These findings suggest that EPR dysfunction in heart failure results in part from functional and molecular alterations in group IV fibers. Furthermore, the responsiveness of these metabolically sensitive neurons appears to be blunted in DCM, indicating that their contribution to the EPR may be reduced. This occurs despite an overall exaggeration of the EPR in heart failure. These insights into the basic mechanisms of EPR dysfunction are essential to the development of effective therapeutic strategies aimed at improving exercise capacity in heart failure.

In hypertension, exercise elicits excessive elevations in mean arterial pressure (MAP) and heart rate (HR) increasing the risk for adverse cardiac events and stroke during physical activity. The exercise pressor reflex (a neural drive originating in skeletal muscle), central command (a neural drive originating in cortical brain centres) and the tonically active arterial baroreflex contribute importantly to cardiovascular control during exercise. Each of these inputs potentially mediates the heightened cardiovascular response to physical activity in hypertension. However, given that exercise pressor reflex overactivity is known to elicit enhanced circulatory responses to exercise in disease states closely related to hypertension (e.g. heart failure), we tested the hypothesis that the exaggerated cardiovascular response to exercise in hypertension is mediated by an overactive exercise pressor reflex. To test this hypothesis, we used a rat model of exercise recently developed in our laboratory that selectively stimulates the exercise pressor reflex independent of central command and/or the arterial baroreflex. Activation of the exercise pressor reflex during electrically induced static muscle contraction in the absence of input from central command resulted in significantly larger increases in MAP and HR in male spontaneously hypertensive rats as compared to normotensive Wistar-Kyoto rats over a wide range of exercise intensities. Similar findings were obtained in animals in which input from both central command and the arterial baroreflex were eliminated. These findings suggest that the enhanced cardiovascular response to exercise in hypertension is mediated by an overactive exercise pressor reflex. Potentially, effective treatment of exercise pressor reflex dysfunction may reduce the cardiovascular risks associated with exercise in hypertension.

Leal AK, Williams MA, Garry MG, Mitchell JH, Smith SA. Evidence for functional alterations in the skeletal muscle mechanoreflex and metaboreflex in hypertensive rats. Am J Physiol Heart Circ Physiol 295: H1429 -H1438, 2008. First published July 18, 2008 doi:10.1152/ajpheart.01365.2007.-Exercise in hypertensive individuals elicits exaggerated increases in mean arterial pressure (MAP) and heart rate (HR) that potentially enhance the risk for adverse cardiac events or stroke. Evidence suggests that exercise pressor reflex function (EPR; a reflex originating in skeletal muscle) is exaggerated in this disease and contributes significantly to the potentiated cardiovascular responsiveness. However, the mechanism of EPR overactivity in hypertension remains unclear. EPR function is mediated by the muscle mechanoreflex (activated by stimulation of mechanically sensitive afferent fibers) and metaboreflex (activated by stimulation of chemically sensitive afferent fibers). Therefore, we hypothesized the enhanced cardiovascular response mediated by the EPR in hypertension is due to functional alterations in the muscle mechanoreflex and metaboreflex. To test this hypothesis, mechanically and chemically sensitive afferent fibers were selectively activated in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) decerebrate rats. Activation of mechanically sensitive fibers by passively stretching hindlimb muscle induced significantly greater increases in MAP and HR in SHR than WKY over a wide range of stimulus intensities. Activation of chemically sensitive fibers by administering capsaicin (0.01-1.00 g/100 l) into the hindlimb arterial supply induced increases in MAP that were significantly greater in SHR compared with WKY. However, HR responses to capsaicin were not different between the two groups at any dose. This data is consistent with the concept that the abnormal EPR control of MAP described previously in hypertension is mediated by both mechanoreflex and metaboreflex overactivity. In contrast, the previously reported alterations in the EPR control of HR in hypertension may be principally due to overactivity of the mechanically sensitive component of the reflex. blood pressure; heart rate; muscle afferents THE CARDIOVASCULAR RESPONSE to exercise is exaggerated in hypertension and is characterized by augmented increases in heart rate (HR), arterial blood pressure (ABP), and vascular resistance (3,15,19,25,38,43). These abnormal hemodynamic responses to physical activity in hypertension are associated with an increased risk for adverse cardiovascular events during and after exercise such as myocardial ischemia or infarction, cardiac arrest, and stroke (13,21,35,36). Therefore, dissection of the regulatory mechanisms underlying the altered hemodynamic responses to exercise in hypertension is important and clinically relevant.The cardiovascular response to exercise is mediated by three neurophysiological mechanisms: the exercise pressor reflex (EPR), central command, and the arterial baroreflex. The EPR is a ...

The skeletal muscle exercise pressor reflex (EPR) induces increases in heart rate (HR) and mean arterial pressure (MAP) during physical activity. This reflex is activated during contraction by stimulation of afferent fibres responsive to mechanical distortion and/or the metabolic by-products of skeletal muscle work. The molecular mechanisms responsible for activating these afferent neurons have yet to be identified. It has been reported that activation of the transient receptor potential vanilloid 1 (TRPv1) receptor within skeletal muscle (localized to unmyelinated afferent fibres) elicits increases in MAP and HR similar to those generated by the EPR. Thus, we hypothesized that stimulation of the TRPv1 receptor during muscle contraction contributes to the activation of the EPR. The EPR was activated by electrically induced static muscle contraction of the hindlimb in decerebrate Sprague-Dawley rats (n = 61) before and after the administration of the TRPv1 receptor antagonists, capsazepine (Capz; 100 μg/100 μl), iodoresinaferatoxin (IRTX; 1 μg/100 μl), or Ruthenium Red (RR; 100 μg/100 μl). Static muscle contraction alone induced increases in both HR (8 ± 2 bpm) and MAP (21 ± 3 mmHg). The HR and MAP responses to contraction were significantly lower (P < 0.05) after the administration of Capz (2 ± 1 bpm; 7 ± 1 mmHg, respectively), IRTX (3 ± 2 bpm; 5 ± 3 mmHg, respectively) and RR (0 ± 1, bpm; 5 ± 2 mmHg, respectively). These data suggest that the TRPv1 receptor contributes importantly to activation of the EPR during skeletal muscle contraction in the rat.

Naseem RH, Meeson AP, DiMaio JM, White MD, Kallhoff J, Humphries C, Goetsch SC, De Windt LJ, Williams MA, Garry MG, Garry DJ. Reparative myocardial mechanisms in adult C57BL/6 and MRL mice following injury. Physiol Genomics 30: 44 -52, 2007. First published February 27, 2007 doi:10.1152/physiolgenomics.00070.2006.-Previous studies have suggested that the heart may be capable of limited repair and regeneration in response to a focal injury, while other studies indicate that the mammalian heart has no regenerative capacity. To further explore this issue, we performed a series of superficial and transmural myocardial injuries in C57BL/6 and MRL/MpJ adult mice. At defined time intervals following the respective injury (days 3, 14, 30 and 60), we examined cardiac function using echocardiography, morphology, fluorescence-activated cell sorting for 5-bromo-2-deoxyuridine-positive cells and molecular signature using microarray analysis. We observed restoration of myocardial function in the superficial MRL cryoinjured heart and significantly less collagen deposition compared with the injured hearts of C57BL/6 mice. Following a severe transmural myocardial injury, the MRL mouse has increased survival and decreased ventricular remodeling compared with the C57BL/6 mouse but without evidence of complete regeneration. The cytoprotective program observed in the severely injured MRL heart is in part due to increased cellular proliferation, increased vasculogenesis, and decreased apoptosis that limits the extension of the injury. We conclude that MRL injured hearts have evidence of myocardial regeneration, in response to superficial injury, but the stabilized left ventricular function and improved survival observed in the MRL mouse following severe injury is not associated with complete myocardial regeneration. myocardial regeneration; cytoprotection; progenitor cells; echocardiography; TUNEL assay; transcriptome analysis AMPHIBIANS AND TELEOST FISH have a remarkable myocardial regenerative capacity following injury (5,6,33). Following the amputation of the ventricular apex in zebrafish, a well-orchestrated molecular and cellular response results in complete myocardial regeneration and an absence of scar formation (33). Studies undertaken in these metazoan models suggest a dynamic balance exists between the fibroproliferative response that produces scar and the regenerative response that produces functional, contractile tissue (6, 33).Adult mammalian tissues typically have a progenitor or stem cell population that function in the maintenance and regeneration of the tissue in which they reside (8,11,38). Bone marrow, skin, liver, skeletal muscle and brain are several examples of adult tissues that harbor somatic progenitor/stem cell populations and are capable of regeneration (8,11,38). Recent studies suggest that the adult murine heart also contains such a progenitor cell population and potentially is capable of limited regeneration (3,10,22,28). Analysis of these cardiac progenitor cell populations and the fibroproliferative r...