Stanley Greenberg

Enhanced responses to tyramine and angiotensin produced by 4,4′-biphenylene bis-[(2-oxoethylene)-bis-(2,2-diethoxyethyl) dimethylammonium bromide] (DMAE)☆

Abstract The contractile responses of the acutely denervated (g.f.n.m.) and decentralized (d.n.m.) nictitatingmembrane of the cat to angiotensin (0.2 – 0.4 μg/kg), tyramine (50 – 100 μg/kg) and norepinephrine (1 – 2 μg/kg) were measured before and after the administration of cumulative doses of DMAE (0.8 – 3.2 mg/kg, i.v.). The contractile responses of the g.f.n.m. and d.n.m. to each of the agonists did not differ. Twenty minutes after the administration of DMAE the contractile responses of both nictitating membranes to angiotensin, tyramine and norepinephrine were enhanced to the same extent. Nerve terminal blockade by bretylium and reserpine-induced catecholamine depletion antagonized the responses to angiotensin and tyramine and blocked DMAE-induced potentiation of the contractile responses to these agonists. Atropine reduced significantly the contractile responses of the g.f.n.m. and d.n.m. to angiotensin but did not affect either the response of the membrane to tyramine or DMAE-induced potentiation of the responses to angiotensin. These results suggest that DMAE acts to enhance, as well as cause, release of catecholamines from the adrenergic nerve terminal. The results also suggest that a portion of the contractile response of the d.n.m. and g.f.n.m. to angiotensin is mediated by stimulation of neuronal cholinergic muscarinic receptors which result in release of norepinephrine.

Evidence for longitudinal smooth muscle fibers in canine mesenteric arteries.

Abstract Superfused helical strips of canine anterior mesenteric arteries relaxed in approximately 12% of the preparations when challenged with vasoconstrictor agents such as serotonin, norepinephrine, barium chloride and KCl. The muscle fibers in most of these preparations were longitudinally oriented.

Lack of Correlation Between Initial Vascular Resistance and Responses to Vasoconstrictor Stimuli in the Perfused Canine Hindpaw

Summary The effect of initial vascular resistance on the vascular responses of the perfused canine hindpaw to nitroglycerin, norepinephrine, tyramine, sympathetic nerve stimulation and angiotensin was evaluated. Initial resistances were altered by (a) vasodilator drugs (nitroglycerin and prostaglandin B1) and (b) background infusions of norepinephrine and prostaglandin B2. Over a wide range of initial vascular resistances, the absolute magnitude of dilator responses of the perfused canine hindpaw to nitroglycerin is directly proportional to the level of initial vascular resistance. Over the pressure range of most physiologic and pharmacologic perfusions (80-400 mm Hg; 2.7-18.5 peripheral resistance units), the change in resistance produced by stimulation of the sympathetic nerves and intraarterial norepinephrine, tyramine and angiotensin was independent of the initial vascular resistance and the mode by which these resistances were altered. Although the larger total vascular resistances developed when initial resistances were higher, the magnitude of induced increases in vascular resistance was unchanged. If these results are extrapolated to constant flow perfusion experiments utilizing the canine hindpaw, in which the initial vascular resistance increases as a result of physiologic or pharmacologic interventions, they indicate that changes in response to a given constrictor agonist produced during drug-induced changes in vascular resistance would result from the intrinsic activity of the drug and not secondary to the change in vascular resistance. The authors gratefully acknowledge the generous gift of prostaglandins from Drs. J. R. Week and J. E. Pike of the Upjohn Co., Kalamazoo, MI. We also express our appreciation to Dr. M. J. Brody for his helpful suggestions and critical appraisal of this manuscript.

A comparison of the effects of cocaine in arterial and venous smooth muscle responses to vasoactive stimuli.

Summary Cocaine (2.3 × 10~6- M) enhanced the contractile responses of super-fused mesenteric arteries, and cutaneous arteries and veins to norepinephrine. This effect was probably related to inhibition of the neuronal catecholamine reuptake mechanism and not to nonspecific supersensitivity since the contractile responses to tyramine were significantly reduced but the contractile responses to barium and potassium chlorides essentially unchanged. The adrenergic nerves of these blood vessels were confined to a dense innervation in the region of the adventitial medial border with some nerves apparently present in the outer portion of the media (dorsal metatarsal vein). In contrast to these findings, the anterior mesenteric veins responded only with a small response to tyramine, which was inhibited by cocaine. However, the contractile responses to norepinephrine were not enhanced 30 min after the addition of cocaine to the superfusate. The anterior mesenteric vein displayed a sparse and diffuse adrenergic innervation. It was concluded that the inability of cocaine to enhance the contractile responses of mesenteric veins to norepinephrine resulted from the sparse distribution of the nerve endings in this vein and perhaps from a difference in the neuronal membrane adrenergic amine reuptake mechanism.

Effects of Prostaglandin B2 on Renal Hemodynamics and Excretion

Summary and Conclusion The infusion of PGB2 into canine renal arteries produces a dose related increase in total RBF and U Na V. The increasing variability in RBF and N Na V with increasing dose may be due to a transition from vasodilator to vasoconstrictor action. The results obtained demonstrate that PGB2 affects renal hemodynamics and excretion qualitatively the same as PGE1, PGE2, PGA1 and PGA2.

Interaction of ouabain and diphenylhydantoin (DPH) with the cardiovascular actions of prostaglandin B2 and prostaglandin A2

Abstract Several reports have appeared indicating that ouabain may interact at sites on smooth muscle susceptible to activation by prostaglandins. This study reports on the interaction between ouabain (0) and diphenylhydantoin (DPH) with the cardiovascular actions of prostaglandin B 2 (PGB 2 ) and prostaglandin A 2 (PGA 2 ). Fifteen μg/kg i.v. of 0 enhanced the pressor response of the canine hindpaw to norepinephrine and tyramine but did not affect the pressor responses to sympathetic nerve stimulation (SNS), PGB 2 or PGA 2 . PGB 2 -induced bronchoconstriction (mediated solely by stimulation of smooth muscle) was reduced by ouabain. In a separate group of animals not receiving PG before 0, 0 reduced (p 2 . DPH enhanced the cutaneous pressor responses to SNS, NE, PGB 2 and PGA 2 but did not affect the bronchoconstrictor response to PGB 2 . These data are consistent with the following conclusions: 1) Ouabain antagonizes the smooth muscle contractions produced by PGB 2 . 2) The presence of PGB 2 antagonizes the prostaglandin inhibitory effects of ouabain suggesting that PGB 2 may compete for similar sites or allosterically interact with ouabain in smooth muscle. 3) DPH induced enhancement of PGB 2 and PGA 2 induced vasoconstriction may reflect DPH induced enhancement of adrenergic neurotransmitter release or inhibition of transmitter reuptake.

Cardiovascular pharmacology of prostaglandin B1 and B2 in the intact dog.

Summary The effects of intravenous PGB1 and PGB2 on systemic pressure, HLPP, HP PP, PAP and LVP were evaluated in intact anesthetized dogs. Both PGB1 or PGB2 decreased SAP, LVP and HR but did not affect either RAP or LVEDP. These PGB-induced decreases in systemic pressure probably reflected the decreased LVP as well as vasodilatation in the renal bed. Since PGB1 and PGB2 both increased PAP without increased LVEDP, the data suggest that these prostaglandins increased the resistance across the lungs. Furthermore, PGB2 was a potent constrictor of the perfused canine hindpaw when administered intra-arterially into the paw or intravenously. The data are compatible with the conclusion that PGB1 and PGB2 possess vasodilator and vasoconstrictor activity on the canine cardiovascular system. PGB2 is a more potent prostaglandin than PGB1. The authors express their appreciation to Miss Marilyn F. Mosle for her excellent technical assistance. The generous gift of PGB1 and PGB2 from Drs. J. R. Weeks and J. E. Pike of the Upjohn Co., Kalamazoo, MI, is gratefully acknowledged.

Effects of prostaglandin B2 on vascular tone and reactivity.

Abstract Superfused helical strips of canine anterior mesenteric arteries and veins and canine dorsal metatarsal veins contract in response to prostaglandin B 2 (PGB 2 ). Reserpine pretreatment and phentolamine reduce the constrictor response to PGB 2 . PGB 2 enhances the contractile responses of these preparations to potassium, barium and norepinephrine. PGB 2 also produced a shift to the left in the duration of the barium response curve. The data presented demonstrate that PGB 2 is not an inactive metabolite of PGA 2 metabolism but possesses potent constrictor activity probably dependent on release of norepinephrine from adrenergic nerves. Furthermore, PGB 2 enhances the responses of vascular smooth muscle to vasoactive stimuli.

Effect of Prostaglandin F2 (PGF2 ) on Venous Contractility and 45Ca Uptake

Summary PGF2α enhanced the contractile responses of superfused helical strips of canine cutaneous venous smooth muscle to norepinephrine and the ionic stimulant, barium chloride, in the absence of any significant effect of PGF2α on venous tone. PGF2α also enhanced norepinephrine-induced 45Ca uptake as well as the rate of 45Ca exchange. It was concluded that PGF2α acts to enhance smooth muscle membrane permeability to calcium ion. In addition, it appears that PGF2α may act within the smooth muscle cell to enhance the rate of transcellular calcium exchange.

Enhancement of neural and thermal vasoconstriction by prostaglandin B1.

Summary The vascular effects of prosta-glandin B1 (PGB1) were studied during constant-flow perfusion of the canine hind-paw. The effects of PGB1 (50-200 ng/kg/ min ia) on systemic and hindpaw perfusion pressures and on responses to local cooling (4°C for 90 sec) and local heating (45°C for 60 sec) were measured in 15 dogs. PGB1 (50-100 ng/kg/min) decreased perfusion pressure without any significant effect on systemic arterial pressure. Higher concentrations of PGB1 (200 ng/kg/min) elevated perfusion pressure to control values. The pressor responses to local cooling were increased from 11 to 32 mmHg while the dilator responses to local heating and nitro-glycerin were reduced during infusions of PGB1. PGB1 also enhanced the pressor responses to norepinephrine or tyramine. These findings support the conclusions that (1) low concentrations of prostaglandin B1 enhance neurotransmitter release with minimal effects on vascular smooth muscle cells and (2) these effects are not secondary to increased perfusion pressures or vascular wall stresses since infusions of PGB1 resulted in vasodilation. The generous supply of prostaglandin B used in this study was donated by Drs. J. R. Weeks and J. E. Pike of the Upjohn Company.