Tyrosine kinases regulate intracellular calcium during alpha(2)-adrenergic contraction in rat aorta.
We have demonstrated enhanced contractile sensitivity to the alpha(2)-adrenoreceptor (alpha(2)-AR) agonist UK-14304 in arteries from rats made hypertensive with chronic nitric oxide synthase (NOS) inhibition (LHR) compared with arteries from normotensive rats (NR); additionally, this contraction requires Ca(2+) entry. We hypothesized that tyrosine kinases augment alpha(2)-AR contraction in LHR arteries by increasing Ca(2+). The tyrosine kinase inhibitor tyrphostin 23 significantly attenuated UK-14304 contraction of denuded thoracic aortic rings from NR and LHR. However, tyrphostin 23 did not alter UK-14304 contraction in ionomycin-permeabilized aorta, which indicates that tyrosine kinases regulate intracellular Ca(2+) concentration. The Src family inhibitor PP1 and the epidermal growth factor receptor kinase inhibitor AG-1478 did not alter alpha(2)-AR contraction, whereas the mitogen-activated protein kinase extracellular signal-regulated kinase kinase inhibitor PD-98059 attenuated the contraction. Contraction to CaCl(2) in ionomycin-permeabilized LHR rings was greater than in NR rings. UK-14304 augmented CaCl(2) contraction in ionomycin-permeabilized rings from both groups but to a greater extent in LHR aorta. Together, these data suggest that alpha(2)-AR stimulates contraction via two pathways. One, which is enhanced with NOS inhibition hypertension, activates Ca(2+) sensitivity and is independent of tyrosine kinases. The other is tyrosine kinase dependent and regulates intracellular Ca(2+) concentration.
Carter
Rebecca W
RW
Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque 87131-5218, USA. bcarter@salud.unm.edu
Kanagy
Nancy L
NL
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000502:physiology*; D000068438:Brimonidine Tartrate; D002118:Calcium / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006973:Hypertension / Q000378:metabolism; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology
C108123:4-amino-5-(4-methylphenyl)-7-(tert-butyl)pyrazolo(3,4-d)pyrimidine; D000316:Adrenergic alpha-Agonists; D004791:Enzyme Inhibitors; D005419:Flavonoids; D011720:Pyrazoles; D011743:Pyrimidines; D011799:Quinazolines; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D020032:Tyrphostins; C101044:RTKI cpd; D000068438:Brimonidine Tartrate; D019001:Nitric Oxide Synthase; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases; C060641:tyrphostin A23; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium