Bernell R. Coleman

Effect of Hypertension on Elasticity and Geometry of Aortic Tissue From Dogs

Inflation-extension experiments were carried out on segments of the descending thoracic aortas from 4 normotensive and 4 hypertensive dogs rendered hypertensive using either unilateral or bilateral renal artery constriction. Intravascular pressures up to 200 mm Hg and axial forces up to 200 g were used. The external diameter of the segment and the distance between two longitudinally spaced gage marks were recorded photographically at each pressure-force level combination. Dimensions in the underformed configuration were measured at the end of the inflation-extension experiment. Data were analyzed for changes in geometry and force-deformation response. Results indicate that: 1. Under sustained hypertension the wall thickness in the underformed configuration increases with a concurrent reduction in the in-situ longitudinal extension ratio. 2. This dual tissue response accomplishes substantial reductions in the circumferential and longitudinal stresses from the levels that would be reached at equivalent pressures in the absence of these geometric changes. 3. At comparable intravascular pressures the extensibility in the circumferential direction is slightly greater for the hypertensive aortas as compared to normals. However, the stress-extension ratio relationship in the circumferential direction is similar in the two groups. 4. The stress-extension ratio relationship in the longitudinal direction indicates that the hypertensive aorta is stiffer than its normotensive counterpart.

Regulation of L-type inward calcium channel activity by captopril and angiotensin II via the phosphatidyl inositol 3- kinase pathway in cardiomyocytes from volume-overload hypertrophied rat hearts

Heart failure can be caused by pro-hypertrophic humoral factors such as angiotensin II (Ang II), which regulates protein kinase activities. The intermingled responses of these kinases lead to the early compensated cardiac hypertrophy, but later to the uncompensated phase of heart failure. We have shown that although beneficial, cardiac hypertrophy is associated with modifications in ion channels that are mainly mediated through mitogen-activated protein (MAP) kinase and phosphatidylinositol 3-kinase (PI3K) activation. This study evaluates the control of L-type Ca(2+) current (I(Ca,L)) by the Ang II/PI3K pathway in hypertrophied ventricular myocytes from volume-overload rats using the perforated patch-clamp technique. To assess activation of the I(Ca,L) in cardiomyocytes, voltages of 350 ms in 10 mV increments from a holding potential of -85 mV were applied to cardiocytes, with a pre-pulse to -45 mV for 300 ms. Volume overload-induced hypertrophy reduces I(Ca,L), whereas addition of Ang II alleviates the hypertrophic-induced decrease in a PI3K-dependent manner. Acute administration of Ang II (10(-6) mol/L) to normal adult cardiomyocytes had no effect; however, captopril reduced their basal I(Ca,L). In parallel, captopril regressed the hypertrophy and inverted the Ang II effect on I(Ca,L) seemingly through a PI3K upstream effector. Thus, it seems that regression of cardiac hypertrophy by captopril improved I(Ca,L) partly through PI3K.

Alpha-7 and alpha-4 nicotinic receptor subunit immunoreactivity in genioglossus muscle motoneurons

In the present study, immunohistochemistry combined with retrograde labeling techniques were used to determine if hypoglossal motoneurons (HMNs), retrogradely labeled after cholera toxin B subunit (CTB) injection to the genioglossus muscle in rats, show immunoreactivity for alpha-7 and alpha-4 subunits of nicotinic acetylcholine receptors (nAChRs). CTB-positive HMNs projecting to the genioglossus muscle were consistently labeled throughout the rostrocaudal extent of the hypoglossal nuclei with the greatest labeling at and caudal to area postrema. Alpha-7 subunit immunoreactivity was found in 39.44+/-5.10% of 870 CTB-labeled motoneurons and the alpha-4 subunit in 51.01+/-3.71% of 983 CTB-positive neurons. Rostrally, the number of genioglossal motoneurons demonstrating immunoreactivity for the alpha-7 subunit was 45.85+/-10.04% compared to 34.96+/-5.11% at and caudal to area postrema (P>0.1). The number of genioglossal motoneurons that showed immunoreactivity for the alpha-4 subunit was 55.03+/-4.83% at and caudal to area postrema compared to 42.98+/-3.90% in rostral areas (P=0.074). These results demonstrate that nAChR immunoreactivity is present in genioglossal motoneurons and suggest a role for alpha-7 and alpha-4 subunits containing nAChRs in the regulation of upper airway patency.

Aerobic Exercise Attenuates an Exaggerated Exercise Blood Pressure Response in Normotensive Young Adult African-American Men

An exaggerated exercise blood pressure response (EEBPR) may be associated with an increased risk of hypertension. We hypothesized that aerobic exercise training can decrease EEBPR and the risk for hypertension by decreasing arterial resistance. We studied the effects of aerobic training on the submaximal exercise blood pressure (BP) of eight normotensive young adult African-American men with an EEBPR. Subjects were trained on a stationary bicycle at an intensity of 70% peak oxygen uptake (VO 2peak ), for 30 min, three times per week, for 8 weeks. BP, heart rate, cardiac output (CO), stroke volume (SV) and total peripheral vascular resistance (TPR) were measured at rest and during submaximal exercise at a work intensity of 50% VO 2peak. Significance of the training effects were evaluated by comparing the pre- and post-training measures ( t -test, p < 0.05). A 15% post-training increase in VO 2peak (34.6 - 1.4 to 40 - 1.4 ml/kg/min) and a 9.5 ml post-training increase in mean resting stroke volume were found. A 16.2 mmHg decrement in mean systolic BP, an 11.5 mmHg decrement in mean diastolic BP, a 120 dyne/s/cm 5 decrement in TPR and a 1.2 l/min increase in CO were detected during the posttraining submaximal exercise tests. These results suggest that reductions in TPR may attenuate the EEBPR of normotensive African-American males following an 8-week training regimen of stationary bicycling at 70% VO 2peak . Aerobic exercise training may, therefore, reduce the risk of hypertension in normotensive African-American males by the mechanism of a reduction in TPR. Because of the limited number of subjects, the results of this study should be interpreted cautiously pending confirmation by a larger controlled trial.

Modulation of atrial contraction by PKA and PKC during the compensated phase of eccentric cardiac hypertrophy

Abstract.Calcium homeostasis is intimately regulated by protein kinase phosphorylation cascades that are also involved in the induction and maintenance of cardiac hypertrophy. In addition, the development of cardiac hypertrophy has been associated with alteration in the activation of the adrenergic system. Therefore, we investigated the specific role of protein kinase A (PKA) and C (PKC) on cardiac muscle contractile activity in the presence and absence of adrenergic stimulation. Isolated left atrial preparations from sham– and volume overload–induced cardiac hypertrophied rats were superfused with Tyrode and electrically stimulated at 0.75 Hz. Contraction was assessed in the basal and pre–stimulated (norepinephrine, 10–9M) states. Specific inhibitors, KT 5720 for PKA and Ro-32-0432 for PKC, were used. Peak tension development in left atria from sham–operated rats was more sensitive to PKC– than PKA–inhibition, whereas this differential sensitivity was abolished in the hypertrophied hearts. This difference was mainly due to an increase in the role of PKA in the contractile response. Developed peak tension by left atria from shunt rats was higher than that from sham rats, but when expressed to relative tissue mass, hypertrophied muscle showed weaker contraction than that from the sham group. In addition, the left atrial velocity of contraction in the sham is PKA–sensitive, while that of the shunt is PKC–sensitive. Furthermore, the velocity of relaxation shows dependency on both protein kinases, with PKC having a greater effect than PKA in the hypertrophied group. NE increased the PTD and the velocity of contraction (+dT/dt) through PKA and PKC dependent mechanisms, without affecting the velocity of relaxation (–dT/dt) in atrial muscle from sham rats. In contrast, during eccentric hypertrophy NE effectively reduced PTD as well as the –dT/dt through a PKC–dependent mechanism. The present study demonstrates that during early development of moderate eccentric cardiac hypertrophy there is: (1) a reduced specific peak tension developed due to an imbalance in the PKA and PKC activation; (2) a change in the protein kinase dependence of the velocity of contraction and relaxation from PKA to PKC with atrial hypertrophy; and (3) a negative inotropic response to adrenergic receptor stimulation. These functional responses may play a critical role in the cardiac performance during the progression of eccentric cardiac hypertrophy into the decompensated phase and heart failure.

Regulation of the instantaneous inward rectifier and the delayed outward rectifier potassium channels by Captopril and Angiotensin II via the Phosphoinositide-3 kinase pathway in volume-overload-induced hypertrophied cardiac myocytes

Summary Background Early development of cardiac hypertrophy may be beneficial but sustained hypertrophic activation leads to myocardial dysfunction. Regulation of the repolarizing currents can be modulated by the activation of humoral factors, such as angiotensin II (ANG II) through protein kinases. The aim of this work is to assess the regulation of IK and IK1 by ANG II through the PI3-K pathway in hypertrophied ventricular myocytes. Material/Methods Cardiac eccentric hypertrophy was induced through volume-overload in adult male rats by aorto-caval shunt (3 weeks). After one week half of the rats were given captopril (2 weeks; 0.5 g/l/day) and the other half served as control. The voltage-clamp and western blot techniques were used to measure the delayed outward rectifier potassium current (IK) and the instantaneous inward rectifier potassium current (IK1) and Akt activity, respectively. Results Hypertrophied cardiomyocytes showed reduction in IK and IK1. Treatment with captopril alleviated this difference seen between sham and shunt cardiomyocytes. Acute administration of ANG II (10−6M) to cardiocytes treated with captopril reduced IK and IK1 in shunts, but not in sham. Captopril treatment reversed ANG II effects on IK and IK1 in a PI3-K-independent manner. However in the absence of angiotensin converting enzyme inhibition, ANG II increased both IK and IK1 in a PI3-K-dependent manner in hypertrophied cardiomyocytes. Conclusions Thus, captopril treatment reveals a negative effect of ANG II on IK and IK1, which is PI3-K independent, whereas in the absence of angiotensin converting enzyme inhibition IK and IK1 regulation is dependent upon PI3-K.

Peripheral Vascular Compliance

The purpose of this paper is to describe some recent advances in the field of vascular compliance with particular reference to a noninvasive method to compute distensibility of small blood vessels in man. Vascular compliance is defined in physiology as the ratio of a change in volume (∆V) for a given change in pressure (∆P) in any region of the vascular bed. Its value depends on the size of the vascular bed and the elastic properties of vascular wall. If the wall properties are of primary importance, then a correction is made in the compliance calculation for size and one calculates vascular distensibility, D, defined as

Adrenergic-mediated effects of cocaine on the myocardial force-frequency relationship

D=100\left( \Delta V/V \right)/\left( \Delta P \right)