Robert W. Watkins

Antiplatelet and antiproliferative effects of SCH 51866, a novel type 1 and type 5 phosphodiesterase inhibitor.

SCH 51866 is a potent and selective PDE1 and PDE5 inhibitor. The antiplatelet, antiproliferative, and hemodynamic effects of SCH 51866 were compared with those of E4021, a highly selective PDE5 inhibitor. SCH 51866 inhibited PDE1 and PDE5 isozymes with a 50% inhibitory concentration (IC50) of 70 and 60 nM, respectively. SCH 51866 and E4021 inhibited washed human platelet aggregation induced by collagen with an IC50 of 10 and 4 microM, respectively, and attenuated (p < 0.05) the adhesion of 111indium-labeled platelets to the nylon filament-injured rat aorta. The doses of SCH 51866 and E4021 that inhibited platelet adhesion caused significant increases in platelet cyclic guanosine monophosphate (cGMP; p < 0.05). SCH 51866 (1-10 mg/kg, p.o. twice daily) but not E4021 (3-30 mg/kg, p.o twice daily) inhibited neointima formation in the carotid arteries of spontaneously hypertensive rats (SHRs) subjected to balloon angioplasty. Moreover, SCH 51866 (0.3-10 mg/kg, p.o.) elicited dose-dependent reduction in blood pressure in SHRs, whereas E4021 (3-30 mg/kg, p.o.) did not affect blood pressure in SHRs. In conclusion, the data suggest that inhibition of PDE1 and PDE5 isozymes by SCH 51866 exerts antiplatelet and vascular protective effects. In comparison, inhibition of PDE5 alone by E4021 exhibited antiplatelet effects without affecting neointima formation.

Comparative effects of nitroprusside and nitroglycerin; actions on phasic and tonic components of arterial smooth muscle contraction

Abstract Nitroprusside shares many of the pharmacological actions of nitroglycerin. We investigated the characteristics of the relaxant action of these two vasodilators on vascular smooth muscle. Both drugs completely reduced, in a dose-related fashion, the maximal tension developed in rabbit aortic strips isometrically contracted with angiotensin-II or a submaximal epinephrine contraction (70% of maximal). The ED 50 values for the two drugs were similar, but their dose-response curves were not parallel. For aortic strips maximally contracted with epinephrine, only 70% relaxation was achieved with single maximal effective doses of nitroprusside or nitroglycerin, and the ED 50 was increased 25- and 630-fold respectively. Complete relaxation could not be induced by combined effects of single doses of the two drugs although cumulative exposure to nitroprusside, but not to nitroglycerin, caused complete relaxation. Pretreatment of aortic strips with nitroprusside or nitroglycerin decreased their reactivity to epinephrine (decrease of potency and intrinsic activity) and completely blocked angiotensin contractions. Contraction velocity analysis revealed that nitroprusside and nitroglycerin reduced the tonic contribution to total epinephrine contraction by 64 and 47% respectively; the phasic contribution was reduced by approximately 50% by either vasodilator. Angiotensin-induced contraction was reduced also by nitroprusside and nitroglycerin. It is postulated that the limitation of both phasic and tonic modalities of contraction by nitroprusside and nitroglycerin is due to a membranal action of the vasodilators to promote not only less uptake but also a loss of Ca 2+ which could explain the attenuation of phasic (angiotensin) contraction and in addition the decrease observed for the tonic component of epinephrine-induced contraction.

Contraction velocity analysis of norepinephrine and angiotensin-II activation of vascular smooth muscle.

The contractile response of vascular smooth muscle is known to consist of fast and slow components of contraction. We investigated the effect of norepinephrine and angiotensin-II on these functional properties of vascular smooth muscle in a quantitative fashion by analyzing the velocity of isometric tension development in rabbit aortic strips as a function of time. Basic premises for contraction velocity analysis are: (1) tension development is proportional to agonist concentration and relates to the amount of calcium fixed by the contractile proteins; (2) the rate of tension development (Qt) reflects the rate calcium is mobilized; (3) the rate at which calcium is made available relates to agonist concentration; (4) calcium is available from internal and external sites; (5) the calcium source)s) activated are characteristic of the mechanism of action of a particular agonist, and (6) the source of calcium activated is identifiable. Aortic strips were contracted maximally with norepinephrine and the velocity of contraction found to decrease with time according to the empirical expression Qt = phi 1e-phi 2t + theta 1e-the 2t. Experiments in calcium-free medium served to identify the tonic component of norepinephrine-induced contraction as the second term while angiotensin demonstrated only one term (phasic) which was independent of extracellular calcium. Strips contracted with different concentrations of norepinephrine or angiotensin showed dose-dependent actions on these functional properties of vascular smooth muscle as revealed by their effects on the contraction velocity parameters. An expression describing the contribution of each component to total tension developed was derived by integrating the above expression to give Qtot = phi 1 (1--e-phi 2tmax)/phi 2 + theta 1 (1--e-theta 2tmax)/theta 2. The contribution of each component to total tension development was donse-dependent and their sum gave the total tension observed experimentally with norepinephrine. For angiotensin, the first term of the preceeding expression gave the observed tension response. It is concluded that contraction velocity analysis affords a new approach for studying the effects of vasoactive agents on the functional properties of vascular smooth muscle.

Effects of the antihypertensive dilevalol on aortic compliance in anesthetized dogs.

The present study examined the actions of dilevalol, an antihypertensive β-adrenoceptor blocker with arterial vasodilator actions, on aortic compliance (AC) in anesthetized dogs. AC was measured by sonomicrometric determination of the ratio of aortic systolic-diastolic diameters (mm) and arterial pulse pressure (mm Hg). One AC unit (ACU) equals 10−3 mm/mm Hg. Dilevalol (0.032, 0.1, and 3.2 mg/kg intravenously, i.v.) significantly (p < .05) increased AC by 1.4 ± 0.3, 3.7 ± 1.4, and 4.5 ± 1.2 ACU from basal values of 4.7 ± 0.4–5.6 ± 0.4 ACU while reducing blood pressure by 20 ± 2, 31 ± 9, and 41 ± 10 mm Hg, respectively (p < 0.05). Increases in AC were not the passive result of altered blood pressure. Proximal mechanical aortic occlusion dropped systolic blood pressure as much as 70 mm Hg without altering AC. Hydralazine also (0.3 and 1.0 mg/kg i.v.) lowered blood pressure significantly (p < 0.05) by 14 ± 3 and 40 ± 4 mm Hg but increased AC only at 1.0 mg/kg (+ 1.6 ± 0.4 ACU, p < 0.05). Phenylephrine (1–30 μg/kg i.v.) significantly raised blood pressure 25 ± 3–95 ± 8 mm Hg but decreased AC significantly by 1.2 ± 0.3–2.4 ± 0.3 ACU. Isoproterenol (ISO) (0.01–1.0 μg/kg) produced effects on AC similar to those of dilevalol. Propranolol pretreatment attenuated dilevalol and ISO-induced increases in AC. Propranolol (0.32 and 1.0 mg/kg) did not significantly change AC. Pindolol (0.1–1.0 mg/kg i.v.) lowered blood pressure 17 ± 3 (p < 0.05) to 34 ± 7 mm Hg (p < 0.05) while significantly increasing AC by 1.2 ± 2–2.7 ± .7 ACU. Nitroglycerin was the most effective agent studied: At 0.1–10 μg/kg i.v., it increased AC by 0.3 ± .1–7.9 ± 2.0 ACU. The data show that dilevalol, unlike propranolol, increases AC substantially at antihypertensive doses. The inhibition of dilevalol-induced AC increases by propranolol demonstrates a β-adrenoceptor agonist activity in large arteries.

Nitroprusside, but not ANF inhibits venoconstriction in an in situ rat model

Potential venodilator actions of nitroprusside (10 and 50 micrograms/min) and ANF (23 amino acid rat sequence, 10 and 30 micrograms/min) were assessed in rats subjected to cardiopulmonary bypass. Norepinephrine (NE, 10 micrograms) caused arterial pressor, i.e. increased perfusion pressure and venoconstrictor, i.e. increased venous flow, effects. ANF infusion failed to alter NE-induced pressor and venoconstrictor effects while nitroprusside significantly inhibited NE responses. Thus nitroprusside but not ANF, shows venodilator properties in this in situ rat model.