Figure 2.

Modulators of vascular contractility. This is a schematic representation of the main regulatory pathways of vascular smooth muscle contraction, based on Brewster et al.[12,72]. Creatine kinase (CK) is colocalized with Ca²⁺ ATPase and myosin ATPase, and evidence suggests the enzyme is also colocalized with myosin light chain (LC) kinase, to rapidly supply these enzymes with ATP using creatine phosphate (Creatine ~ P) [11,12,72,88-90]. The guanidino compounds creatine and nitric oxide (NO) have a common precursor in L-Arginine [12]. NO, RhoA/Rho kinase, and calcium-dependent pathways are intracellular effectors of blood pressure-regulating systems that converge on metabolic processes fueled by CK [11,12,72,88-91,93-95]. CK is high in persons of African ancestry [11,12,72,73], and this is thought to lead to greater contractility of vascular smooth muscle [11,12,72]. Vascular contractile responses can be reduced through enhancing NO-dependent pathways, including with ACE inhibitor (ACE-i) or nebivolol-induced NO synthesis, or through indirect inhibition of CK-dependent pathways, as with calcium blockers (CaB) or β-adrenergic agonists. Calcium blockers may block the entry of calcium in the cell as well as the outflow from the sarcoendoplasmic reticulum (SER) [93]. β-adrenergic agonists reduce contractility mainly through inhibition of myosin light chain kinase [91]. β-adrenergic blockers antagonize this beneficial effect, which may help explain the more frequent occurrence of blood pressure increase with β-blockers in persons of African ancestry [3,92], within the context of the greater vascular contractility in this population subgroup [11,12,36,37,39,72]. cGMP, guanosine cyclic 3′,5′-(monophosphate); MLCP, myosin light chain phosphatase.