B M Chapnick

Influence of inhibitors of prostaglandin synthesis on renal vascular resistance and on renal vascular responses to vasopressor and vasodilator agents in the cat.

We determined the effects of indomethacin and meclofenamate, two inhibitors of prostaglandin synthesis, on renal vascular resistance and on renal responses to nerve stimulation, pressor and depressor hormones in the in situ feline kidney under conditions of controlled blood flow. Both inhibitors produced a gradual rise in renal vascular resistance which became maximal 15-20 minutes after administration. The increase in renal resistance after indomethacin was not attenuated during intrarenal infusion of either phentolamine or SQ 20881. Pretreat-ment with propranolol, in a dose sufficient to inhibit renin secretion, also did not attenuate the increase in renal resistance produced by indomethacin. However, infusion of [Sar1,Ala8]angiotensin II, an angiotensin II antagonist, did attenuate the indomethacin-induced increase in renal vascular resistance. After indomethacin, the vasoconstrictor response to norepinephrine was enhanced, whereas responses to nerve stimulation and angiotensin were unaffected. Although meclofenamate enhanced renal vascular resistance, its effects on vasoconstrictor responses were inconsistent. After indomethacin, the renal dilator response to bradykinin was enhanced; however, dilator responses to nitroglycerin were unaltered. The present data indicate that the increase in renal vascular resistance after indomethacin does not depend on the adrenergic system but may be dependent on the renin-angiotensin system. The inconsistent effect of the inhibitors of synthesis on renal constrictor responses to nerve stimulation suggests that endogenous prostaglandins do not serve to modulate the effects of the sympathetic nervous system on the feline renal vascular bed. These results also indicate that renal dilator responses to bradykinin are not mediated by prostaglandins in the cat.

Influence of prostaglandin E2, indomethacin, and reserpine on renal vascular responses to nerve stimulation, pressor and depressor hormones.

The effects of prostaglandin E2 (PGE2) indomethacin, and reserpine were evaluated in the rabbit renal vascular bed in situ under conditions of controlled blood flow. Intrarenal infusion of PGE2, 0.03 and 0.3 microgram/min, decreased responses to renal nerve stimulation, intra-arterial norepinephrine, and angiotensin. Responses to nerve stimulation were decreased to a greater extent than responses to norepinephrine. At lower concentrations the effects of PGE2 on pressor responses and on vascular resistance could be separated. Reserpine decreased the histochemical evidence of adrenergic innervation and reduced the response to renal nerve stimulation, enhanced the response to norepinephrine, and was without effect on the response to angiotensin. Indomethacin decreased depressor responses to arachidonic acid, produced a small increase in renal vascular resistance but did not enhance renal pressor responses. The increase in renal vascular resistance after indomethacin was not modified by reserpine pretreatment. Indomethacin enhanced the renal response to bradykinin. These data show that PGE2 possesses the ability to modulate pressor responses in the kidney. However, experiments with indomethacin suggest that endogenous prostaglandins neither modulate pressor responses nor mediate the response of the renal vascular bed to bradykinin. In addition, these data suggest that the increase in renal resistance after indomethacin is not dependent on the adrenergic nervous system.

Inhibition of vasoconstrictor responses by 6-keto-PGE1 in the feline mesenteric vascular bed.

The effects of 6-keto-PGE1 on vascular resistance and vascular responses to sympathetic nerve stimulation and vasoconstrictor hormones were investigated in the feline mesenteric vascular bed. Infusions of 6-keto-PGE1 into the superior mesenteric artery dilated the mesenteric vascular bed and markedly inhibited vasoconstrictor responses to sympathetic nerve stimulation, norepinephrine and angiotensin II. The effects of 6-keto-PGE1 and PGE1 on vascular resistance and vasoconstrictor responses were quite similar and both substances inhibited responses to nerve stimulation and pressor hormones in a reversible manner. Responses to nerve stimulation, norepinephrine and angiotensin II were inhibited to a similar extent during infusion of 6-keto-PGE1 and PGE1. Results of these studies suggest that 6-keto-PGE1, a newly identified prostaglandin metabolite, and PGE1 possess the ability to inhibit the vasoconstrictor effects of sympathetic nerve stimulation and pressor hormones by a non-specific action on vascular smooth muscle in the feline small intestine.

Evidence for separate PGD2 and PGF2α receptors in the canine mesenteric vascular bed

Abstract Potential interactions between PGD2 and PGF2α in the mesenteric and renal vascular beds were investigated in the anesthetized dog. Regional blood flows were measured with electromagnetic flow probes. PGD2, PGF2α and Norepinephrine (NE) were injected as a bolus directly into the appropriate artery, and responses to these agents were obtained before, during and after infusion of either PGD2 or PGF2α into the left ventricle. In each case, the infused prostaglandin caused vascular effects of its own. Left ventricular infusion of PGD2 reduced responses to local injections of PGD2 in the intestine, and a similar effect was observed for PGF2α, suggesting significant receptor or receptor-like interactions for each of the prostanoids. However, systemic infusion of prostaglandin F2α (20–100 ng/kg/min) had no effect on renal or mesenteric vascular responses to local injection of prostaglandin D2. Similarly, PGD2 administration (100 ng/kg/min) did not affect responses to PGF2α in the intestine. The present results therefore suggest that these prostaglandins, i.e., D2 and F2α, act through separate receptors in the mesenteric and renal vascular beds. In addition, increased prostaglandin F2α levels produced by infusion of F2α reduced mesenteric but not renal blood flow, suggesting that redistribution of cardiac output might participate in side effects often observed with clinical use of this prostaglandin, such as nausea and abdominal pain.

Influence of prostaglandins on vasoconstrictor responses in the hindquarters vascular bed of the cat

The effects of prostaglandins (PG), A1, A2, B2, E1, 6-keto-E1, F2 alpha and indomethacin on vascular resistance and vasoconstrictor responses were investigated in the feline hindquarters vascular bed under conditions of controlled flow so that changes in perfusion pressure directly reflect changes in vascular resistance. Infusion of PGE1, PGE2 and 6-keto-PGE1 (3 microgram/min) into the abdominal aorta significantly dilated the hindquarters vascular bed and inhibited vasoconstrictor responses to sympathetic nerve stimulation and intra-arterial injections of angiotensin, whereas hindquarters vasoconstrictor responses to tyramine and exogenous norepinephrine were unaffected. Infusion of PGA1, A2, B2 and F2 alpha at a similar rate produced transient changes in hindquarters vascular resistance and did not consistently alter vasoconstrictor responses to sympathetic nerve stimulation, angiotensin, norepinephrine and tyramine. Indomethacin in a dose which greatly attenuates the response to intravenous administration of arachidonic acid enhanced responses to nerve stimulation and norepinephrine. In addition, indomethacin had little or no effect on hindquarters perfusion pressure and systemic arterial pressure. These data suggest that E series prostaglandins possess the ability to modulate the actions of the sympathetic nervous system and angiotensin in the feline hindquarters vascular bed. In addition, these data suggest that PGEs, upon enzymatic conversion and dehydration to A and B series prostaglandins, lose their ability to consistently affect vasoconstrictor responses. Experiments with indomethacin further suggest that locally formed prostaglandins do modulate the effects of the sympathetic nervous system of the feline hindquarters.

Effects of 13, 14-dehydroprostacyclin methyl ester on the feline intestinal vascular bed

The effects of a stable PGI2 analog, 13, 14-dehydro-PGI2 methyl ester and several vasoactive hormones were compared in the feline intestinal vascular bed under conditions of controlled blood flow so that changes in perfusion pressure directly reflect changes in vascular resistance. The PGI2 analog decreased perfusion pressure in a dose-dependent fashion when injected in the range of dose of 0.03-3 microgram and was quite similar to PGE2 whereas isoproterenol was somewhat more potent as a vasodilagor in the feline intestinal vascular bed. The present data show that 13, 14-dehydro-PGI2 methyl ester has potent vasodilator activity in the intestinal vascular bed.

The influence of indomethacin on vasodilator responses to bradykinin and nitroglycerin in the cat.

The effects of indomethacin, a cyclooxygenase inhibitor, on vasodilator responses to bradykinin and nitroglycerin were investigated in the peripheral vascular bed of the anesthetized cat. Intra-arterial injections of bradykinin and nitroglycerin elicited dose-related decreases in mesenteric and hindquarters vascular resistance. Mesenteric vasodilator responses to nitroglycerin in absolute units were unchanged 30 min after administration of indomethacin whereas responses to bradykinin expressed as an absolute mm Hg decrease in perfusion pressure were increased. Indomethacin was also without effect on vasodilator responses to lower doses of nitroglycerin whereas responses to higher doses of nitroglycerin and bradykinin in absolute units were enhanced in the hindquarters vascular bed. Indomethacin increased vascular resistance in the mesenteric and hindquarters vascular beds and decreased systemic vasodepressor responses to the prostaglandin precursor, arachidonic acid. When the increase in (initial value) vascular resistance was taken into account by expressing vasodilator responses on a percent decrease basis, indomethacin only enhanced the vasodilator response to the highest does of bradykinin studies. Result of the present study suggest that products in the cyclooxygenase pathway may serve to maintain the peripheral vascular bed of the cat in a dilated state but that these metabolites do not mediate vasodilator responses to bradykinin. The present data further suggest that products in the cyclooxygenase pathway may play a minor role in modulating the dilator effects of bradykinin in the mesenteric and hindquarters vascular beds of the cat.

Comparison of α-MSH and several vasoactive substances on vascular resistance in the feline mesenteric vascular bed ☆

The effects of alpha-MSH and several other vasoactive substances on the mesenteric vascular bed were studied in the anesthetized cat under conditions of controlled blood flow. Intra-arterial injections of alpha-MSH in doses of 10, 30, and 100 mug resulted in significant dose-related decreases in mesenteric arterial perfusion pressure but little or no effect on systemic arterial pressure. The vasodilator response to alpha-MSH was breif in duration and resistance to flow was decreased 10, 18, and 26 percent at 10, 30, and 100 mug. These significant changes after alpha-MSH were of a much smaller magnitude than were observed after prostaglandins E1 and E2, isoproterenol, bradykinin or glyceryl trinitrate and differed completely from the increased resistance after angiotensin II and norepinephrine.

The effect of PGH2 on blood flow in the canine renal and superior mesenteric vascular beds

Effects of the prostaglandin endoperoxide, PGH2, were investigated in the renal and superior mesenteric vascular beds in anesthetized dogs. Vascular effects of a stable PGH2 analog were also studied in the intestine. Blood flow was measured with electromagnetic flowmeters and vasoactive hormones were administered by close intra-arterial injection. Authentic PGH2 increased blood flow in the kidney and intestine in a dose-related manner. Mesenteric blood flow was reduced by the PGH2 analog in a dose-dependent fashion which was similar to the vasoconstrictor activity of norepinephrine in this organ. PGH2 is biologically unstable and the type and activity of its metabolic products may vary in different regional vascular beds. Most of the known products of PGH2 metabolism in the kidney are vasodilators whereas in the intestine both vasodilator and vasoconstrictor metabolites are formed. It has been suggested that the vascular activity of PGH2 in an organ is dependent on the predominant type and activity of specific terminal enzymes that convert PGH2 to its various vaso-active products.

COMPARISON OF VASODEPRESSOR AND VASODILATOR EFFECTS OF PROSTAGLANDINS E1, E2, I2 AND 6-KETO-E1*

This chapter presents a comparison of the vasodepressor and vasodilator effects of prostaglandins (PGs) E 1 , E 2 , I 2 and 6–Keto–E. PGs E 1 , E 2 , and I 2 reduce blood pressure and increase blood flow in most peripheral vascular beds. These substances produce renal and mesenteric vasodilation when administered either intravenously (I.V.) or by direct, close-arterial injection or infusion. A novel metabolite of prostacyclin PGI 2 has been identified, which appears to possess the properties that are similar to those of PGI 2 . This substance, 6–Keto—PGE 1 , inhibits platelet aggregation and lowers blood pressure and renal vascular resistance in the rat. It has been suggested that 6–Keto–PGE 1 may mediate some of the effects of PGI 2 . The aim of a study described in the chapter was to compare the activity of 6–Keto–PGE 1 with that of PGI 2 on blood pressure and renal and mesenteric hemodynamics in the dog—a species in which the effects of 6–Keto–PGE 1 have not been studied.