| Summary: | 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 > NTG. DEA/NO, SNAP, CpCr(NO)₂(ONO) and SNP but not NTG lowered MCFP with efficacy: DEA/NO >
SNAP > CpCr(NO)₂(ONO) ≈ SNP. All five drugs reduced Rv with efficacy: DEA/NO ≈
SNAP ≈ CpCr(NO)₂(ONO) ≈ SNP > 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 === Medicine, Faculty of === Anesthesiology, Pharmacology and Therapeutics, Department of === Graduate
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