Emergence of acetylcholine resistance and loss of rhythmic activity associated with the development of hypertension, obesity, and type 2 diabetes

The aim of this work was to study the influence of aging, obesity, metabolic syndrome (MS), hypertension (HT), and type 2 diabetes (T2D) on the endogenous rhythmic activity and the development acetylcholine resistance in aorta rings of male rats. T2D was produced by a free access to fat (lard). It was shown that phenylephrine (PE) or 5-hydroxytryptamine (5-HT) induces two types of rhythmic contractions: with periods T₁ = 3–10 s and T₂ = 50–70 s and amplitudes A₁ = 1–5% and A₂ = 20–40% of the maximal contraction force (F_max), respectively. Such periodic modes can be caused by the operation of two known positive feedback loops (PFL) based on the Ca²⁺-induced activation of IP3 receptor (IP3R) or phospholipase C PFL1 and PFL2, respectively, and are not eliminated by L-NAME. Slow rhythmic activity induced by acetylcholine (Ach) with period T₃ = 7–20 min and amplitude A₃ = 20–30% of F_max was observed only in young animals (under 6 months) and can be determined by the operation of PFL3, involving Ca²⁺, NO, kinase G, cADP-ribose, and the ryanodine receptor (RyR). Fast mode of contractions (T₁, A₁) is maintained regardless of age and the presence of MS and HT (140 mm Hg and higher) and disappears only at later stages of the T2D development. Probability of intermediate mode of contractions (T₂, A₂) decreases to 0.20–0.25 at the age of 14–16 months or during the development of HT and MS. In these circumstances, Ach could cause relaxation of preconstricted rings only to 40 and 60% of F_max, respectively. At the stages of the T2D development characterized by high values of arterial pressure (above 150 mm Hg) and of the glucose (10–12 mM), ammonium (120–180 μM), and blood lipid levels, as well as by liver dysfunction (fibrosis/cirrhosis), the rhythmic activity of any type is lost and dysfunction of the initial part of the signaling cascade with the participation of PFL3 is manifested by the absence of responses to Ach or L-NAME. Coenzyme NAD (agonist of the P2Y receptors, К⁺ channel activator and a precursor of cADP-ribose) can exert a partial relaxation of aorta rings from healthy animals and animals with MS. Nicotinamide (product and an inhibitor of ADP-ribosyl cyclase) and SNP (donor of NO) produce an effective relaxation of aorta rings from healthy animals and animals with T2D. Relaxing effect of nicotinamide may suggest a tandem operation of IP3R and RyR in the control of intracellular Ca²⁺ stores in vascular cells.