Calcium channel blocking drugs (CCBs) target voltage-gated L-type Ca2+ (CaL) channels and are used to treat human essential hypertension and coronary insufficiency. Most antihypertensive drugs are designed to target the arterial circulation, but the venous circulation is equally important in blood pressure regulation as venous return determines cardiac output. Although understanding contractile mechanisms regulating venoconstriction is crucial for the development of new venodilator drugs for the treatment of hypertension, the venous circulation is an understudied component of the circulatory system. We hypothesize that voltage- gated, L-type Ca2+ channels are expressed but inactivated in venous SMCs. Our initial findings of """"""""silent"""""""" CaL channels in the venous circulation may provide new insight into the insensitivity of the venous circulation to CCBs, and also help to design new experiments to define alternative mechanisms that regulate venous tone. To address our central hypothesis, we have developed the following specific aims: 1: Demonstrate that depolarization-induced constriction of rat small mesenteric veins in vitro and in vitro is not dependent on Ca2+ influx via L-type Ca2+ (CaL) channels like in arteries, but instead depends on Ca2+ release from intracellular stores. 2: Determine if CaL channels fail to express in SMCs of rat small mesenteric veins, show abnormal voltage-activation or inactivation properties, or are insensitive to dihydropyridine blockers compared to arterial CaL channels. 3: Begin to define the contribution of specific intracellular Ca2+ stores to depolarization-induced contraction in rat small mesenteric veins, focusing first on the IP3 receptors and ryanodine receptors. Relevance: Approximately 60 million American suffer from hypertension and many of these patients require two or more drugs to achieve adequate blood pressure control. The role of the venous circulation in blood pressure regulation has been historically overlooked. Thus, understanding mechanisms of venoconstriction may lead to the development of more effective and novel therapies for the treatment of hypertension.
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| Joseph, Biny K; Thakali, Keshari M; Pathan, Asif R et al. (2011) Postsynaptic density-95 scaffolding of Shaker-type K? channels in smooth muscle cells regulates the diameter of cerebral arteries. J Physiol 589:5143-52 |
| Thakali, Keshari M; Kharade, Sujay V; Sonkusare, Swapnil K et al. (2010) Intracellular Ca2+ silences L-type Ca2+ channels in mesenteric veins: mechanism of venous smooth muscle resistance to calcium channel blockers. Circ Res 106:739-47 |
