Influence of long-term beta receptor stimulation with prenalterol on intrinsic heart rate in rats

Previous studies have shown that the intrinsic heart rate (IHR) may undergo changes, e.g., decrease after long-term endurance training. The mechanism for this adaptation is not known. In this study, rats were subjected to long-term oral treatment with the beta receptor stimulating drug prenalterol. During the treatment period heart rates at rest and during submaximal exercise were measured. Heart rate after 30 min rest and also 2 min after exercise was higher in the treated animals, due to the beta stimulation. The treated rats had a significantly lower heart rate increase during exercise than untreated controls, consistent with a partial beta-blocking effect of the drug in states with a high endogenous sympathetic activity. Therefore, the animals were not trained but only exposed to the increased stimulation of cardiac beta receptors accomplished by the drug while at rest. After 25 weeks, prenalterol was withdrawn and the IHR was measured in situ after a denervation procedure. The treatment with prenalterol had not altered the IHR. Our previous results from training studies indicate that a heart rate increase above a certain level or the stimulation for a lower setting of the IHR as seen after endurance training. In this study chronic beta receptor stimulation with prenalterol did not influence the IHR, which supports that hypothesis.     

Training-induced changes in skeletal muscle Na+-K+ pump number and isoform expression in rats with chronic heart failure.

The mechanisms responsible for the decrements in exercise performance in chronic heart failure (CHF) remain poorly understood, but it has been suggested that sarcolemmal alterations could contribute to the early onset of muscular fatigue. Previously, our laboratory demonstrated that the maximal number of ouabain binding sites (B(max)) is reduced in the skeletal muscle of rats with CHF (Musch TI, Wolfram S, Hageman KS, and Pickar JG. J Appl Physiol 92: 2326-2334, 2002). These reductions may coincide with changes in the Na(+)-K(+)-ATPase isoform (alpha and beta) expression. In the present study, we tested the hypothesis that reductions in B(max) would coincide with alterations in the alpha- and beta-subunit expression of the sarcolemmal Na(+)-K(+)-ATPase of rats with CHF. Moreover, we tested the hypothesis that exercise training would increase B(max) along with producing significant changes in alpha- and beta-subunit expression. Rats underwent a sham operation (sham; n = 10) or a surgically induced myocardial infarction followed by random assignment to either a control (MI; n = 16) or exercise training group (MI-T; n = 16). The MI-T rats performed exercise training (ET) for 6-8 wk. Hemodynamic indexes demonstrated that MI and MI-T rats suffered from severe left ventricular dysfunction and congestive CHF. Maximal oxygen uptake (Vo(2 max)) and endurance capacity (run time to fatigue) were reduced in MI rats compared with sham. B(max) in the soleus and plantaris muscles and the expression of the alpha(2)-isoform of the Na(+)-K(+)-ATPase in the red portion of the gastrocnemius (gastrocnemius(red)) muscle were reduced in MI rats. After ET, Vo(2 max) and run time to fatigue were increased in the MI-T group of rats. This coincided with increases in soleus and plantaris B(max) and the expression of the alpha(2)-isoform in the gastrocnemius(red) muscle. In addition, the expression of the beta(2)-isoform of the gastrocnemius(red) muscle was increased in the MI-T rats compared with their sedentary counterparts. This study demonstrates that CHF-induced alterations in skeletal muscle Na(+)-K(+)-ATPase, including B(max) and isoform expression, can be partially reversed by ET.     

Oxyntomodulin increases intrinsic heart rate in mice independent of the glucagon-like peptide-1 receptor

Oxyntomodulin (OXM), a postprandially released intestinal hormone, inhibits food intake via the glucagon-like peptide-1 receptor (GLP-1R). Although OXM may have clinical value in treating obesity, the cardiovascular effects of OXM are not well understood. Using telemetry to measure heart rate (HR), body temperature (Tb), and activity in conscious and freely moving mice, we tested 1) whether OXM affects HR and 2) whether this effect is mediated by the GLP-1R. We found that peripherally administered OXM significantly increased HR in wild-type mice, raising HR by >200 beats/min to a maximum of 728 +/- 11 beats/min. To determine the extent to which the sympathetic nervous system mediates the tachycardia of OXM, we delivered this hormone to mice deficient in dopamine-beta-hydroxylase [Dbh(-/-) mice], littermate controls [Dbh(+/-) mice], and autonomically blocked C57Bl mice. OXM increased HR equally in all groups (192 +/- 13, 197 +/- 21, and 216 +/- 11 beats/min, respectively), indicating that OXM elevated intrinsic HR. Intrinsic HR was also vigorously elevated by OXM in Glp-1R(-/-) mice (200 +/- 28 beats/min). In addition, peripherally administered OXM inhibited food intake and activity levels in wild-type mice and lowered Tb in autonomically blocked mice. None of these effects were observed in Glp-1R(-/-) mice. These data suggest multiple modes of action of OXM: 1) it directly elevates murine intrinsic HR through a GLP-1R-independent mechanism, perhaps via the glucagon receptor or an unidentified OXM receptor, and 2) it lowers food intake, activity, and Tb in a GLP-1R-dependent fashion.     

Aging and baroreflex control of RSNA and heart rate in rats

Aging is associated with altered autonomic control of cardiovascular function, but baroreflex function in animal models of aging remains controversial. In this study, pressor and depressor agent-induced reflex bradycardia and tachycardia were attenuated in conscious old (24 mo) rats [57 and 59% of responses in young (10 wk) Wistar rats, respectively]. The intrinsic heart rate (HR, 339 +/- 5 vs. 410 +/- 10 beats/min) was reduced in aged animals, but no intergroup differences in resting mean arterial blood pressure (MAP, 112 +/- 3 vs. 113 +/- 5 mmHg) or HR (344 +/- 9 vs. 347 +/- 9 beats/min) existed between old and young rats, respectively. The aged group also exhibited a depressed (49%) parasympathetic contribution to the resting HR value (vagal effect) but preserved sympathetic function after intravenous methylatropine and propranolol. An implantable electrode revealed tonic renal sympathetic nerve activity (RSNA) was similar between groups. However, old rats showed impaired baroreflex control of HR and RSNA after intravenous nitroprusside (-0.63 +/- 0. 18 vs. -1.84 +/- 0.4 bars x cycle(-1) x mmHg(-1) x s(-1)). Therefore, aging in rats is associated with 1) preserved baseline MAP, HR, and RSNA, 2) impaired baroreflex control of HR and RSNA, and 3) altered autonomic control of resting HR.     

Impaired capsaicin-induced decrease in heart rate and coronary flow in isolated heart of diabetic rats

The effect of capsaicin (0.1 microM) on heart rate and coronary flow was studied in Langendorff-perfused heart from streptozotocin-induced (50 mg/kg i.v.) diabetic rats where sensory neuropathy developed. In hearts from animals 4- and 8-week diabetes baseline heart rate and coronary flow decreased from 317.9 +/- 2.9 b.p.m. and 13.4 +/- 0.7 m/min to 255.1 +/- 12.7 and 219.8 +/- 2.8 b.p.m. and 8.9 +/- 0.6 and 10.0 +/- 0.1 ml/min (P<0.05), respectively. Capsaicin significantly decreased both variables in either normal or 4-week diabetic animals its effects, however, on coronary flow or heart rate were missing in preparations from 8-week diabetic rats. Endothelin-1 (0.1 nM), the putative mediator of the capsaicin effect, significantly decreased heart rate and coronary flow irrespective of the presence or absence of diabetes. In the femoral nerve of streptozotocin-treated animals conduction velocity involving both fast conducting A- and slow-conducting C-fibres was decreased proportional to the duration of the pre-existing diabetic state. It is concluded that in insulin deficient diabetes the diminished responses evoked by capsaicin on heart rate and coronary flow are signs of sensory neuropathy. This is related to a feeble endothelin release from sensory nerve endings without changes in post-receptor mechanisms mediating the endothelin effects.     

M-chlorophenylpiperazine increases blood pressure and heart rate in pithed and conscious rats

In pithed rats, m-chlorophenylpiperazine (m-CPP) produced marked, dose-dependent (ED50 = 0.18 mumol) increases in mean arterial blood pressure which peaked within 1 minute and were sustained over 15 minutes. Two serotonin antagonists, metergoline and ritanserin, completely blocked the pressor responses to 2.5 mg/kg m-CPP in pithed adrenal demedullated rats, while alpha-adrenergic blockade by prazosin plus yohimbine was without effect, suggesting that the doubling in blood pressure produced by m-CPP was mediated via serotonin receptors within blood vessels. Somewhat smaller increases in blood pressure over baseline values were observed after m-CPP administration to conscious, freely moving rats. A small but statistically significant increase in heart rate peaked 5 minutes after m-CPP and also was blocked by metergoline but was only minimally affected by ritanserin or the prazosin-yohimbine combination. These results with m-CPP support other evidence for two or more separable effects of serotonergic agonists on the peripheral cardiovascular system.     

Changes in ultraweak photon emission and heart rate variability of epinephrine-injected rats

Ultraweak photons which are spontaneously emitted from a living body may be applicable as a non-invasive tool to characterize the physiological state of the living body. We investigated changes in the intensity of ultraweak photon emission, body temperature and the cardiovascular autonomic activity induced by epinephrine injection to rats. A high dose of epinephrine can make changes to the cardiovascular autonomic activity or body temperature. Photon emission of the dorsal part, rectal temperature and heart rate variability (HRV) were measured from eight Sprague-Dawley rats. The intensities of photon emissions for saline injections, which were used as a control, decreased from 13042+/-71 counts/min at the start of measurements to 8709+/-915 counts/min at 1 h after the injections. In the case with epinephrine injections, the intensity of photon emission reduced slowly from 13361+/-354 counts/min to 11040+/-433 counts/min. Rectal temperature increased in both saline- and epinephrine-injected rats, but one hour after the injections the temperature in the epinephrine case was slightly higher than that in the saline case. The standard deviation of the QRS wave complex interval (RR interval) increased from 1 to 4 (p<0.05) and the spectral ratio of the low frequency component to the high frequency component in the HRV data LF (0.19 approximately 0.74 Hz) / HF (0.78 approximately 2.50 Hz) decreased from 0.81 to 0.26 (p<0.05) in the case of epinephrine injection while no change was found in the case of saline injection. Thus, ultraweak photon emission was closely related to the cardiovascular autonomic activity.     

CRF-evoked bradycardia in urethane-anesthetized rats is blocked by naloxone

CRF, injected IV at a dose of 6 nmol/kg, produced a fall in blood pressure and in heart rate in urethane-anesthetized rats. The CRF-bradycardia was not obtained in hypophysectomized animals, in animals pretreated with dexamethasone, or in animals pretreated with the narcotic antagonist, naloxone (1 mg/kg, IV). By contrast, the hypotensive effects of CRF were not affected by these procedures. Vagotomy or pretreatment with a low dose of N-methylnaloxone did not affect the CRF-bradycardia, indicating that the slowing of the heart was not due to parasympathetic stimulation or due to a peripherally mediated opioid chemoreflex. The results suggested that the CRF-bradycardia was mediated by the release of opioid peptides from the pituitary.     

Laboratory demonstration of baroreflex control of heart rate in conscious rats

We have developed a laboratory exercise that demonstrates arterial baroreflex control of heart rate (HR) in the conscious unrestrained rat, incorporating graduate level physiological topics as well as a hands-on exposure to conscious animal research. This demonstration utilizes rats chronically instrumented to measure cardiac output (CO), HR, and arterial blood pressure in response to agents that raise or lower blood pressure. The HR response to progressive increases or decreases in blood pressure is recorded, and a baroreflex curve is generated by plotting mean arterial blood pressure (MABP) vs. HR. Observation of altered CO allows for discussion of the relationship between MAP, CO, HR, stroke volume, and total peripheral resistance. Administration of arginine vasopressin demonstrates the ability of this hormone to alter the sensitivity of the baroreflex. Throughout the demonstration, students answer questions from a handout about general cardiovascular physiology, specific pathways of agonists, and the baroreflex system, encouraging group and individual critical analysis of the results. Interpretation of the data reemphasizes lecture material and allows students to observe the baroreflex response in a physiological setting.     

Decreased maximal heart rate with aging is related to reduced {beta}-adrenergic responsiveness but is largely explained by a reduction in intrinsic heart rate.

A decrease in maximal exercise heart rate (HR(max)) is a key contributor to reductions in aerobic exercise capacity with aging. However, the mechanisms involved are incompletely understood. We sought to gain insight into the respective roles of intrinsic heart rate (HR(int)) and chronotropic beta-adrenergic responsiveness in the reductions in HR(max) with aging in healthy adults. HR(max) (Balke treadmill protocol to exhaustion), HR(int) (HR during acute ganglionic blockade with intravenous trimethaphan), and chronotropic beta-adrenergic responsiveness (increase in HR with incremental intravenous infusion of isoproterenol during ganglionic blockade) were determined in 15 older (65 +/- 5 yr) and 15 young (25 +/- 4 yr) healthy men. In the older men, HR(max) was lower (162 +/- 9 vs. 191 +/- 11 beats/min, P < 0.0001) and was associated with a lower HR(int) (58 +/- 7 vs. 83 +/- 9 beats/min, P < 0.0001) and chronotropic beta-adrenergic responsiveness (0.094 +/- 0.036 vs. 0.154 +/- 0.045 DeltaHR/[isoproterenol]: P < 0.0001). Both HR(int) (r = 0.87, P < 0.0001) and chronotropic beta-adrenergic responsiveness (r = 0.61, P < 0.0001) were positively related to HR(max). Accounting for the effects of HR(int) and chronotropic beta-adrenergic responsiveness reduced the age-related difference in HR(max) by 83%, rendering it statistically nonsignificant (P = 0.2). Maximal oxygen consumption was lower in the older men (34.9 +/- 8.1 vs. 48.6 +/- 6.7 ml x kg(-1) x min(-1), P < 0.0001) and was positively related to HR(max) (r = 0.62, P < 0.0001), HR(int) (r = 0.51, P = 0.002), and chronotropic beta-adrenergic responsiveness (r = 0.47, P = 0.005). Our findings indicate that, together, reductions in HR(int) and chronotropic responsiveness to beta-adrenergic stimulation largely explain decreases in HR(max) with aging, with the reduction in HR(int) playing by far the greatest role.     

Effect of neuromuscular blocking drugs on arterial pressure and heart rate in rats

The effects of neuromuscular blocking drugs on mean arterial pressure (MAP) and heart rate (HR) were studied in rats which were anaesthetised, tracheotomized and ventilated artificially. The arterial pressure was recorded from the carotid artery. Seven neuromuscular blocking drugs were injected intravenously at doses of 1, 5, and 25 mumol/kg. d-Tubocurarine, alcuronium and vecuronium lowered MAP in a dose dependent manner (maximum 40%). Succinylcholine, 1 mumol/kg, reduced MAP and HR, whereas the two larger doses increased them. Gallamine, 25 mumol/kg, or metocurine and pancuronium, 1 or 5 mumol/kg, each, induced short-lasting rises in MAP. Pancuronium, 25 mumol/kg, decreased MAP by 25%, while the largest dose of metocurine appeared to be toxic. The cardiovascular responses to neuromuscular blocking drugs were antagonized or abolished by pretreatment with the ganglionic blocking agent pentolinium. Pentolinium itself markedly reduced MAP and HR. After ganglionic blockade and restoration of MAP by noradrenaline infusion, all the neuromuscular blocking drugs induced short-lasting increases in MAP (10-30%), except d-tubocurarine which still reduced MAP by 30%, a fall which, in contrast to the effect in the absence of the pretreatments, was transient. This response to d-tubocurarine could not be abolished by a combined pretreatment with H1 and H2 antagonists showing that the hypotensive effect of this drug was not due to the liberation of histamine. These results suggest that the cardiovascular responses to neuromuscular blocking drugs in rats might be partly due to ganglionic effects. Other mechanisms are also involved since after the restoration of blood pressure by noradrenaline during the ganglionic blockade some cardiovascular responses to these drugs still occurred.