veratrine and Ventricular-Dysfunction--Left

Experiments were undertaken to determine whether angiotensin (Ang) II concentration increases during massive sympathetic nervous system (SNS) activation and whether such an increase plays a role in the pathogenesis of SNS-induced left ventricular (LV) dysfunction. We also sought to determine whether excessive Ca2+ uptake through L-type channels due to intense adrenoceptor activation is responsible for the LV dysfunction. AngII concentration was measured in the plasma and myocardium before and after massively activating the SNS with an intracisternal injection of veratrine. In separate experiments, rabbits were given losartan, enalaprilat, enalaprilat plus HOE-140, nifedipine, -Bay K 4866, or saline before massively activating the SNS. LV function was evaluated 2.5 h later. The intense SNS activity caused plasma and myocardial AngII to increase by 400 and 437%, respectively. AngII receptor blockade did not prevent LV dysfunction. In contrast, enalaprilat reduced the degree of dysfunction, but its cardioprotection was abolished by HOE-140. Although nifedipine prevented SNS-induced LV dysfunction, administration of the Ca2+ channel opener, -Bay K 4866, did not increase its severity. Our results indicate that AngII is not involved in the pathogenesis of SNS-induced LV dysfunction and that the cardioprotection provided by angiotensin converting enzyme (ACE) inhibition is due to activation of a bradykinin pathway. Furthermore, the finding that the magnitude of the LV dysfunction was reduced by enalaprilat, and not increased by -Bay K 4866, suggests that intense adrenoceptor activation of L-type Ca2+ channels is not the primary pathogenetic mechanism.

Topics: Adrenergic beta-Antagonists; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Arrhythmia Agents; Antihypertensive Agents; Blood Pressure; Calcium; Calcium Channel Agonists; Calcium Channel Blockers; Calcium Channels, L-Type; Heart Rate; Rabbits; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Sympathetic Nervous System; Vasoconstrictor Agents; Ventricular Dysfunction, Left; Veratrine

This study was undertaken to determine whether endothelium-derived relaxing factor (EDRF) modulates the pulmonary and systemic hemodynamic responses to massive sympathetic nervous system (SNS) activation and, in so doing, also modulates the degree of SNS-induced left ventricular (LV) dysfunction and the likelihood for pulmonary edema formation. The SNS of 13 anesthetized untreated rabbits and 14 anesthetized rabbits pretreated with the EDRF inhibitor, N omega-nitro-L-arginine (L-NNA, 20 mg/kg), was massively activated with an intracisternal injection of veratrine. Pulmonary and systemic arterial pressures increased to the same extent in both groups, but LV end-diastolic pressure was significantly lower in untreated rabbits. During this time, cardiac output decreased by 37% in L-NNA pretreated rabbits compared with 8% in untreated animals. Peak systemic and pulmonary vascular resistances increased significantly in L-NNA rabbits, whereas only systemic vascular resistance increased significantly in untreated rabbits. However, this increase in systemic vascular resistance was threefold less than that observed for L-NNA-treated animals. Although the degree of LV dysfunction was greater in the L-NNA rabbits, pulmonary edema developed less frequently in this group. We suggest that when EDRF release is inhibited during massive SNS activity, pulmonary vascular resistance increases markedly, which causes the right ventricle to fail. We further suggest that the reduced right ventricular output maintains pulmonary microvascular pressure below levels required for edema development.

Topics: Animals; Arginine; Epinephrine; Extravascular Lung Water; Hemodynamics; In Vitro Techniques; Nitric Oxide; Nitroarginine; Norepinephrine; Pulmonary Circulation; Pulmonary Edema; Rabbits; Sympathetic Nervous System; Ventricular Dysfunction, Left; Ventricular Function, Right; Veratrine