increasing [Ca2+]i on diaphragmatic contraction was assessed by comparing contractions induced by 120 mM K+ in the small muscle strips before and after the addition of ouabain or monensin. Monensin (20 microM) and ouabain (1-100 microM) augmented contractions up to threefold. Treatment of diaphragm strips with 3 nM ryanodine increased baseline tension 360% above the original resting tension but only if the diaphragm was electrically stimulated concurrently; 100 microM ryanodine induced contracture in quiescent tissue. High K+ contractures were of greater magnitude in the presence of ryanodine compared with control, and relaxation time was prolonged by greater than 200%. Ca(2+)-free conditions ameliorated these actions of ryanodine. Ryanodine reduced contractions induced by 10 mM caffeine and nearly abolished them in Ca(2+)-free solution. The data demonstrate that extracellular Ca2+ is important in certain types of contractile responses of the diaphragm and suggest that the processes necessary to utilize extracellular Ca2+ are present in the diaphragm.

Chronic cocaine administration decreases norepinephrine-induced phosphoinositide hydrolysis in rat aorta.

The effect of chronic cocaine administration on norepinephrine stimulated hydrolysis of inositol 1,4,5-trisphosphate from the membrane phosphatidylinositol phosphate pool in isolated rat aorta was investigated. Rats received saline (controls), or 10 or 20 mg/kg cocaine once a day for 15 days. This treatment resulted in a dose-dependent reduction in norepinephrine (0.36 microM) stimulated phosphoinositide hydrolysis. The effect of acute cocaine was determined by adding 30 microM cocaine to the in vitro incubation solution. When aortas were exposed to cocaine and norepinephrine simultaneously, in vitro, inositol phosphate formation doubled. By itself, cocaine did not affect phosphoinositide hydrolysis. Contraction of aortic helical strips by norepinephrine decreased in tissues from rats chronically treated with 20 mg/kg cocaine. In vitro cocaine shifted the norepinephrine concentration/response curve to the left and increased the maximum response. Neither acute nor chronic cocaine treatment affected prazosin's apparent dissociation constant, suggesting that cocaine did not affect receptor affinity. These data suggest that chronic, but not acute cocaine administration may interfere with pharmacomechanical coupling in rat aorta.

Effects of diaphragmatic fatigue on phosphoinositide hydrolysis.

We evaluated the effects of diaphragmatic fatigue on muscle phosphatidylinositol phosphate (PIP) metabolism. Results revealed that the total PIP pool was 76% greater in fatigued rat diaphragms compared to controls, which suggests that fatigue was associated with inhibition of sarcolemmal membrane bound PIP hydrolysis.

The bronchodilator terbutaline enhances digitalis-induced arrhythmia.

The hypothesis that beta 2-sympathomimetics augment digitalis-induced arrhythmias and antagonize its positive inotropic action was tested in isolated, electrically driven guinea-pig left atria. Alone, 0.3 mM terbutaline enhanced myocardial force generation but did not induce dysrhythmia. Terbutaline shortened the time to the onset of 3 microM ouabain-induced arrhythmia by approximately 75% from 19.7 +/- 3.2 minutes to 5.7 +/- 1.2 minutes (p less than 0.005). The enhancement of arrhythmias appeared to be the result of triggering ouabain-induced delayed afterdepolarizations (DAD) into overt arrhythmia. The effect of terbutaline was antagonized by blocking cardiac beta-adrenoceptors with propranolol. Terbutaline did not affect the ability of ouabain to increase myocardial contractility.

Effect of amiloride on diaphragmatic contractility: evidence of a role for Na(+)-Ca2+ exchange.

Extracellular Ca2+ has been shown to be important for the normal function of the diaphragm. In this study we have examined the potential importance of Na(+)-Ca2+ exchange as a mechanism for Ca2+ influx during the contractile process by studying the effect of inhibition or stimulation of Na(+)-Ca2+ exchange. Blockade of Na(+)-Ca2+ exchange with amiloride attenuated the twitch response, altered the force-frequency response curve, and enhanced the development of fatigue. The effect of amiloride could be partially reversed by increasing the extracellular Ca2+ concentration. The ability of amiloride to decrease force was associated with decreased Ca2+ uptake by the diaphragm. Enhancing intracellular Na(+)-extracellular Ca2+ exchange by inhibiting the Na(+)-K+ pump significantly decreased the rate of the development of muscle fatigue (89%). The maximal inhibition of diaphragmatic force produced by the amiloride analogue benzamil, which possesses 10-fold greater selectivity for Na(+)-Ca2+ exchange, was not significantly different from that produced by amiloride (76.2 +/- 1.1%), with a concentration that decreased maximum force by 50% equal to 46 microM compared with 460 microM for amiloride. Both agents slowed the maximal rate of relaxation up to 90%. Benzamil elevated resting tension during continuous stimulation of the diaphragm at 0.15 Hz. The results suggest that Na(+)-Ca2+ exchange may have a role in the normal function of the diaphragm.

Diaphragmatic fatigue is associated with decreased inositol 1,4,5-trisphosphate formation.

The ability of the rat diaphragm to produce inositol 1,4,5-trisphosphate (InsP3) in response to a maximal contractile stimulus was determine in vitro in both fatigued and nonfatigued diaphragms. InsP3 was produced during a maximal contraction of the diaphragm. After inducing fatigue, there was a significant reduction in the production of InsP3 compared with that in nonfatigued muscle. The maximal force generated by the diaphragm was also decreased after fatigue. A significant positive linear correlation was found between the force developed by the diaphragm and the amount of InsP3 liberated.

Theophylline affects the inotropic status of guinea-pig left atria by actions on the sarcolemma and sarcoplasmic reticulum.

Theophylline (0.1, 0.3 mM) produced a positive inotropism which was maximum by 15 min but was partially or completely absent by 45 min. The mechanism for this response was investigated using post-rest potentiation and positive staircase, phenomenon associated with the sarcoplasmic reticulum and sarcolemma, respectively. Staircase was enhanced at 15 min, but not after 45 min. Post-rest potentiation was attenuated by theophylline. The data suggest that theophylline's effect on cardiac contractility results from opposing actions on the sarcolemma and sarcoplasmic reticulum.

Comparison of digitoxin and its major glucuronidated metabolite: inhibition of Na-K-ATPase and reactivity with the radioimmunoassay.

The metabolism of digitoxin is known to occur through several major pathways including oxidation and glucuronidation. Several studies have compared the behavior of the various unconjugated metabolites with respect to reactivity toward Na-K-ATPase and toward the radioimmunoassay (RIA). Other studies with conjugated products synthesized chemically have also been performed. However, the activity of the conjugated products produced in vivo has not been reported and these metabolites are generally assumed to be inactive. In the present studies we have prepared and purified the glucuronide conjugate of digitoxigenin monodigitoxoside formed by rat liver microsomes and determined the activity of this metabolite as measured by inhibition of Na-K-ATPase and by the RIA. The concentration of the conjugated product needed to cause a fifty per cent inhibition of Na-K-ATPase was 5.40 microM compared to 0.68 for digitoxin and 0.08 for digitoxigenin monodigitoxoside. However, the conjugated product had a two-fold greater affinity for the antibody in the RIA procedure than did either digitoxin or digitoxigenin monodigitoxoside. Although these data cannot be extrapolated to the effects of these drugs on cardiac contractility, the results suggest that the contribution of the glucuronide conjugate to the therapeutic or toxic effect of digitoxin may be minimal. This metabolite may, however, lead to inaccurate estimation of blood levels by the RIA.

Interaction between theophylline and ouabain in the rabbit heart: effect on (Na+ + K+)-ATPase.

In electrically stimulated rabbit ventricular strips, theophylline (0.3-30 mM) antagonized the increased contractility produced by ouabain (0.8 microM). Initial velocity of specific [3H]ouabain binding to homogenates prepared from the muscle strips was used to determine the fraction of binding sites occupied by ouabain. Theophylline decreased the binding of ouabain to (Na+ + K+)-ATPase. It is concluded that the effect of theophylline on ouabain-induced positive inotropism may be mediated by decreased ouabain binding to (Na+ + K+)-ATPase.

Negative inotropic effect of the combination of theophylline and ouabain in rabbit right ventricle: relation to elevated baseline tension.

The effects of the combined administration of theophylline and ouabain were examined in isolated right ventricular strips from the rabbit heart. Separately, each drug produced positive inotropism. If ouabain was added 10 minutes after theophylline, a decrease in dF/dt was observed. The presence of theophylline augmented the increase in baseline tension induced by ouabain, although theophylline, by itself, did not augment baseline tension at the concentrations tested. There was a significant correlation between the decrease in dF/dt and the rise in baseline tension. Theophylline did not enhance the ability of ouabain to induce arrhythmia. The actions of caffeine, theobromine and digoxin were also examined and gave similar results.

Histamine receptors in the myenteric plexus-longitudinal muscle of the guinea-pig ileum: H1- and H2-receptor-mediated potentiation of the contractile response to electrical stimulation.

The effect of histamine on the contractile response to low frequency-electrical field stimulation in the myenteric plexus-longitudinal muscle preparation of the guinea-pig ileum was investigated. By blocking the direct increase in smooth muscle tone caused by histamine with low concentrations of pyrilamine (10(-9)--5 x 10(-8) M) a dose-dependent, histamine-induced potentiation of the twitch response to electrical stimulation was observed. Blocking the direct actions of histamine with concentrations of pyrilamine greater than 10(-7) M resulted in a biphasic histamine dose-response curve: lower histamine concentrations produced a dose-dependent decrease of the twitch response; higher concentrations produced a potentiation. The potentiating effect of histamine was inhibited by high concentrations of H2-receptor antagonists. Tiotidine (ICI 125, 211) had a pA2 of 5.25, 100 times greater than its pA2 in isolated guinea-pig atria. Blockade of the actions of the H2-receptor agonists dimaprit and tetrahydrozoline also required greater antagonist concentrations. The selective H1-receptor agonist, 2-(2-thiazolyl)-ethylamine, also enhanced the response to electrical stimulation. The potentiating effect of histamine could be blocked by hexamethonium (10(-7)--10(-5) M) but not by atropine. Atropine (10(-9)--10(-8) M) did prevent the decrease in the contraction amplitude induced by histamine in the presence of 10(-7) M pyrilamine. The purinergic antagonist theophylline, adrenergic antagonists or depletion of endogenous catecholamines were without effect. Tetrodotoxin (10(-6) M) inhibited the augmentation induced by histamine. Our results demonstrate that histamine potentiates the acetylcholine-mediated contractile response to electrical field stimulation of guniea-pig ileum via H1- and what may be an H2-receptor subtype.

Cardiac and pulmonary anaphylaxis in guinea pigs and rabbits induced by glycoprotein isolated from tobacco leaves and cigarette smoke condensate.

Cigarette smoking is a major risk factor for heart attack. The pathologic mechanisms responsible for this association are obscure. It has been reported that approximately one-third of human volunteers, smokers and nonsmokers, exhibit immediate cutaneous hypersensitivity to a glycoprotein antigen (TGP) purified from cured tobacco leaves and present in cigarette smoke. It is also known that the heart is a primary target organ for anaphylactic reaction in many animals, including primates. In experiments described herein anaphylaxis was induced in the isolated hearts and lungs of rabbits and guinea pigs previously sensitized by immunization with TGP and challenged with TGP isolated from either tobacco leaf or cigarette smoke condensate. Cardiac anaphylaxis was characterized by sinus tachycardia, decreased contractility, decreased coronary perfusion accompanied by hypoxic electrocardiographic changes, and a variety of rhythm disturbances, including idioventricular tachyarrhythmias. These observations suggest that allergic reactions to tobacco constituents may initiate cardiac arrhythmia and sudden death in some smokers and may, in part, underly the association between cigarette smoking and heart attack.