The venous effects of nitric oxide donors and the phosphodiesterase type V inhibitor, Zaprinast
Creators: name: Ng, Sylvia S. W.
Publisher: name: University of British Columbia
Year: 2009

description: It is well-documented that agents which release nitric oxide (NO) or inhibit the degradation of cGMP promote vasodilatation by interacting with the endogenous Larginine/ NO pathway. There are few published in vivo studies examining the actions of these agents on the venous circulation. Although the venous system is not as extensively studied as the arterial system, it plays a significant role in the regulation of circulatory homeostasis. By altering the activity of venous smooth muscle, capacitance vessels maintain venous return and cardiac output. Similar to its arterial counterpart, venous smooth muscle activity can be altered passively according to inflow pressure or volume, or actively via reflex- or neurohumoral-mediated mechanisms. Drugs that influence venous smooth muscle tone or reflex control of the venous system have profound effects on venous return, cardiac output and blood pressure. Venodilatation unequivocally contributes to the therapeutic effectiveness of sodium nitroprusside and nitroglycerin in the management of hypertensive emergencies and chronic heart failure, respectively. It should be noted that not all vasodilator drugs dilate capacitance vessels. Hydralazine, for example, is an efficacious arterial dilator which lacks venodilator action. Therefore, better knowledge of the in vivo venous actions of vasodilators is essential to improving treatment strategies in cardiovascular pathology. The current thesis investigated the effects of five nitrovasodilators, diethylamine/nitric oxide (DEA/NO) complex, S-nitroso-N-acetylpenicillamine (SNAP), nitroxy(ɳ5-cyclopentadienyl)- dinitrosylchromium (CpCr(NO)₂(ONO)), sodium nitroprusside (SNP) and nitroglycerin (NTG), as well as the phosphodiesterase type V inhibitor, zaprinast, on mean arterial pressure (MAP), arterial resistance (Ra), cardiac output (CO), heart rate (HR), mean circulatory filling pressure (MCFP) and venous resistance (Rv) in groups of thiobutabarbital anaesthetized rats under basal conditions, and in the presence of mecamylamine (3.7 μmol kg⁻¹) and noradrenaline (7.3 nmol kg⁻¹ min⁻¹). Mecamylamine and noradrenaline were used to suppress autonomic reflexes and elevate venomotor tone, respectively. This protocol enhances the assessment of the venodilator activity of drugs. Experimentally, MCFP is the mean vascular pressure that would exist following circulatory arrest and instantaneous redistribution of blood throughout the circulation. Thus, MCFP is conceptually the driving force of venous return at the level of the venules. Total body venous resistance (Rv) is best estimated by the ratio of (MCFP - right atrial pressure) to CO. In intact rats, zaprinast (ED₄₀ and ED₈₀ doses, 1.5, 3.0 mg kg⁻¹ min⁻¹, respectively) and SNP (8.0, 64.0 μg kg kg⁻¹ min⁻¹) dose dependently reduced MAP and Ra, but did not alter CO and Rv . Both increased HR, with the effect of zaprinast less than that of SNP. In ganglion-blocked rats with elevated venomotor tone, zaprinast and SNP elicited dose-dependent reductions in MAP, MCFP, Ra and Rv . Both increased CO, with the effect of zaprinast greater than that of SNP at the low dose. Zaprinast but not SNP reduced HR. It was concluded that zaprinast, similar to SNP, dilates both resistance and capacitance vessels in ganglion-blocked rats with restored vasomotor tone. Zaprinast but not SNP has a direct, negative chronotropic effect on the heart. In the second series of experiments, all the thiobutabarbital-anaesthetized rats were pretreated with mecamylamine (3.7 umol kg⁻¹, i.v. bolus) and continuously infused with noradrenaline (6.8 nmol kg⁻¹ min⁻¹) for the reasons mentioned above. DEA/NO (ED₃₀, ED₈₀ and ED₁₀₀, 4, 32 and 256 μg kg"1 min"1, respectively), SNAP (4, 32 and 256 ug kg"1 min"1), CpCr(NO)₂(ONO) (4, 32 and 256 μg kg⁻¹ min⁻¹), SNP (8, 32 and 128 μgkg⁻¹ min⁻¹) and NTG (0.2, 0.8 and 6.4 μg kg⁻¹ min⁻¹) caused similar dose-dependent increments in CO. HR was not altered by any of the five nitrovasodilators. All five drugs dose-dependently reduced both MAP and Ra with efficacy: DEA/NO ≈ SNAP ≈ CpCr(NO)₂(ONO) ≈ SNP &gt; NTG. DEA/NO, SNAP, CpCr(NO)₂(ONO) and SNP but not NTG lowered MCFP with efficacy: DEA/NO &gt; SNAP &gt; CpCr(NO)₂(ONO) ≈ SNP. All five drugs reduced Rv with efficacy: DEA/NO ≈ SNAP ≈ CpCr(NO)₂(ONO) ≈ SNP &gt; NTG. Therefore, the hypotensive, arterial and venous dilator actions of DEA/NO, SNAP and CpCr(NO)₂(ONO) are comparable to those of SNP but greater than those of NTG. It would be of interest to evaluate the therapeutic potential of these new NO donors as alternatives for SNP and NTG in the management of cardiovascular dysfunction in future studies. Key words: zaprinast; cGMP-selective phosphodiesterase; NO/nucleophile complexes; Snitrosothiols; organotransition-metal dinitrosyl complexes; sodium nitroprusside; nitroglycerin; capacitance vessels; mean circulatory filling pressure; venous resistance