Increased susceptibility to ventricular arrhythmias in hypertensive paraplegic rats.

Individuals with spinal cord injury (SCI) between thoracic vertebrae four (T4) and five (T5) have elevated levels of sympathetic activity to the heart. Notably, female spontaneously hypertensive rats (SHR) also have increased cardiac sympathetic nerve activity (SNA). Since elevated levels of cardiac SNA increase the risk for cardiac arrhythmias, we tested the hypothesis that hypertensive, paraplegic rats have an increased susceptibility to ventricular arrhythmias. To test this hypothesis, intact (n = 7) and paraplegic hypertensive rats (n = 6) were chronically instrumented with silver stimulating electrodes on the left ventricle, electrocardiogram (ECG) recording electrodes and an arterial catheter. After recovery, the effective refractory period, the electrical stimulation threshold to induce ventricular arrhythmias and cardiac sympathetic tonus (ST) were determined. Paraplegic rats had a lower effective refractory period (35%), lower electrical stimulation threshold to induce ventricular arrhythmias (62%), and higher cardiac ST (84%). These data document an increased susceptibility to ventricular arrhythmias in hypertensive, paraplegic rats.

Daily exercise reduces measures of heart rate and blood pressure variability in hypertensive rats.

This study was designed to test the hypothesis that daily spontaneous running (DSR) reduces measures of heart rate and blood pressure variability in spontaneously hypertensive rats (SHR). After 8 weeks of DSR or sedentary control, rats were chronically instrumented with arterial catheters. Daily exercise reduced most measures of heart rate (HR) and blood pressure variability. Specifically DSR decreased heart rate, Low Frequency Power (LF: 0.19-0.61 Hz), and Low Frequency/High Frequency (HF: 1.2-2.5 Hz) ratio of HR. Furthermore, Total Power (TP), LF power, and LF/HF ratio of systolic blood pressure were reduced by daily spontaneous running. Finally, TP, LF and HF powers and LF/HF ratios of diastolic blood pressure were reduced by daily spontaneous running. These data demonstrate that daily exercise reduces sympathetic activity and possibly increases cardiac reserve in hypertensive animals.

Central blockade of vasopressin V(1) receptors attenuates postexercise hypotension.

We tested the hypothesis that central arginine vasopressin (AVP) mediates postexercise reductions in arterial pressure (AP) and heart rate (HR). To test this hypothesis, nine spontaneously hypertensive rats (SHR) were instrumented with a 22-gauge stainless steel guide cannula in the right lateral cerebral ventricle and with a carotid arterial catheter. After the rats recovered, AP and HR were assessed before and after a single bout of dynamic exercise with the central administration of vehicle or the selective AVP V(1)-receptor antagonist d(CH(3))(5) Tyr(Me)-AVP (AVP-X). AP and HR were significantly decreased below preexercise values with central administration of vehicle [P < 0.05, change (Delta)-21 +/- 4 mmHg and Delta-20 +/- 6 beats/min, respectively]. In sharp contrast, after exercise with central administration of AVP-X, both AP (Delta+8 +/- 5 mmHg) and HR (Delta+24 +/- 9 beats/min) were not significantly different from preexercise values (P > 0.05). Furthermore, AVP-X at rest did not significantly alter AP (181 +/- 11 vs. 178 +/- 11 mmHg, P > 0.05) or HR (328 +/- 24 vs. 331 +/- 22 beats/min, P > 0.05). Thus central blockade of AVP V(1) receptors prevented postexercise reductions in AP and HR. These data suggest that AVP, acting within the central nervous system, mediates postexercise reductions in AP and HR in the SHR.

Inactivation of one copy of the mouse neurotrophin-3 gene induces cardiac sympathetic deficits.

Whether two copies of the neurotrophin-3 (NT3) gene are necessary for proper development of cardiac sympathetic innervation was investigated in mice carrying a targeted inactivation of the NT3 gene. Heterozygous (+/-) and null (-/-) mutant mice had fewer stellate ganglion neurons than did wild-type (+/+) mice at postnatal day 0 (P0 or birth), and this deficit was maintained between adult (P60) +/- and +/+ mice. The sympathetic innervation of the heart matured postnatally in +/+ and +/- mice. Tyrosine hydroxylase (TH)-positive axons were restricted largely to the epicardium at P0, were concentrated around large blood vessels in the myocardium at P21, and were present among cardiac myocytes at P60. Cardiac norepinephrine (NE) concentrations paralleled the growth of the sympathetic axons into the heart. NE concentrations were equivalent among +/+, +/-, and -/- mice at birth, but differences between +/- and +/+ mice increased with age. Adult +/- mice also exhibited lower resting heart rates and sympathetic tonus than +/+ mice. Thus deletion of one copy of the NT3 gene translates into anatomical, biochemical, and functional deficits in cardiac sympathetic innervation of postnatal mice, thereby indicating a gene-dosage effect for the NT3 gene.

Daily exercise attenuated the sympathetic component of the spontaneous arterial baroreflex control of heart rate in hypertensive rats.

The influence of daily spontaneous running on the sympathetic and parasympathetic components of the spontaneous arterial baroreflex control of heart rate was examined in 22 female spontaneously hypertensive rats [12 sedentary and 10 daily spontaneous running]. Following 8 weeks of sedentary control or daily spontaneous running, animals were chronically instrumented with an arterial catheter. Daily spontaneous running resulted in an increased heart weight/body weight ratio (5.2 +/- 0.27 vs 4.3 +/- 0.01 g/kg) and a resting bradycardia (321+/- 8 bpm vs 360 +/- 6). The spontaneous changes in arterial pressure and the reflex responses of heart rate were examined under three experimental conditions: 1) pre-blockade, 2) following beta1-adrenergic receptor blockade, and 3) following muscarinic-cholinergic receptor blockade. Daily spontaneous running attenuated the spontaneous gain of the arterial baroreflex control of heart rate (56%). After muscarinic-cholinergic receptor blockade, the spontaneous gain remained reduced in daily spontaneous running rats (57%). In contrast, after beta1-adrenergic receptor blockade the spontaneous gain was not different between sedentary control and daily spontaneous running animals. Results demonstrate that daily spontaneous running decreased the sympathetic component resulting in an apparently greater influence of the parasympathetic component on the spontaneous arterial baroreflex control of heart rate.

Daily exercise attenuates the development of arterial blood pressure related cardiovascular risk factors in hypertensive rats.

This study was designed to test the hypothesis that daily spontaneous running (DSR) attenuates the development of blood pressure-related cardiovascular disease risk factors (BP-related CVD risk factors) in spontaneously hypertensive rats (SHR). After 8 weeks of DSR or sedentary control, rats were chronically instrumented with arterial catheters. Daily exercise attenuated the development of all measures of BP-related CVD risk factors. Specifically DSR attenuated the increase in systolic blood pressure (delta--22 mmHg), systolic blood pressure variability (delta--2.5 mmHg), and systolic blood pressure load (delta--27%). Similarly, DSR attenuated the increase in diastolic blood pressure (delta--15 mmHg), diastolic blood pressure variability (delta--1.19 mmHg), and diastolic blood pressure load (delta--17%). Finally, DSR attenuated the development of tachycardia (delta--63 bpm). These data demonstrate that daily exercise attenuates the development of hypertension and tachycardia in animals predisposed to hypertension.

Who wants to be a physician? An educational tool for reviewing pulmonary physiology.

Traditional review sessions are typically focused on instructor-based learning. However, experts in the field of higher education have long recommended teaching modalities that incorporate student-based active-learning strategies. Given this, we developed an educational game in pulmonary physiology for first-year medical students based loosely on the popular television game show Who Wants To Be A Millionaire. The purpose of our game, Who Wants To Be A Physician, was to provide students with an educational tool by which to review material previously presented in class. Our goal in designing this game was to encourage students to be active participants in their own learning process. The Who Wants To Be A Physician game was constructed in the form of a manual consisting of a bank of questions in various areas of pulmonary physiology: basic concepts, pulmonary mechanics, ventilation, pulmonary blood flow, pulmonary gas exchange, gas transport, and control of ventilation. Detailed answers are included in the manual to assist the instructor or player in comprehension of the material. In addition, an evaluation instrument was used to assess the effectiveness of this instructional tool in an academic setting. Specifically, the evaluation instrument addressed five major components, including goals and objectives, participation, content, components and organization, and summary and recommendations. Students responded positively to our game and the concept of active learning. Moreover, we are confident that this educational tool has enhanced the students' learning process and their ability to understand and retain information.

An inquiry-based teaching tool for understanding arterial blood pressure regulation and cardiovascular function.

Educators are placing a greater emphasis on the development of cooperative laboratory experiences that supplement the traditional lecture format. The new laboratory materials should encourage active learning, problem-solving, and inquiry-based approaches. To address these goals, we developed a laboratory exercise designed to introduce students to the hemodynamic variables (heart rate, stroke volume, total peripheral resistance, and compliance) that alter arterial pressure. For this experience, students are presented with "unknown" chart recordings illustrating pulsatile arterial pressure before and in response to several interventions. Students must analyze and interpret these unknown recordings and match each recording with the appropriate intervention. These active learning procedures help students understand and apply basic science concepts in a challenging and interactive format. Furthermore, laboratory experiences may enhance the students' level of understanding and ability to synthesize and apply information. In conducting this exercise, students are introduced to the joys and excitement of inquiry-based learning through experimentation.

Construction of a model demonstrating cardiovascular principles.

We developed a laboratory exercise that involves the construction and subsequent manipulation of a model of the cardiovascular system. The laboratory was designed to engage students in interactive, inquiry-based learning and to stimulate interest for future science study. The model presents a concrete means by which cardiovascular mechanics can be understood as well as a focal point for student interaction and discussion of cardiovascular principles. The laboratory contains directions for the construction of an inexpensive, easy-to-build model as well as an experimental protocol. From this experience students may gain an appreciation fo science that cannot be obtained by reading a book or interacting with a computer. Students not only learn the significant physiological concepts but also appreciate the importance of laboratory experimentation for understanding complex concepts. Model construction provides a hands-on experience that may substantially improve performance in science processes. We believe that model construction is an appropriate method for teaching advanced concepts.

Phenotypic differences in cardiovascular regulation in inbred rat models of aerobic capacity.

The Dark Aouti (DA) inbred strain of rats has superior aerobic treadmill running capacity compared with the Copenhagen (COP) strain of inbred rats. This difference in aerobic capacity provides a model to explore the genetic basis of variation in this trait. The present study evaluated intermediate phenotypic differences between 10 male COP inbred rats and 10 male DA inbred rats that might contribute to the difference in aerobic capacity between the strains. Five autonomically regulated cardiovascular variables were evaluated during rest or exercise by measuring the response to autonomic antagonists. The DA rat had enhanced autonomic function for the regulation of peripheral blood flow and cardiac output. Specifically, at rest the DA rats had significantly more sympathetic (123 +/- 8 vs. 99 +/- 7 beats/min) and parasympathetic (35 +/- 5 vs. 12 +/- 3 beats/min) tonus for heart rate control and more sympathetic support of blood pressure (70 +/- 7 vs. 38 +/- 6 mmHg) compared with the COP rats. During three graded levels of treadmill exercise the DA rats had higher blood pressures (16% on average) and higher heart rates (4% on average) relative to the COP rats. In addition, the DA rats had a 27% greater heart weight-to-body weight ratio compared with the COP strain of rats (3.63 +/- 0.08 vs. 2.85 +/- 0.07 g/kg). All five of these intermediate phenotypes could participate as variables causative of the difference in treadmill running capacity between the DA and COP strains of rats.

Dynamic exercise shifts the operating point and reduces the gain of the arterial baroreflex in rats.

We tested the hypothesis that dynamic exercise resets the operating point and attenuates the gain of the arterial baroreflex regulation of heart rate (HR) in rats. Seven adult female spontaneously hypertensive rats (SHR) were chronically instrumented with left carotid arterial catheters. After the rats recovered, arterial baroreflex function was examined by recording reflex changes in HR in response to spontaneous changes in arterial pressure (AP) during a preexercise condition and during steady-state treadmill running at 6 and 18 m/min. Dynamic exercise at 6 and 18 m/min, respectively, reduced the spontaneous range (by 55 and 70%) and spontaneous gain (by 64 and 82%) of the arterial baroreflex control of HR. Dynamic exercise at 6 and 18 m/min, respectively, also increased the pressure at the midpoint of the spontaneous pressure range (by 7 and 12%), the spontaneous minimum HR response (by 35 and 59%), the HR at the midpoint of the spontaneous HR range (by 31 and 52%), and the spontaneous maximum HR response (by 27 and 46%). Sinoaortic denervation eliminated the relationship between AP and HR by reducing the spontaneous gain 95%. These results demonstrate that dynamic exercise shifted the operating point of the arterial baroreflex to a higher pressure and reduced the spontaneous gain in female SHR.

Arterial baroreflex resetting mediates postexercise reductions in arterial pressure and heart rate.

We tested the hypothesis that postexercise reductions in arterial pressure and heart rate (HR) are mediated by a lowering of the operating point and a reduction in the gain of the arterial baroreflex. To test this hypothesis, spontaneous changes in arterial pressure and the reflex responses of HR were examined before and after a single bout of mild to moderate dynamic exercise in 19 spontaneously hypertensive rats (SHR, 10 male and 9 female). Eleven SHR subjected to sinoaortic denervation (SAD) (6 male, 5 female) were also studied. All rats were instrumented with an arterial catheter for the measurement of arterial pressure and HR. After exercise, arterial pressure and HR were reduced below preexercise levels. Furthermore, the operating point and spontaneous gain (G) of the arterial baroreflex were reduced. Specifically, after exercise, the spontaneous range of HR (P1, 50%), the pressure at the midpoint of the pressure range (P3, 13%) and the HR at the midpoint of the HR range (H3, 10%), the spontaneous minimum HR (P4, 8%) and maximum HR (10%), and G (76%) were significantly attenuated. SAD significantly attenuated the relationship between arterial pressure and HR by reducing G (males 94%, females 95%). These results demonstrate that acute exercise resulted in a postexercise resetting of the operating point and a reduction in the gain of the arterial baroreflex. Furthermore, these data suggest that postexercise reductions in arterial pressure and HR are mediated by a lowering of the operating point of the arterial baroreflex.