Sex differences to myocardial ischemia and beta-adrenergic receptor blockade in conscious rats

We recently documented sex differences in the susceptibility to reperfusion-induced sustained ventricular tachycardia and beta-adrenergic receptor blockade in conscious rats. However, the effect of sex on ischemia-induced ventricular arrhythmias and beta-adrenergic receptor blockade is under-investigated. Therefore, we tested the hypothesis that gonadal hormones influence the ventricular arrhythmia threshold (VAT) induced by coronary artery occlusion as well as the response to beta-adrenergic receptor blockade. The VAT was defined as the time from coronary occlusion to sustained ventricular tachycardia resulting in a reduction in arterial pressure. Male and female intact and gonadectomized (GnX) rats were instrumented with a radiotelemetry device for recording arterial pressure, temperature, and ECG, as well as a Doppler ultrasonic flow probe to measure cardiac output and a snare around the left main coronary artery. The VAT was determined in conscious rats by pulling on the snare. The VAT was significantly longer in intact females (5.56 +/- 0.19) vs. intact males (4.31 +/- 0.14 min). This sex difference was abolished by GnX. Specifically, GnX decreased the VAT in females (4.55 +/- 0.22) and increased the VAT in males (5.14 +/- 0.30 min). Thus male sex hormones increase and female sex hormones decrease the susceptibility to ischemia-induced sustained ventricular tachycardia. beta-Adrenergic receptor blockade increased the VAT in intact males and GnX females only. Thus gonadal hormones influence the response to beta-adrenergic receptor blockade. Uncovering major differences between males and females in the pathophysiology of the cardiovascular system may result in sex-specific optimization of patient treatments.     

Diabetes-like action of intermittent fasting on sarcoplasmic reticulum Ca2+-pump ATPase and myosin isoenzymes can be prevented by sucrose

Experimental diabetes results in a reduction of the sarcoplasmic reticulum (SR) Ca2+-stimulated ATPase activity and a redirection of myosin isoenzymes from V1 to V3. Similar, but less pronounced, changes were induced by subjecting rats to intermittent fasting for 6 weeks. Low amounts of sucrose (0.8%) in the drinking water prevented the subcellular changes in fasted rats; however, sucrose neither affected the levels of plasma thyroid hormones nor normalized the reduced body weight. Plasma glucose was lowered without any changes in plasma insulin in the fasted rats receiving sucrose; this suggested an enhanced peripheral glucose utilization. Thus, the signals in the diabetic heart leading to changes in SR and myosin can be mimicked by intermittent fasting and seem to be linked to a shift in fuel utilization by the myocytes.     

Modulation of myosin isoenzyme populations and activities of monoamine oxidase and phenylethanolamine-N-methyltransferase in pressure loaded and normal rat heart by swimming exercise and stress arising from electrostimulation in pairs

The question of whether the effects of physical exercise on the heart of 15-weeks normotensive and hypertensive rats can be modulated by additional stressors was studied. Intermittent swimming (33-35 degrees C water, maximum 2 X 1.5 h/day, 2-6 weeks) was employed as a model of exercise. Electrostimulation of rats in pairs (maximum 2 X 1.5 h/day, 6 weeks) served as a model leading predominantly to stress. When the above procedures were combined, electrostimulation in pairs was performed in one session and was followed up by swimming. The myosin isoenzyme population was used as a marker of changes in contractile performance of myofibrils. Activities of the catecholamine-degrading enzyme monoamine oxidase (MAO) and the adrenaline-synthesizing enzyme phenylethanolamine-N-methyltransferase (PNMT) served to monitor chronic alterations of catecholamine turnover in myocardium. Redistribution in favour of VM-1 (ventricular myosin isoenzyme 1) occurred as early as 2 weeks after the onset of intermittent swimming and was observed under several experimental conditions. The redirection of genetic expression of the isoenzymes was not linked to the presence of an increased ratio of right to left ventricular weight, most probably arising from intermittent hypoxia during drownproofing. The myosin isoenzyme population of swimming spontaneously hypertensive rats (SHR) resembled that of sedentary Wistar rats. The enzyme activities of MAO and PNMT were both significantly reduced following 6 weeks intermittent swimming in Wistar rats and SHR. This can most probably be attributed to the exercise component of swimming which, on average, led to reduced catecholamine turnover in heart. Electrostimulation of rats in pairs for 6 weeks, which resulted in aggressivity and aggressions, did not alter the myosin isoenzyme population in Wistar rats; in SHR, it further augmented the proportion of VM-3 (ventricular myosin isoenzyme 3), which had already increased in the sedentary state. Furthermore, electrostimulation increased PNMT activity, but did not affect MAO activity. Electrostimulation in pairs, followed by swimming, altered the myosin isoenzyme population in the same way as did swimming alone. However, the activities of PNMT and MAO seemed to be governed by the routine involving stress and not by the exercise routine. This demonstrates that stressors supplementing exercise can decisively modify or even prevent reactions of the organism in response to exercise.(ABSTRACT TRUNCATED AT 400 WORDS)     

Influence of diet and carnitine palmitoyltransferase I inhibition on myosin and sarcoplasmic reticulum.

To examine the role of metabolic signals for ventricular myosin expression and activity of the sarcoplasmic reticulum Ca2+ pump, Wistar rats were treated for 7-8 wk with 5 or 50 mg/kg etomoxir, which inhibits fatty acid utilization. The proportion of myosin V1 was increased (P less than 0.05) with 50 mg/kg etomoxir (75 +/- 5% vs. 62 +/- 6% of control rats), whereas both doses increased the rate of Ca2+ uptake. A carbohydrate-rich fat-free diet or 8% sucrose drinking solutions, however, had no effect on myosin and sarcoplasmic reticulum. When rats were fed diets with an increased content (10 or 20%) of sunflower oil, the calorie intake and myosin V1 increased (56 +/- 8 or 64 +/- 8% vs. 44 +/- 6% of control rats). Isocaloric 10% fat diets of varying fatty acid composition (coconut fat, olive oil, or mackerel oil) also induced a higher calorie intake and increased V1 (64 +/- 6, 60 +/- 9, or 65 +/- 8% for the respective oils vs. 44 +/- 6% of control rats) but did not significantly increase rate of Ca2+ uptake. We concluded that calorie-rich diets changed the myosin expression not by affecting the ratio of fatty acid to glucose utilization but via the increased calorie intake.     

Modification of subcellular organelles in pressure-overloaded heart by etomoxir, a carnitine palmitoyltransferase I inhibitor.

To examine the signals regulating cardiac growth and molecular structure of subcellular organelles, cardiac hypertrophy was induced in rats by constriction of the abdominal aorta for 12-13 wk or by treatment with a carnitine palmitoyltransferase I inhibitor, etomoxir (12-15 mg/kg body wt) for 12-13 wk. In contrast to pressure overload, etomoxir redistributed the myosin isozyme population from V3 to V1 and increased the sarcoplasmic reticulum (SR) Ca(2+)-stimulated ATPase activity. When rats with pressure-overloaded hearts were treated with etomoxir, the cardiac hypertrophy was increased whereas the shift in myosin isozymes from V1 to V3 was prevented and the depression in SR Ca(2+)-stimulated ATPase activity was reversed. Plasma thyroid hormone and insulin concentrations were not altered but triglyceride concentrations were reduced in etomoxir-treated rats with pressure overload. The data demonstrate a dissociation between cardiac muscle growth and changes in subcellular organelles and indicate that a shift in myocardial substrate utilization may represent an important signal for molecular remodeling of the heart.     

Regulation of myosin isoenzyme composition in fetal and neonatal rat ventricle by endogenous thyroid hormones

The effect of thyroid hormone on the expression of ventricular isomyosins V1, V2, and V3 was studied in fetal and neonatal rats. Between 15 and 21 days gestation, V3 accounts for 80-90% of fetal ventricular myosin. After birth, there is a rapid transition from the fetal V3 isotype to an equal mixture of V1 and V3 at 3 days, and to 100% V1 at 3 weeks of age. The endogenous serum levels of thyroxine (T4) and triiodothyronine (T3) increase from trace amounts in the fetus to adult levels at 2-3 weeks of age; this increase correlates with the maximal expression of V1 during the same period. Expression of the V1 isomyosin can be eliminated in the neonatal rat if endogenous thyroid hormone synthesis is suppressed by propylthiouracil (PTU) treatment. In the PTU-treated rats, V3 is the only isomyosin synthesized between 1 and 30 days of age. In fetal ventricle, the amount of V1 is also decreased but not completely eliminated by PTU treatment. Conversely, the relative amount of V1 can be increased in the fetal ventricle by increasing the fetal serum concentrations of T4 and T3 to adult physiological levels. In these fetal ventricles, V1 represents greater than 85% of the total myosin. Likewise, the expression and accumulation of V1 could be stimulated in ventricles of PTU-treated, 12-day-old rats by administration of pharmacological or physiological doses of T3. Within 4 to 8 h after an initial dose of T3, V1 accumulates to 5-10% of the ventricular myosin, and by 72 h comprises 60-80% of the myosin. These results indicate that endogenous thyroid hormone induces the synthesis of ventricular heavy chain alpha, which as a dimer forms the V1 isomyosin, or plays a permissive role for the continued synthesis of heavy chain alpha in ventricles of fetal and neonatal rats.     

Thyroid hormone regulation of beta-adrenergic receptor number.

The effects of exogenous thyroid hormones (thyroxine and triiodothyronine) on beta-adrenergic receptors in the rat myocardium were investigated. The potent beta-adrenergic antagonist, (-)-[3H]dihydroalprenolol, was used to directly estimate the number and affinity of beta-adrenergic receptors in rat heart membranes from control and hyperthyroid rats. Cardiac membranes from hyperthyroid rats contained 196 +/- 7 fmol of (-)-[3H]dihydroalprenolol binding sites/mg of protein which was significantly (p less than 0.005) greater than the number of binding sites (89 +/- 5 fmol/mg of protein) present in control membranes. The equilibrium dissociation constant (KD) for the interaction of receptors with dihydroalprenolol was the same (2 to 15 nM) in membranes from control and hyperthyroid rats. Similarly, there was no significant difference between the control and hyperthyroid membranes in the affinity of the beta-adrenergic receptor binding sites for the beta-adrenergic agonist isoproterenol. The results of this study demonstrate that thyroid hormones can regulate the number of cardiac beta-adrenergic receptors. The increased numbers of receptors may be responsible, at least in part, for the enhanced catecholamine sensitivity of beta-adrenergic-coupled cardiac responses in the hyperthyroid state.     

Ontogenetic transition of cardiac myosin heavy chain isoforms in rat ventricle: effects of fetal exposure to beta-adrenergic agonists or antagonists.

Cardiac myosin heavy chain (MHC) expression undergoes an ontogenetic transition from beta to alpha MHC isoforms. Although thyroid hormone plays a role in this change, the timing of the events suggests the participation of other factors. Using a new, denaturing SDS-PAGE procedure that cleanly resolves the beta and alpha heavy chains, we have assessed the role of beta-adrenergic stimulation on this transition in fetal and neonatal rat hearts. In control animals at embryonic day 20, less than 15% of the MHC was the alpha-form, and the proportion increased to approximately 35% by postnatal day 1 and to 80% by postnatal day 8. Although catecholamine levels rise abruptly at birth, and cyclic AMP levels increase the expression of alpha-MHC in vitro, neither premature beta-adrenergic stimulation (maternal treatment with terbutaline on embryonic days 17, 18 and 19) nor continuous prenatal blockade of beta-receptors (maternal propranolol infusions from embryonic day 7 onward) influenced the developmental profile. Because beta-receptors in fetal and neonatal heart are functionally linked to adenylate cyclase, and cyclic AMP has been shown to promote the expression of alpha-MHC, the lack of effect of terbutaline or propranolol suggests that activation of adenylate cyclase through fetal cardiac beta-receptors is not sufficient to mediate the switchover without participation of other factors, such as thyroid or steroid hormones, or hypoxia.     

Effect of graded doses of tri-iodothyronine on ventricular myosin ATPase activity and isomyosin profile in young and old rats.

Ventricular myosin ATPase activity, V1 isomyosin content and serum T3 (tri-iodothyronine) values decrease with age in male Fischer 344 rats. To determine if the age decrement in ATPase activity and V1 isomyosin content are caused by decreased T3 levels or an age-related decrease in V1 isomyosin induction by T3, 3-, 12- and 24-month-old male Fischer 344 rats were given constant T3 infusions by osmotic minipump. Rats at all ages were given 0.75, 5 and 15 micrograms(/100 g per 24 h) doses of T3, whereas 12- and 24-month-old rats were given an additional 0.4 microgram dose. In control rats, T3 levels decreased from 97 +/- 2.7 at 3 months to 75 +/- 4.7 ng/100 ml at 24 months. Likewise, Ca2+-activated myosin ATPase activity decreased from 1.04 +/- 0.05 to 0.68 +/- 0.05 mumol of Pi/min per mg of protein, and the relative proportion of V1 of isomyosin decreased from 90 +/- 4.0 to 26 +/- 2.0%. The lowest (0.4 microgram) T3 dose, which was sufficient to restore T3 levels in 24-month-old animals to 3-month control values, abolished the age decrement in myosin ATPase activity and markedly increased the proportion of V1 isomyosin present in the ventricle. These findings indicate that the senescent ventricle responds readily to small doses of T3 and strongly suggest that the age decrement in serum T3 levels is sufficient to contribute to the age-related decrease in myosin ATPase activity and V1 isomyosin content. Since these parameters correlate with ventricular contractility, the age decrement in T3 levels may also contribute to the decreased ventricular contractility and cardiac output observed in senescent rats.     

Thyroxine induces transitions in red muscle kinetics and steady swimming kinematics in rainbow trout (Oncorhynchus mykiss)

During normal development, rainbow trout undergo a shift in red muscle contraction kinetics and swimming kinematics. Young trout parr have faster muscle kinetics and faster tailbeat frequency during swimming than older, larger juvenile trout. In this study, the thyroid hormone thyroxine (T(4)) was used to induce these changes in trout parr. This allowed a comparison of swimming kinematics, through the use of video analysis and electromyography, and red muscle contractile properties, through the use of in vitro muscle preparations, between natural parr and same-sized induced juveniles. The red muscle of natural parr has faster contractile properties than induced juveniles, including faster twitch time and a faster maximum shortening velocity (V(max)). Further, natural parr swim with faster tailbeat frequencies than induced juveniles. The results suggest that the natural shift in red muscle contraction kinetics observed during parr-smolt transfomation in trout directly affects swimming behavior in these fish. Also, thyroid hormones appear to induce a shift towards slower isoforms of the muscle protein myosin heavy chain (MHC), a result distinct from work on rats where thyroid hormones induce shifts towards faster forms of MHC. J. Exp. Zool. 290:115-124, 2001.     

Interstitial fluid pressure, composition of interstitium, and interstitial exclusion of albumin in hypothyroid rats

Lack of thyroid hormones may affect the composition and structure of the interstitium. Hypothyrosis was induced in rats by thyroidectomy 4-12 wk before the experiments. In hypothyroid rats (n = 16), interstitial fluid pressure measured with micropipettes in hindlimb skin and muscle averaged +0.1 +/- 0.2 and +0.5 +/- 0.2 mmHg, respectively, with corresponding pressures in control rats (n = 16) of -1.5 +/- 0.1 (P < 0.001) and -0.8 +/- 0.1 mmHg (P < 0.001). Interstitial fluid volume, measured as the difference between the distribution volumes of (51)Cr-EDTA and (125)I-labeled BSA, was similar or lower in skin and higher in hypothyroid muscle. Total protein and albumin concentration in plasma and interstitial fluid (isolated from implanted wicks) was lower in hypothyroid compared with control rats. Hyaluronan content (n = 9) in rat hindlimb skin was 2.05 +/- 0.15 and 1.92 +/- 0.09 mg/g dry wt (P > 0.05) in hypothyroid and control rats, respectively, with corresponding content in hindlimb skeletal muscle of 0.35 +/- 0.07 and 0.23 +/- 0. 01 mg/g dry wt (P < 0.01). Interstitial exclusion of albumin in skin and muscle was measured after (125)I-labeled rat serum albumin infusion for 120-168 h with an implanted osmotic pump. Relative excluded volume for albumin (V(e)/V(i)) was calculated as 1 - V(a)/V(i), and averaged 28 and 28% in hindlimb muscle (P > 0.05), 44 and 45% in hindlimb skin (P > 0.05), and 19 and 32% in back skin (P < 0.05) in hypothyroid and control rats, respectively. Albumin mass was higher in back skin in spite of a lower interstitial fluid albumin concentration, a finding explained by a reduced V(e)/V(i) in back skin in hypothyroid rats. These experiments suggest that lack of thyroid hormones in rats changes the interstitial matrix again leading to reduced interstitial compliance and changes in the transcapillary fluid balance.     

Effect of a myocardial volume overload on lactate transport in skeletal muscle sarcolemmal vesicles

This study sought to determine the effect of a myocardial volume overload (MVO) on sarcolemmal (SL) lactate (La(-)) transport and the aerobic profile of skeletal muscle. SL vesicles were obtained from female rats 10 wk after either a MVO was induced by creation of an infrarenal fistula (n = 10), or sham surgeries were performed (n = 11). Influx of (14)C-labeled L(+)-La(-) was measured at various unlabeled La(-) concentrations under zero-trans conditions. La(-) transport kinetics were determined using a Michaelis-Menten equation with an added linear component to discriminate between carrier-mediated and diffusional transport. Although heart and lung weights were significantly increased (P < 0.0001) in the MVO group, left ventricular function was only modestly altered (P < 0.05). A significant reduction in type I myosin heavy chain (MHC) in the soleus and a strong trend (P = 0.06) for a reduced type IIx MHC in the plantaris were observed in MVO rats, but no differences in citrate synthase activity or monocarboxylate transporter proteins (MCT)-1 expression were noted in any muscle. Carrier-mediated La(-) influx into SL vesicles was similar between sham and MVO (K(m) = 12 +/- 1 and 18 +/- 3 mM; apparent V(max) = 772 +/- 99 and 827 +/- 80 nmol. mg(-1). min(-1), respectively). Total influx at 100 mM was lower in MVO, and this was due to a 30% reduction in membrane diffusion. In conclusion, a 10-wk MVO did not alter MCT-mediated La(-) transport or protein expression but was associated with modest changes in myofibrillar proteins and impaired SL diffusive properties.     

Modification of myosin isozymes and SR Ca2+-pump ATPase of the diabetic rat heart by lipid-lowering interventions

To define metabolic influences on cardiac myosin expression and sarcoplasmic reticulum (SR) Ca²⁺-stimulated ATPase streptozotocin-diabetic rats were treated for 9–10 wk with etomoxir, an inhibitor of carnitine palmitoyl transferase I (CPT-1) and fatty acid synthesis, or an antilipolytic drug, acipimox. Etomoxir reduced myosin V₃ of diabetic rats but did not normalize it. However, the high serum triglyceride, free-fatty acid and cholesterol concentrations in diabetic animals were greatly reduced. After bypassing the CPT-1 inhibition with a medium-chain fatty acid (miglyol) diet, the V₃ contents and serum lipids were still reduced in the etomoxir-treated diabetic rats; V₃ was also reduced in diabetic rats fed miglyol or treated with acipimox. Since low serum insulin or triiodothyronine concentrations in diabetic rats were not improved by these interventions but changes in V₃ were correlated with those in triglyceride, free-fatty acid and cholesterol concentrations, it is likely that myosin may be influenced by some metabolic factors. To assess the role of adrenergic influences, diabetic rats (7–8 wk) were treated with an antisympathotonic drug, moxonidine, a -adrenoceptor blocking drug, propranolol, and a bradycardic drug, tedisamil. Myosin V₃ was not reduced significantly in moxonidine-treated or propranolol-treated rats in comparison to untreated diabetic rats. Serum thyroid hormones and insulin were not altered, whereas triglycerides were reduced but not significantly by these antiadrenergic agents. Lowering serum lipids in diabetic rats by treatment with etomoxir, miglyol and acipimox increased the depressed SR Ca²⁺-stimulated ATPase activity. On the other hand, in diabetic rats treated with moxonidine, propranolol or tedisamil, the ATPase activity was not increased significantly. These results suggest that normalization of blood lipids is important for improving subcellular organelle function in diabetic hearts with impaired glucose utilization.     

Effect of beta-adrenergic drugs on LH, FSH, and growth hormone (GH) secretion in conscious, ovariectomized rats

The effects of third ventricular (3V) injection of the beta-adrenergic antagonist, propranolol (PROPR), a selective beta 1-antagonist, metoprolol (MET), a selective beta 2-antagonist, IPS 339, and a beta-adrenergic agonist (-) isoproterenol (ISOPR), on plasma concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), and growth hormone (GH) were studied in conscious, ovariectomized (OVX) rats. Samples were removed from unrestrained rats which had been previously implanted with atrial and 3V cannulae, and plasma hormone levels were determined by radioimmunoassay (RIA). Intraventricular injection of PROPR (30 micrograms), MET (40 micrograms), or IPS 339 (20 micrograms) induced a gradual elevation in plasma GH concentrations, whereas ISOPR (30 micrograms) reduced plasma GH. ISOPR (30 micrograms) brought about a decrease in plasma LH concentrations, but PROPR, MET and IPS 339 had no effect on LH levels. PROPR (30 micrograms) increased plasma FSH concentrations, but there was no significant effect of MET, IPS 339 or ISOPR on FSH secretion. The results indicate that the beta-adrenergic system can inhibit the release of GH, LH, and FSH. This system appears to have a tonic inhibitory effect on GH and FSH but not LH release in the OVX rat.     

Isomyosin distributions in rodent muscles: effects of altered thyroid state

In this study we examined the effects of 6-8 wk of thyroid hormone manipulation on striated muscle isomyosin expression in adult female rats. Animals were randomly assigned to one of three groups: 1) euthyroid controls, 2) thyroid deficient (propylthiouracil treated), and 3) hyperthyroid (triiodothyronine treated). Thyroid deficiency resulted in a marked increase in the low-adenosinetriphosphatase V3 isoform by 20- and 49-fold in the left and right ventricle, respectively. Conversely, hyperthyroidism induced a modest (3-11%) but significant increase in the high-adenosinetriphosphatase V1 isoform in both ventricles. The thyroid-deficient rats exhibited significant increases in slow myosin in both soleus (8%) and red gastrocnemius (24%), with concomitant reductions in intermediate myosin in both muscles. Interestingly, while the slow-myosin isoform was decreased in both the soleus (-19%) and the red gastrocnemius (-43%) of the hyperthyroid group, the intermediate-myosin isoform was affected differentially in the two muscles, with a fivefold increase in the former vs. a 16% decrease in the latter. Furthermore, hyperthyroidism increased the fast myosins in the red gastrocnemius while exerting no effect on the same isoforms in the white gastrocnemius. Collectively these data suggest both different specificity and sensitivity among the myosin genes of different striated muscle types in response to thyroid hormone.     

Gender difference in baroreflex-mediated bradycardia in young rats: role of cardiac sympathetic and parasympathetic components.

In a previous clinical study we have demonstrated a significantly lower baroreflex-mediated bradycardic response in young women compared with men. The present study determined whether sexual dimorphism in baroreflex sensitivity in young rats also covers the reflex tachycardic response. The study was then extended to test the hypothesis that an attenuated cardiac cholinergic component of the baroreflex heart rate response in females may account for the gender difference. Baroreflex sensitivity (BRS) was expressed as the regression coefficient of the reciprocal relationship between evoked changes in blood pressure and heart rate. BRS measured in conscious rats with phenylephrine (BRS(PE)) and nitroprusside (BRS(NP)) represented the reflex bradycardic and tachycardic responses, respectively. Female rats exhibited significantly lower BRS(PE) compared with male rats (-1.53+/-0.1 vs. -2.36+/-0.13 beats x min(-1) x mmHg(-1); p < 0.05) but similar BRS(NP) (-2.60+/-0.20 vs. -2.29+/-0.17 beats x min(-1) x mmHg(-1)). Blockade of cardiac muscarinic receptors with atropine methyl bromide elicited greater attenuation of BRS(PE) in male than in female rats (72+/-4.6 vs. 53+/-6.7% inhibition; p < 0.01) and abolished the gender difference. In male rats cardiac muscarinic blockade attenuated BRS(PE) significantly more than did cardiac beta-adrenergic receptor blockade with propranolol (72+/-4.6 vs. 43+/-2.7; p < 0.01), which suggests greater dependence of BRS(PE) on the parasympathetic component. In females, muscarinic and beta-adrenergic blockade elicited similar attenuation of BRS(PE). The findings suggest that (i) BRS is differentially influenced by gender; female rats exhibit substantially lower BRS(PE) but similar BRS(NP) compared with age-matched male rats and (ii) the sexual dimorphism in BRS(PE) results, at least partly, from a smaller increase in vagal outflow to the heart in response to baroreceptor activation.     

Sex influences the susceptibility to reperfusion-induced sustained ventricular tachycardia and beta-adrenergic receptor blockade in conscious rats

Reperfusion after a brief period of cardiac ischemia can lead to potentially lethal arrhythmias. Importantly, there are sex-related differences in cardiac physiology and in the types and severity of cardiac arrhythmias. Therefore, we tested the hypothesis that gonadal hormones influence the susceptibility to reperfusion-induced sustained ventricular tachycardia (VT), as well as the response to beta-adrenergic receptor blockade. Male and female intact and gonadectomized rats were instrumented, and arterial pressure, temperature, ECG, and cardiac output were recorded. In addition, a snare was placed around the left main coronary artery. Tension was applied to the snare for determination of susceptibility to sustained VT produced by 3 min of occlusion and reperfusion of the left main coronary artery in conscious rats. Reperfusion culminated in sustained VT in 77% (10 of 13 susceptible) of female rats and 56% (9 of 16 susceptible) of male rats (P > 0.05, male vs. female). beta-Adrenergic receptor blockade prevented sustained VT in females only [1 of 9 susceptible females (11%) vs. 6 of 9 susceptible males (67%), P < 0.05]. Ovariectomy did not significantly reduce the susceptibility to reperfusion arrhythmias [5 of 9 susceptible (56%)]. In sharp contrast, orchidectomy significantly increased the susceptibility to reperfusion arrhythmias [9 of 9 susceptible (100%)]. Finally, beta-adrenergic receptor blockade prevented sustained VT in ovariectomized females [0 of 4 susceptible (0%)] and orchidectomized males [0 of 7 susceptible (0%)], but the protective effect of beta-blockade was due to a reduction in heart rate in males only. Thus gonadal hormones influence the susceptibility to reperfusion-induced arrhythmias, as well as the effects and mechanisms of beta-adrenergic receptor blockade.     

Effect of swimming training on cardiac function and myosin ATPase activity in SHR

Male spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive rats (WKY) were subjected to swimming training 6 times/wk, commencing at 4 wk of age, to determine whether this type of endurance exercise might alter contractile proteins and cardiac function in young adult SHR. The total duration of exercise was 190 h. Myofibrillar adenosinetriphosphatase (ATPase) activity was assayed at various free [Ca2+] ranging from 10(-7) to 10(-5) M. Ca2+-stimulated ATPase activity of actomyosin and purified myosin was determined at various Ca2+ concentrations both in the low and high ionic strength buffers. Actin-activated myosin ATPase activity of purified myosin was assayed at several concentrations of actin purified from rabbit skeletal muscle. Under all these conditions the contractile protein ATPase activity was comparable between trained and untrained WKY and SHR. Analysis of myosin isoenzymes on pyrophosphate gels showed a single band corresponding to V1 isoenzyme, and there were no differences between swimming-trained and nontrained WKY and SHR. Ventricular performance was assessed by measuring cardiac output and stroke volume after rapid intravenous volume overloading. Both cardiac index and stroke index were comparable in nontrained WKY and SHR but were significantly increased in the trained groups compared with their respective nontrained controls. These results suggest that myosin ATPase activity and distribution of myosin isoenzymes are not altered in the moderately hypertrophied left ventricle whether the hypertrophy is due to genetic hypertension (SHR) or to exercise training (trained WKY). Moreover, the data indicate that SHR, despite the persistence of a pressure overload, undergo similar increases in left ventricular mass and peak cardiac index after training, as do normotensive WKY.     

Mechanisms of aortic smooth muscle hyporeactivity after prolonged hypoxia in rats.

The aim of this study was to determine whether the effects of hypoxia on aortic contractility reflect a decrease in smooth muscle activation [phosphorylation of the 20-kDa myosin regulatory light chain (LC(20))], the capacity for myofibrillar ATP hydrolysis (mATPase activity), or both. Our results indicate that, in endothelium-denuded aortic rings from rats exposed to hypoxia for 48 h (inspired O(2) concentration = 10%), contractions to phenylephrine and potassium chloride (KCl) are impaired compared with rings from normoxic rats. The proportion of phosphorylated to total LC(20) during aortic contraction induced by 10(-5) M phenylephrine was reduced after hypoxia (51.4 +/- 5.4% in normoxic control rats vs. 32.5 +/- 4.7% in hypoxic rats, P < 0.01). Aortic mATPase activity was also decreased (maximum ATPase rate = 29.6 +/- 3.4 and 20.7 +/- 3.7 nmol. min(-1). mg protein(-1) in control and hypoxic rats, respectively, P < 0.05). Neither proliferation nor dedifferentiation of aortic smooth muscle was evident in this model; immunostaining for smooth muscle expression of the proliferating cell nuclear antigen was negative and smooth muscle-specific isoforms of myosin heavy chains, h-caldesmon, and calponin were increased, not decreased, after hypoxic exposure. Decreased aortic reactivity after hypoxia is associated with both impairment of smooth muscle activation and diminished capacity of the actomyosin complex, once activated, to hydrolyze ATP. These changes cannot be attributed to smooth muscle dedifferentiation or to reduced contractile protein expression.     

Effects of chronic beta-adrenergic blockade on exercise training in dogs

To assess the role of beta-adrenergic stimulation in cardiovascular conditioning we examined the effects of a beta-adrenergic blocker, propranolol, in mongrel dogs during an 8-wk treadmill-training program. Seven dogs were trained without a drug (NP), six were trained on propranolol 10 mg.kg-1.day-1 (P), and five served as caged controls (C). Effective beta-adrenergic blockade was documented by a decrease in peak exercise heart rate of 54 +/- 11 (SE) beats/min (P less than 0.05) and a one-log magnitude of increase in the isoproterenol-heart rate dose-response curve. Testing was performed before drug treatment or training and again after training without the drug for 5 days. Submaximal exercise heart rate decreased similarly in both NP and P (-26 +/- 4 NP vs. -25 +/- 9 beats/min P, P less than 0.05 for both) but peak heart rate decreased only with NP (-33 +/- 9 beats/min, P less than 0.05). Treadmill exercise time increased similarly in both groups: 3.4 +/- 0.6 min in NP and 3.0 +/- 0.2 min in P (both P less than 0.05). Blood volume also increased after training in both groups: 605 +/- 250 ml (26%) in NP and 377 +/- 140 ml (17%) in P (both P less than 0.05). Submaximal exercise arterial lactates were reduced similarly in both groups but peak exercise lactate was reduced more in NP (-1.4 +/- 0.3 NP vs -0.3 +/- 0.12 mmol/l P, P less than 0.05). Lactate threshold increased in both groups but the increase was greater in NP (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)