The long range objective of this research project is to determine the role played by the arterial wall in the development and maintenance of hypertension. The approach proposed in this application involves the integrated study of arterial smooth muscle mechanics, contractile protein biochemistry, and collagen biochemistry. Studies will be conducted using two animal models of hypertension: a) desoxycorticosterone acetate plus saline in Wistar rats with one kidney and, b) spontaneously hypertensive rats of the Okamoto strain. Segments from the thoracic aorta, carotid and tail arteries will be employed for experimental study. Intact arterial segments from control (normotensive) and hypertensive animals will be used for the determination of mechanics with active and passive smooth muscle. Passive mechanics will be correlated with connective tissue studies, and active mechanics with contractile protein studies. Studies of arterial smooth muscle (ASM) mechanics will attempt to define some of the mechanisms involved in the changes in active force-development which occur in hypertension including: a) The effects of series elasticity, b) types of cells in the arterial wall, c) inhibition of collagen cross-linking; and d) the contractile protein content of arteries. Dose-response relations using norepinephrine and K+ activation will be determined using ASM from control and hypertensive arteries with regard to: a) muscle length dependence, b) dependence on extracellular Ca++, and c) force development verus shortening as measures of contractile function. Studies of contractile protein biochemistry will focus on: a) content of actin, myosin and tropomyosin, b) myosin ATPase activity and its regulation by actin, divalent cations and tropomyosin, and c) myosin isoenzymes. These will be correlated with measurements of force development, force-velocity relations, and series elasticity. Collagen studies will focus on: a) the effects of inhibitors of extracellular cross-linking and, b) changes in collagen types, crosslinking, and rate of synthesis. These studies will be correlated with changes in blood pressure and arterial wall mechanics.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Experimental Cardiovascular Sciences Study Section (ECS)
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Graduate Hospital (Philadelphia)
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Cox, Robert H; Fromme, Samantha (2016) Functional Expression Profile of Voltage-Gated K(+) Channel Subunits in Rat Small Mesenteric Arteries. Cell Biochem Biophys 74:263-76
Cox, Robert H; Fromme, Samantha (2015) Expression of Calcium Channel Subunit Variants in Small Mesenteric Arteries of WKY and SHR. Am J Hypertens 28:1229-39
Cox, Robert H; Fromme, Samantha J (2013) A naturally occurring truncated Cav1.2 ?1-subunit inhibits Ca2+ current in A7r5 cells. Am J Physiol Cell Physiol 305:C896-905
Ren, Gongyi; Jacob, Robert F; Kaulin, Yuri et al. (2011) Alterations in membrane caveolae and BKCa channel activity in skin fibroblasts in Smith-Lemli-Opitz syndrome. Mol Genet Metab 104:346-55
Sun, Yaxun; Quan, Xiao-Qing; Fromme, Samantha et al. (2011) A novel mutation in the KCNH2 gene associated with short QT syndrome. J Mol Cell Cardiol 50:433-41
Guo, Donglin; Lian, Jianfang; Liu, Tengxian et al. (2011) Contribution of late sodium current (I(Na-L)) to rate adaptation of ventricular repolarization and reverse use-dependence of QT-prolonging agents. Heart Rhythm 8:762-9
Cox, Robert H; Fromme, Samantha J; Folander, Kimberly L et al. (2008) Voltage gated K+ channel expression in arteries of Wistar-Kyoto and spontaneously hypertensive rats. Am J Hypertens 21:213-8
Cox, Robert H (2005) Molecular determinants of voltage-gated potassium currents in vascular smooth muscle. Cell Biochem Biophys 42:167-95
Cox, Robert H; Lozinskaya, Irina; Matsuda, Kyoko et al. (2002) Ramipril treatment alters Ca(2+) and K(+) channels in small mesenteric arteries from Wistar-Kyoto and spontaneously hypertensive rats. Am J Hypertens 15:879-90
Cox, Robert H (2002) Changes in the expression and function of arterial potassium channels during hypertension. Vascul Pharmacol 38:13-23

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