Relative contribution of Rho kinase and protein kinase C to myogenic tone in rat cerebral arteries in hypertension

Abstract

Arterial smooth muscle constriction in response to pressure, i.e., myogenic tone, may involve calcium-dependent and calcium-sensitization mechanisms. Calcium sensitization in vascular smooth muscle is regulated by kinases such as PKC and Rho kinase, and activity of these kinases is known to be altered in cardiovascular disorders. In the present study, we evaluated the relative contribution of PKC and Rho kinase to myogenic tone in cerebral arteries in hypertension. Myogenic tone and arterial wall calcium in Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were measured simultaneously, and the effect of PKC and Rho kinase inhibitors on myogenic tone was evaluated. SHR arteries showed significantly greater myogenic tone than WKY arteries. Pressure/wall tension-arterial wall calcium curves showed a hyperbolic relation in WKY rats, but the curves for SHR arteries were parabolic. Myogenic tone was decreased by the Rho kinase inhibitors Y-27632 and HA-1077, with a significantly greater effect in SHR than in WKY arteries. Reduction in myogenic tone produced by the PKC inhibitor bisindolylmaleimide I in WKY and SHR arteries was significantly less than that produced by Rho kinase inhibition. The pressure-dependent increase in myogenic tone was significantly decreased by Y-27632, and the decrease was markedly greater than that produced by bisindolylmaleimide I in SHR arteries. In WKY arteries, the pressure-dependent increase in myogenic tone was decreased to a similar extent by Y-27632 and bisindolylmaleimide I. These results suggest greater myogenic tone with increased calcium sensitization in SHR arteries, largely because of Rho kinase activation, with a minor contribution of PKC activation.

Inhibition of Arterial Myogenic Responses by a Mixed Aqueous Extract of Salvia Miltiorrhiza and Panax Notoginseng (PASEL) Showing Antihypertensive Effects

“…The Plum-dependent contraction is referred to as the myogenic response (MR) because the sensing mechanisms are intrinsic to the arterial smooth muscle cells. MR is critical for setting the peripheral vascular resistance and autoregulation of blood flow (Dora, 2005;Hill et al, 2006), derangement of which could promote hypertension (Koller, 2002;Jarajapu andKnot, 2005, Ahn et al, 2007). A number of signaling pathways have been suggested such as mechanosensitive nonselective cation channels (NSCms), Rho kinase (ROCK), and protein kinase C (PKC) (Hill et al, 2006;Shubert et al, 2008).…”

“…The physiological role of MR consists of regulating basal peripheral vascular resistance as well as local blood flow (Dora, 2005;Hill et al, 2006). A deranged MR has been suggested to be the result of pathophysiological changes in hypertension (Koller, 2002;Jarajapu andKnot, 2005, Ahn et al, 2007). Since MR is not observed in conduit arteries such as the femoral artery, we investigated the effects of PASEL on the MR of rat cerebral arteries.…”

Characteristics of myogenic reactivity in isolated rat mesenteric veins

“…In a second set of experiments, nifedipine (1 M) (50, 57), chelerythrine (2.5 M) (46), or Y-27632 (3 M) (12,17,44,51) was applied to the superfusing solution. These drug concentrations were chosen based on previous studies and initial preliminary work done in our laboratory.…”

The Role of Actin Filament Dynamics in the Myogenic Response of Cerebral Resistance Arteries

“…57,71 RhoA-GTP activates ROCK, which phosphorylates the regulatory subunit of MLCP, leading to inhibition of phosphatase activity. 72 Studies with PKC inhibitors have suggested a role for this kinase in the myogenic response of resistance arteries, including cerebral arteries, 14,54,73,74 but the underlying mechanism remains unclear. For example, the PKC inhibitors GF109203X (a general PKC inhibitor) and Gö 6976 (a selective inhibitor of the Ca 2 þ -dependent PKC isoforms) suppressed the myogenic response of rat middle cerebral arteries.…”