Mini-Symposium Atrial Natriuretic Factor

Regulation of Guanylate Cyclase by Atrial Natriuretic Factor and the Role of Cyclic GMP in Vasodilation

The present study investigated the analgesic effect of a novel synthetic cyclohexanone derivative, 2,6-bis-4-(hydroxyl-3-methoxybenzilidine)-cyclohexanone or BHMC in a mouse model of chronic constriction injury-induced neuropathic pain. It was demonstrated that intraperitoneal administration of BHMC (0.03, 0.1, 0.3 and 1.0 mg/kg) exhibited dose-dependent inhibition of chronic constriction injury-induced neuropathic pain in mice, when evaluated using Randall–Selitto mechanical analgesiometer. It was also demonstrated that pretreatment of naloxone (non-selective opioid receptor blocker), nor-binaltorphimine (nor-BNI, selective κ-opioid receptor blocker), but not β-funaltrexamine (β-FN, selective μ-opioid receptor blocker) and naltrindole hydrochloride (NTI, selective δ-opioid receptor blocker), reversed the anti-nociceptive effect of BHMC. In addition, the analgesic effect of BHMC was also reverted by pretreatment of 1H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one (ODQ, soluble guanosyl cyclase blocker) and glibenclamide (ATP-sensitive potassium channel blocker) but not Nω-nitro-l-arginine (l-NAME, a nitric oxide synthase blocker). Taken together, the present study demonstrated that the systemic administration of BHMC attenuated chronic constriction, injury-induced neuropathic pain. We also suggested that the possible mechanisms include κ-opioid receptor activation and nitric oxide-independent cyclic guanosine monophosphate activation of ATP-sensitive potassium channel opening.

Background B-type natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) are secreted from the heart and are thought to be equally important factors in the regulation of vascular tone in health and in congestive heart failure (CHF). However, no studies directly compare vasodilator effects of these peptides in healthy subjects and in patients with CHF. Methods Plethysmography was used to determine the vasodilatory effects of BNP and to compare these to the effects of ANP in patients with CHF (n = 15) and age-matched healthy subjects (n = 16). Graded doses of ANP and BNP (8, 16, 32, and 48 pmol/min per 100 ml of tissue volume for both) were administered randomly into the brachial artery. Forearm blood flow (FBF) was measured, and cyclic GMP (cGMP) spillover was calculated. Results Responses in FBF to both peptides in CHF were significantly lower than those of healthy subjects (BNP p < 0.05; ANP p < 0.01). Similarly, forearm spillover of cGMP was significantly lower in CHF than in healthy subjects (BNP p < 0.05; ANP p < 0.01). When vascular responses in healthy subjects were compared between BNP and ANP, BNP-induced changes in FBF (p < 0.05) and forearm cGMP spillover (p < 0.01) were significantly less than changes induced by ANP. In CHF, though, FBF change and cGMP spillover induced by the two peptides were not significantly different. Conclusions These results suggest that the metabolism and action of these natriuretic peptides in CHF may differ from the healthy state. (Am Heart J 1998;135:414-20.)

We investigated intracoronary cyclic-guanosine monophosphate (c-GMP) levels during percutaneous transluminal coronary angioplasty (PTCA) since experimental studies have shown the endothelial origin of c-GMP production. Intracoronary c-GMP and cyclic adenosine monophosphate (c-AMP) were measured during coronary angioplasty in 24 patients with chronic coronary artery disease. Four coronary blood samples were taken through a catheter from the coronary artery the first sample before coronary angiography and the other three from distal to coronary obstruction, as follows: before the balloon inflation, at the maximum inflation and 5 min after restoration of coronary flow. c-GMP increased from 7.9 ± 1.0 pmol/ml and 7.5 ± 0.9 pmol/ml before angiography and balloon inflation to 11.1 ± 1.3 pmol/ml at the maximum inflation (P < 0.01), with a trend to decrease 5 min after the end of the intervention (9.5 ± 1.0 pmol/ml, P: NS). Intracoronary c-AMP levels remained almost unchanged. Five venous samples were taken to measure c-AMP before coronary angiography, before PTCA, and 5 min, 2 h and 24 h after PTCA. c-AMP values 2 and 24 h after PTCA (17.8 ± 1.7 pmol/ml and 17.5 + 1.7 pmol/ml, respectively) were lower than the highest value (22.1 ± 2.1 pmol/ml) found 5 min after PTCA, (P < 0.001). c-GMP increases distal to coronary obstructive lesion during PTCA at the time of balloon inflation, while c-AMP remains unchanged. c-AMP rises in venous circulation only. PTCA stimulates the mechanism of c-GMP release, while systemic c-AMP increase seems to be related to the stress occurring during catheterisation and PTCA.

In animal studies, the bronchial effects of urodilatin (URO, CDD/ANP-95-126, INN: ularitide) were superior to those of cardiodilatin/atrial natriuretic peptide (CDD, CDD/ANP-99-126). We compared the bronchodilating properties of intravenous URO and CDD in 36 clinically stable asthmatics showing a β₂-agonist-induced increase of the FEV₁ by ≥ 15%. Any aerosol medication was discontinued for at least 8 h prior to the study. After baseline measurements of lung function parameters (FEV₁, VC, PEF, MEF₇₅, MEF₅₀, MEF₂₅) an intravenous infusion of 5.7, 11.4 or 17.1 pmol/kg/min URO or CDD was administered for 40 min in the morning. All measurements were repeated every 10 min during the infusion, for 30 min thereafter, and after the inhalation of 1.25 mg salbutamol (SALB). Both peptides had significant effects. While 11.4 pmol/kg/min URO dilated the central airways (FEV₁, PEF, MEF₇₅) slightly more potently than the peripheral bronchioles (MEF₅₀, MEF₂₅), 17.1 pmol/kg/min URO was as effective as SALB at all levels of the tracheobronchial tree. CDD reached only 50% of the SALB effect without a predominant localization of its action. The cardiovascular parameters revealed a significantly stronger vasorelaxant activity of CDD. In conclusion, the dose-dependent bronchodilating properties of intravenous URO were significantly superior to those of CDD.

The present study was carried out to evaluate the effects of biologically active atriopeptin II (APII) in synchronously contracting monolayer cultures of rat ventricular myocytes. The effects of 10 nm APII on Ca influx, contractile behavior and cyclic nucleotide content of the cells were measured. Applied acutely APII had no effect on Ca influx. There was however a time-dependent effect such that after 30 min Ca influx (pmol/cm²/s) had declined from a control (mean ± s.e.m.) of 1.53 ± 0.16 to 1.02 ± 0.07 (P<0.001; n = 6). There was parallel decline in both the magnitude and velocity of cell edge motion which was maximal in 30 min at which time cell edge motion measured 65.3 ± 4.4% of control. Treatment with APII for 30 min decreased cAMP (pmol/mg protein) from 5.35 ± 0.17 to 2.86 ± 0.24 (P<0.001; n = 5). At the same time cGMP (pmol/mg protein) increased from 0.86 ± 0.21 to 2.21 ± 0.33 (P<0.001; n = 5). Further studies elucidated the fact that the decline in Ca influx and contractile behavior was dependent on the decrease in cAMP rather than the increase in cGMP. Pre-treatment of the cells with 5 ng/ml of pertussis toxin to ADP-ribosylate the G_i protein abolished the effects of APII on cAMP, Ca influx and contractile behavior. The results indicate that in myocardial cells, as in other cells, APII stimulates guanylate cyclase and inhibits adenylate cyclase. The resultant fall in cAMP decreases Ca influx and negatively influences the contractile behavior of the cells.