Up-regulation of vascular and renal mitogen-activated protein kinases in hypertensive rats is normalized by inhibitors of the Na+/Mg2+ exchanger.
In the present in vivo study, we have investigated whether inhibitors of the Na(+)/Mg(2+) exchanger quinidine and imipramine influence the development of hypertension and whether this is associated with modulation of mitogen-activated protein (MAP) kinase activation in arteries and kidneys of hypertensive rats. Sprague-Dawley rats were divided into four groups (n =6/group): control (vehicle), angiotensin II (Ang II; 150 ng/kg of body weight per min subcutaneously), quinidine [Ang II (150 ng/kg of body weight per min)+quinidine (5 mg/kg of body weight per day in food)] and imipramine groups [Ang II (150 ng/kg of body weight per min)+imipramine (5 mg/kg/day in food)]. Rats were studied for 3 weeks. Phosphorylation of vascular and renal extracellular-signal-regulated protein kinase 1/2 (ERK1/2), p38MAP kinase and c-Jun N-terminal kinase (JNK) were assessed using phospho-specific antibodies. Ang II increased systolic blood pressure from 112+/-5 mmHg to 215+/-9 mmHg ( P <0.01). Development of hypertension was attenuated in Ang II-infused rats treated with quinidine (173+/-6 mmHg) and imipramine (152+/-6 mmHg) (P <0.01). Phosphorylation of ERK1/2, p38MAP kinase and JNK, which were increased 2-3-fold in arteries of the Ang II group, were reduced by quinidine and imipramine (P <0.05). Activation of renal MAP kinases was also increased in the Ang II group (P <0.05). Quinidine and imipramine reduced the phosphorylation of renal ERK1/2, but did not modify renal p38MAP kinase or JNK. Our data demonstrate that Ang II induces severe hypertension in Sprague-Dawley rats and this is associated with increased phosphorylation of vascular and renal MAP kinases. Quinidine and imipramine attenuated the development of hypertension and normalized MAP kinase activity. The findings from this study suggest a possible role for the Na(+)/Mg(2+) exchanger in vascular signalling events associated with blood pressure elevation in Ang II-dependent hypertension.
Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, 110 Pine Ave West, Montreal, Quebec, Canada H2W 1R7. touyzr@ircm.qc.ca
Rhian M
RM
Touyz
Guoying
G
Yao
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D017920:Antiporters / Q000037:antagonists & inhibitors / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control; D007099:Imipramine / Q000494:pharmacology / Q000627:therapeutic use; D007672:Kidney Cortex / Q000201:enzymology; D008297:Male; D008638:Mesenteric Arteries / Q000201:enzymology; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011802:Quinidine / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects*
D017920:Antiporters; C046250:sodium-magnesium antiporter; D000804:Angiotensin II; D020928:Mitogen-Activated Protein Kinases; D011802:Quinidine; D007099:Imipramine