Increased cAMP signaling can ameliorate the hypertensive condition in spontaneously hypertensive rats

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).

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

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.

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.