Variations in cell signaling pathways for different vasoconstrictor agonists in renal circulation of the rat.
BACKGROUND
Major cell signaling pathways involved in agonist-induced vasoconstriction are recognized to be Ca2+ mobilization via inositol-1,4,5 triphosphate (IP3), Ca2+ influx through l-type channels, activation of protein kinase C (PKC), and of Rho-associated kinase (ROK). However, their contribution for renal vasoconstriction induced by different agonists is not well characterized.


METHODS
Increasing doses of angiotensin II (Ang II), norepinephrine, and arginine vasopressin (AVP) were infused into the left renal artery of anesthetized rats to reduce renal blood flow from a threshold value to about 50%. Rightward shift of the dose-response curves due to coinfusion of inhibitors served to assess contribution of different pathways: trimethoxybenzoate (TMB-8) against Ca2+ mobilization, nifedipine against Ca2+ influx, staurosporine and Ro-318220 against PKC, and Y-27632 and HA-1077 against ROK. Effects of inhibitors were also determined for renal response to a single dose of U-46619, a thromboxane A2 agonist. Composite response to U-46619 consisting of a fast and slow component did not permit determination of dose-response curves.


RESULTS
Inhibition of ROK by Y-27632 or HA-1077 had the largest effect on renal responses to agonists. They shifted dose-response curves of Ang II, norepinephrine, and AVP to sevenfold and higher values. Staurosporine, nifedipine, and TMB-8 had variable effect on agonist responses. They attenuated effects of Ang II and norepinephrine in an additive manner, and each of them increased effective dose values about fourfold. TMB-8 did not attenuate response to AVP and U-46619. Staurosporine and nifedipine diminished effects of AVP in a nonadditive manner, and attenuated additively the fast component of U-46619 response.


CONCLUSIONS
In contrast to other cell signaling pathways, ROK plays a common role for all vasoconstrictor agonistsis in renal circulation.
Bauer
Johannes
J
Department of Physiology and Pathophysiology, University of Heidelberg, Heidelberg, Germany.
Parekh
Niranjan
N
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D009543:Nifedipine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D019311:Staurosporine / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D000577:Amides; D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D007211:Indoles; D011725:Pyridines; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D001127:Arginine Vasopressin; C108830:Y 27632; C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; D005707:Gallic Acid; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D019311:Staurosporine; D009543:Nifedipine; C049347:fasudil; C064758:Ro 31-8220; D009638:Norepinephrine