Increased cAMP signaling can ameliorate the hypertensive condition in spontaneously hypertensive rats.
OBJECTIVE
Augmented adrenergic control of total peripheral vascular resistance (TPVR) in spontaneously hypertensive rats (SHR) may result from deficiencies in the vasodilatory system(s). Here, we studied the effect of cyclic AMP (cAMP) on TPVR-baseline and adrenergic vasoconstriction in SHR and normotensive controls (WKY).


METHODS
Blood pressure and cardiac output were monitored in anesthetized rats, and TPVR calculated.


RESULTS
cAMP-analogue (8CPT-cAMP) and phosphodiesterase (PDE) 3 inhibitor (milrinone) reduced TPVR in both strains. G(i) inactivator (pertussis toxin) lowered TPVR but not in all SHR. DeltaTPVR induced by alpha(1)-adrenoceptor agonist (phenylephrine) was reduced by 8CPT-cAMP and milrinone in both strains. They also clearly reduced the response to endogenous noradrenaline release (tyramine) in SHR but had little effect in WKY. When pertussis toxin reduced baseline, it also eliminated the tyramine TPVR response. Propranolol did not change the effect of milrinone on the phenylephrine or tyramine response. Strain-related differences in aorta, femoral arteries or skeletal muscle PDE activity (total/PDE3/PDE4) were absent.


CONCLUSIONS
cAMP signaling down-stream of cAMP was functional in SHR, and opposed alpha(1)-adrenoceptor vasoconstriction in both strains. G(i) activity greatly influenced the TPVR baseline and adrenergic TPVR responses, and its activity appeared increased in SHR. Therapeutics aiming to increase signaling through this pathway may turn out to be valuable in the treatment of hypertension.
Department of Physiology, Institute of Basic Medical Sciences, Blindern, Oslo, Norway. torill.berg@medisin.uio.no
Torill
T
Berg
Eva
E
Degerman
Kjetil
K
Tasken
D037361:Adenylate Cyclase Toxin / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism; D005263:Femoral Artery / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D020105:Milrinone / Q000494:pharmacology; D054792:Muscle, Striated / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000502:physiology*; D013873:Thionucleotides / Q000494:pharmacology; D014439:Tyramine / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects*
D037361:Adenylate Cyclase Toxin; D013873:Thionucleotides; D010656:Phenylephrine; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D011433:Propranolol; D000242:Cyclic AMP; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D020105:Milrinone; D014439:Tyramine