β1-Blockers Enhance Inotropy of Endogenous Catecholamines in Chronic Heart Failure

Although β1-blockers impressively reduce mortality in chronic heart failure (CHF), there are concerns about negative inotropic effects and worsening of hemodynamics in acute decompensated heart failure. May receptor theory dispel these concerns and confirm clinical practice to use β1-blockers? In CHF, concentrations of catecholamines at the β1-adrenoceptors usually exceed their dissociation constants (KDs). The homodimeric β1-adrenoceptors have a receptor reserve and display negative cooperativity. We considered the binomial distribution of occupied receptor dimers with respect to the interaction of an exogenous β1-blocker and elevated endogenous agonist concentrations > [KDs], corresponding to an elevated sympathetic tone. Modeling based on binomial distribution suggests that despite the presence of a low concentration of the antagonist, the activation of the dimer receptors is higher than that in its absence. Obviously, the antagonist improves the ratio of the dimer receptors with only single agonist activation compared with the dimer receptors with double activation. This leads to increased positive inotropic effects of endogenous catecholamines due to a β1-blocker. To understand the positive inotropic sequels of β1-blockers in CHF is clinically relevant. This article may help to eliminate the skepticism of clinicians about the use of β1-blockers because of their supposed negative inotropic effect, since, on the contrary, a positive inotropic effect can be expected for receptor-theoretical reasons.

Effect of renal denervation on catecholamines and the renin–angiotensin–aldosterone system

Introduction: The effect of renal sympathetic denervation (RDN) on neurohormonal responses is largely unknown. We aimed to assess the effect of RDN on the renin–angiotensin–aldosterone system (RAAS) and endogenous catecholamines. Methods: A total of 60 patients with hypertension underwent RDN and remained on a stable antihypertensive drug regimen. Samples for plasma aldosterone, plasma renin and urine (nor)metanephrine were collected at baseline and at 6 months post procedure. Ambulatory blood pressure (BP) recordings were obtained at baseline and at 6 months post procedure. Results: Mean age was 64±9 years, and 30/60 patients were male. At 6 months, average daytime systolic and diastolic ambulatory BP decreased by 10 and 6 mmHg, respectively ( p<0.001). No significant change was observed in plasma aldosterone (median=248.0 pmol/L (interquartile range (IQR) 113.3–369.5 pmol/L) vs. median=233.0 pmol/L (IQR 110.3–360.8 pmol/L); p=0.66); renin (median=19.5 µIU/mL (IQR 6.8–119.5 µIU/mL) vs. median=14.3 µIU/mL (IQR 7.2–58.0 µIU/mL); p=0.32), urine metanephrine (median=0.46 µmol/L (IQR 0.24–0.77 µmol/L) vs. median=0.46 µmol/L (IQR 0.22–0.88 µmol/L); p=0.75) and normetanephrine (median=1.41 µmol/L (IQR 0.93–2.00 µmol/L vs. median =1.56 (IQR 0.74–2.50 µmol/L); p=0.58) between baseline and 6 months, respectively. No correlation was found between the decrease in mean systolic daytime BP and changes in RAAS hormones or endogenous catecholamines. Conclusion: Despite significant reductions in ambulatory BP, RDN did not result in a significant change in endogenous catecholamines or in RAAS hormones at 6 months.

Effect of adrenalectomy on pulmonary edema resolution

Purpose: The capacity of the lung to clear edema fluid has been shown to be one of the factors that can influence the prognosis of cardiogenic and noncardiogenic pulmonary edema. Active Na+ transport across the alveolar epithelium is the main driving force involved in this physiological process. Since endogenous catecholamines are known to activate the sodium-dependent mechanism of alveolar edema clearance, the objective of the present study was to explore if adrenalectomy, which prevents the release of endogenous catecholamines and other hormones, such as corticosterone, into circulation, would affect edema resolution in a model of lung injury induced by thiourea. Methods: A high-permeability pulmonary edema was induced in adult male Sprague-Dawley rats using a thiourea-induced pulmonary edema model. To determine if the release of adrenalin and corticosterone is essential for resolution of the thiourea-induced edema, we measured 1) the release of adrenalin and corticosterone in urine and 2) edema resolution in control animals and adrenalectomized animals. Results: The administration of thiourea significantly increased the wet-to-dry ratio after four and eight hours. After 12 and 24 hours, the wet-to-dry ratio gradually returned to baseline. Although thiourea-induced pulmonary edema was associated with a significant increase in urine adrenalin and corticosterone, the absence of adrenalin and corticosterone response in adrenalectomized animals did not prevent the resolution of the edema. Conclusions: These experiments demonstrated that resolution of thioureainduced pulmonary edema can occur in the absence of hormonal secretion by the adrenal glands.

Shock – Classification and Pathophysiological Principles of Therapeutics

The management of patients with shock is extremely challenging because of the myriad of possible clinical presentations in cardiogenic shock, septic shock and hypovolemic shock and the limitations of contemporary therapeutic options. The treatment of shock includes the administration of endogenous catecholamines (epinephrine, norepinephrine, and dopamine) as well as various vasopressor agents that have shown efficacy in the treatment of the various types of shock. In addition to the endogenous catecholamines, dobutamine, isoproterenol, phenylephrine, and milrinone have served as the mainstays of shock therapy for several decades. Recently, experimental studies have suggested that newer agents such as vasopressin, selepressin, calcium-sensitizing agents like levosimendan, cardiac-specific myosin activators like omecamtiv mecarbil (OM), istaroxime, and natriuretic peptides like nesiritide can enhance shock therapy, especially when shock presents a more complex clinical picture than normal. However, their ability to improve clinical outcomes remains to be proven. It is the purpose of this review to describe the mechanism of action, dosage requirements, advantages and disadvantages, and specific indications and contraindications for the use of each of these catecholamines and vasopressors, as well as to elucidate the most important clinical trials that serve as the basis of contemporary shock therapy.

Seizure activity after xylazine administration in a horse

A vicious stallion, schedule for castration, became very stressed during the attempts to place a jugular catheter. Finally, xylazine was injected direcdy from the syringe into the jugular vein and immediately the animal fell down and developed seizures. Acepromazine and fluids were administered to successfully treat the condition. No evidence of haematoma formation was noticed. Xylazine in stressed animals may activate al-adrenoceptors, resulting to central neural system excitement and seizures. Moreover, xylazine may had sensitized the myocardium to endogenous catecholamines, resulting to cardiac arrhythmias, cerebral hypoxia and seizures. Xylazine administration in stressed animals may increase the incidence of adverse reactions.