Paul D. Joiner

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 sympathetic stimulation and vasoactive substances on the canine pulmonary veins.

The contribution of the intrapulmonary lobar veins to the increase in pulmonary vascular resistance in response to sympathetic stimulation was studied under conditions of controlled blood flow in the anesthetized dog in which vascular pressures were measured simultaneously in the perfused lobar artery, an intrapulmonary lobar vein 2-3 mm in diameter and in the left atrium. Stimulation of the stellate ganglia at 3, 10, and 30 cycles/s increased pressure in the lobar artery and small vein in a stimulus-related manner but decreased pressure in the left atrium. Injection of norepinephrine into the perfused lobar artery also increased pressure in the lobar artery and small vein but decreased pressure in the left atrium. The increase in lobar arterial and venous pressure in response to either injected norepinephrine or to nerve stimulation was antagonized by an alpha receptor blocking agent. The rise in pressure in both labor artery and small vein with nerve stimulation but not administered norepinephrine was inhibited by an adrenergic nerve terminal blocking agent. The results suggest that under conditions of steady flow, sympathetic nerve stimulation increases the resistance to flow in the lung by constricting pulmonary veins and vessels upstream to the small veins, and that at each stimulus-frequency studied approximately 50% of the total increase in resistance may be due to venoconstriction. It is concluded that the increase in resistance to flow in the lung in response to nerve stimulation is thre result of activation of alpha adrenergic receptors by norephinephrine liberated from adrenergic nerve terminals in venous segments and in vessels upstream to samll veins, presumed to be small arteries.

Effect of prostaglandin E2 on pulmonary vascular resistance in intact dog, swine and lamb.

The effects of prostaglandin E2 (PGE2) on pulmonary vascular resistance in the intact dog, swine and lamb were studied using a right heart catheterization technique to isolate and perfuse the left lower lung lobe at controlled blood flow. Infusion of PGE2 into the lobar artery increased lobar arterial perfusion pressure but did not alter pressure in the left atrium in all 3 species. The increase in lobar arterial pressure was associated with a rise in pressure in the small intrapulmonary lobar vein in the dog but no change in pressure in these veins in the swine and lamb. Infusion of PGE2 into the iliac artery produced a marked decrease in perfusion pressure in the hindlimb of the dog. The effects of PGE2 on the canine lung occurred in the absence of any significant change in arterial blood gases, pH, hematocrit or rate and volume of respiration, and this substance increased pulmonary vascular resistance when the lung was perfused with dextran instead of blood. These results show that in dog, swine and lamb, PGE2 increases pulmonary vascular resistance; however, the site of vasoconstriction is different in the dog and swine or lamb. In the swine and lamb vasoconstriction occurred primarily in vessels upstream to the small veins, presumably small arteries, whereas in the dog lung, the pre- and postcapillary vessels were actively constricted by this naturally occurring substance.

Effects of prostaglandins E1 and F2a on the swine pulmonary circulation.

Summary The effects of PGF2α and PGE1 on the swine pulmonary circulation were studied using a new right heart catheterization technique. Infusion of PGF2α into the lobar artery increased lobar arterial pressure but did not change pressures in the small lobar vein or the left atrium. Infusion of PGE1 into the lobar artery decreased lobar arterial pressure but did not alter pressure in the small lobar vein or the left atrium. These results indicate that under conditions of controlled blood flow in the swine PGF2α increases pulmonary vascular resistance by actively constricting vessels upstream from the small lobar veins. Present results show that PGE1 decreases pulmonary vascular resistance in this species by actively dilating vessels upstream from small lobar veins, presumably the lobar arteries. It is concluded that in the swine pulmonary circulation the precapillary vessels are very responsive to prostaglandins E1 and F2α.

Effect of sympathetic nerve stimulation on pulmonary vascular resistance in the intact spontaneously breathing dog.

Summary The effects of sympathetic nerve stimulation on pulmonary vascular resistance under conditions of controlled blood flow were evaluated in the intact spontaneously breathing dog. Stimulation of the sympathetic nerves to the lung resulted in a significant stimulus-related increase in pulmonary vascular resistance in the intact animal. Injected norepinephrine had similar effects on the pulmonary vascular bed and responses to both norepinephrine and nerve stimulation were blocked by phentolamine, an alpha receptor blocking agent. It is concluded that the pressor response to nerve stimulation is mediated by alpha receptors in the pulmonary vascular bed and that this response is similar in magnitude in both the intact spontaneously breathing and open-chest animal.

Influence of prostaglandins E1 and F2a on pulmonary vascular resistance in the sheep.

Summary The effects of PGF2α and PGE1 on pulmonary vascular resistance in the intact sheep were investigated using a new right heart catheterization technique. PGF2α increased lobar arterial pressure but did not change pressures in the small lobar vein or left atrium. PGE1 decreased lobar arterial pressure but did not alter pressure in the small lobar vein or the left atrium. These results indicate under conditions of controlled blood flow PGF2α increases pulmonary vascular resistance by constricting vessels upstream from the small lobar veins whereas PGE1 decreases pulmonary vascular resistance by dilating upstream vessels, presumably the lobar arteries. Neither prostaglandin altered systemic arterial pressure. It is concluded that in the sheep lung the precapillary vessels are responsive to prostaglandins E1 and F2α.

Effects of indomethacin on venoconstrictor responses to bradykinin and norepinephrine.

In order to determine whether the venoconstrictor response to BK was dependent on prostaglandin (PG) synthesis, effects of indomethacin (INDO) on responses to bradykinin (BK) and norepinephrine (NE) were studied in canine lateral saphenous vein. Cumlative dose-response curves (10-9-10-6M BK or NE) were done in the presence and absence of INDO (10-6M). In the presence of INDO, responses to BK were markedly enhanced while responses to NE were unchanged. After prolonged periods in the bath, responses to BK were enhanced in control strips while responses of strips which had been treated with INDO were depressed. These results suggest that BK does not normally cause venoconstriction by stimulating synthesis of a venoconstrictor PG and that the increase in response to BK after prolonged periods in the bath may be related to changes in PG synthesis.

Bronchopulmonary arterial shunting without anatomic anastomosis in the dog.

The effects of bronchial arterial administration of vasoactive substances on the pulmonary circulation were studied by a new technique for selective catheterization of a bronchial artery in intact dogs. In most experiments, this technique permitted pressor agents to be distributed mainly to one lung with smaller amounts to the other lung. The intercostal arteries were avoided, and in all but 2 of 23 experiments only microscopic quantities of injected India ink could be identified in the distributions of the esophageal and mediastinal branches. These studies indicate that serotonin, angiotensin, histamine, and norepinephrine injected selectively into a bronchial artery increase lobar arterial pressure. Since blood flow was constant and left atrial pressure did not change, the increase in pressure suggests active pulmonary vasoconstriction. Additionally, the responses to bronchial and lobar arterial injections of pressor agents were similar. The contribution of bronchopulmonary shunt flow to pulmonary flow was small, since, under conditions of controlled lobar blood flow, changes in bronchial flow elicited by 65–75-mm Hg changes in bronchial arterial pressure produced little if any change in pressure in the perfused lobar artery or small vein. Bronchoconstriction contributed little to the response to bronchial administration of pressor agents, since responses were similar in the ventilated and the collapsed lobe. Injection of vasoflavine dyes into the bronchial-artery showed the close proximity of bronchial and pulmonary arteries and confirmed the bronchial arterial origin of the vasa vasorum of pulmonary arteries. No vasa venorum were identified. Although no direct anatomic bronchial artery-pulmonary artery shunt was identified, ascorbic acid and 5-hydroxydopamine diffused rapidly into intrapulmonary arteries from the bronchial artery. These data suggest that the pulmonary pressor response results from passage of the vasoactive agents from the bronchial artery to the lobar artery through the vasa vasorum and by diffusion. Since no vasa venorum were found, pulmonary venoconstriction probably resulted from pressor agents reaching the veins by way of bronchopulmonary shunt flow. These results suggest a mechanism by which pressor substances present or liberated in the bronchial vascular bed can affect tone in the pulmonary vascular bed.

Actions of prostaglandins E1 and F2alpha on isolated intrapulmonary vascular smooth muscle.

Summary The effects of PGE1 and PGF2α were studied on isolated strips of intrapulmonary arteries and veins from dog, sheep, swine and man. PGF2α contracted human arterial strips in a dose-dependent fashion, relaxed slightly sheep arteries and had no effect on dog arteries. Canine, sheep and human venous strips were contracted by PGF2α. PGE1 relaxed slightly both veins and arteries from dog and sheep. Human arteries usually contracted slightly and human veins usually relaxed slightly to PGE1. In a limited number of experiments, swine arteries and veins failed to respond to PGF2α or PGE1. All the vascular strips contracted well when exposed to NE. These results suggest that the responses of intrapulmonary vessels to PGF2α and PGE1 are species-dependent. PGF2α generally exhibits a contractile action, especially on veins. PGE1 usually relaxes intrapulmonary vessels. With regard to vessels from man, PGF2α is a powerful stimulant while PGE1 produces only small, variable effects.

Differential Effects of Phentolamine and Bretylium on Pulmonary Vascular Responses to Norepinephrine and Nerve Stimulation

Summary The effects of specific adrenergic blocking agents on pulmonary vascular responses to sympathetic nerve stimulation and norepinephrine were evaluated in the perfused dog lung using a new right heart catheterization procedure which avoids dissection and cannulation of lobar vessels. The increase in pulmonary vascular resistance in response to nerve stimulation and norepinephrine but not serotonin was antagonized by phentolamine, an alpha receptor blocking agent. Responses to nerve stimulation but not exogenous norepinephrine were antagonized by bretylium, an adrenergic nerve terminal blocking agent. It is concluded that the pressor response to nerve stimulation is due to activation of alpha receptors by endogenous norepinephrine released from sympathetic nerve endings in the pulmonary blood vessels.