Biomedical subjects
Publications and source records attributed to B Pernow.
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The undecapeptide substance P (SP) is a normal constituent of most tissues, particularly the central and peripheral nervous system. SP-immunoreactive cell bodies and terminal networks are distributed in most areas of the brain. Particular interest has been focused on the presence and function of SP in the primary sensory neuron. SP is released from both the central and peripheral part of the sensory neuron following stimulation of the dorsal roots and peripheral sensory nerves. Evidence is given for a transmitter role of SP in the sensory neurons and for the hypothesis that SP is involved in the vascular effects induced by sensory stimulation, referred to as the axon reflex. SP is present in large amounts in the gastro-intestinal tract. By immunohistochemistry SP is demonstrated within nerve cell bodies and terminals of the intramular plexuses but also in extrinsic neurons. It is released both from intrinsic sensory neurons of the gut and from the gastro-intestinal lumen in response to vagal stimulation. SP stimulates motor activity and is ascribed a regulatory role for both the intestinal motility and blood flow. SP has numerous pharmacological effects, the most obvious being excitation of spinal motoneurons, vasodilation and stimulation of salivary and pancreatic secretion. It is a normal constituent of blood plasma but there is no evidence that SP acts as a circulating hormone.
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By means of the immunohistochemical technique of Coons and collaborators, numerous peptide-containing neurons have been observed in the brain, spinal cord and periphery. These neurons may contain peptides such as substance P, vasoactive intestinal polypeptide (VIP), enkephalin or somatostatin. Some systems are very extensive. For example, immunoreactive substance P has been observed in more than 30 cell groups in the central nervous system, in primary sensory neurons, in sensory neurons in the vagus nerve and in taste buds, and in intestinal neurons. Thus, one and the same peptide can be utilized at many different levels in the nervous system. Several examples are now known where a regulatory peptide occurs together with a classical transmitter, such as a catecholamine, in the same neuron, which suggests the possibility that a neuron can release more than one transmitter substance. Of particular interest is the occurrence of VIP in presumed cholinergic neurons innervating exocrine glands in the cat, and the coexistence of a cholecystokinin (CCK)-like peptide in dopamine neurons projecting mainly to limbic areas. In the former system VIP seems to be responsible mainly for vasodilation, whereas acetylcholine mainly causes secretion. Furthermore, combined infusion of both substances in very low doses results in a marked potentiation of the secretory and vasodilatory responses. Thus, we have an example where two putative transmitters, released from the same nerve endings, seem to cooperate to activate a physiological response (secretion). With regard to the central CCK/dopamine neurons the type of interaction between the two coexisting transmitter candidates is at present unclear. It is suggested that elucidation of different types of coexistence phenomena may advance our understanding of chemical transmission at synapses under normal and pathological conditions, and may lead to new approaches to the treatment of some nervous disorders.
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1. A thermodilution method was developed for the determination of human leg blood flow. The method is based on bolus injection of an indicator distally into the femoral vein, at room temperature, and recording of the dilution curve in the same vessel at the level of the inguinal ligament. The blood flow was computed automatically with two thermistors and an integrator. 2. The leg blood flow determined by this method at rest and during exercise at work loads of 50, 100 and 150 W in six healthy subjects was found to agree closely with measurements by an intraarterial indicator-dilution technique. A linear relationship was found between leg blood flow and work. The reproducibility of the blood flow determinations, expressed as the coefficient of variation for a single determination, was 12.9 at rest and 5.3 or less during exercise. 3. The method was used in two patients with occlusive arterial disease of the leg. Extremely low leg blood flows were found in these patients when they were forced to interrupt the exercise by severe calf pain
The indirect immunofluorescence technique of Coons and collaborators was used to study the distribution of substance P-like and luliberin (luteinizing hormone-releasing hormone)-like immunoreactivity in the eminentia mediana (eminentia medialis or infundibulum) of rats, monkeys, and human beings. In rats, abundant luliberin-positive fibers were present in the external layer (mainly lateral parts) whereas almost no substance P-immunoreactive nerves were observed in this region. In contrast, in the external layer of the primate eminentia medialis a dense plexus of substance P-positive nerve terminals was observed close to the blood vessels supplying the anterior pituitary gland. Luliberin-immunoreactive fibers were also present, but with a more even distribution all over the eminentia medialis and in lower numbers. The present findings indicate that substance P may play a role in the control of hormone secretion from the anterior pituitary, either by being released into the portal vessels, i.e., acting as a releasing or inhibitory hormone, or by an action as local regulator (modulator or transmitter) at the level of the eminentia medialis. Thus, in agreement with many earlier studies, substances other than the "classical" releasing and inhibitory hormones may be important for the regulation of the pituitary gland. Furthermore, there may exist marked species differences with regard to the type of substances involved in the central control of the pituitary.
Intradermal injection of synthetic substance P (10(-7)--10(-5) M in humans produced flare, wheal and itching. These responses were inhibited by oral pretreatment of the subjects with an antihistaminic drug (chlorcyclizine) or by local pretreatment with Compound 48/80 administered to deplete the local stores of mast-cell bound histamine. The findings indicate that the responses induced by substance P were mainly mediated by histamine released from the dermal mast cells. In contrast to previously studied histamine liberators, substance P was less potent when acting on rat mast cells in vitro than on human skin mast cells in vivo. When incubated with rat peritoneal mast cells, about 100 times higher concentrations (10(-5) M) were required to induce histamine release than in the in vivo studies on humans. It was concluded that substance P is a potent histamine liberator in human skin.
Ten patients with essential hypertension have been studied at rest, during and after exercise following oral treatment for on an average 16 months with a beta-adrenoreceptor blocking agent, pindolol. The study was a direct continuation of an earlier, performed after 2 months' treatment. The hypotensive effect of pindolol was highly significant after 2 as well as 16 months of treatment. Heart rate was similarly lowered at 2 and 16 months, while carciac output, which was significantly lower during exercise after 2 months, had increased to the pretreatment level after 16 months. Peripheral vascular resistance, which was not affected after 2 months, had decreased significantly during and after exercise in the long-term study. A comparison between the hemodynamic situations after 2 and 16 months thus suggests that while a decrease in cardiac output is an early mechanism in the lowering of BP, changes in systemic vascular resistance seem to be more important after long-term treatment with pindolol.
Five men and five women, mean age 48 years, with hypertension in stages I or II of the WHO classification, were given preoral treatment with pindolol. The pindolol treatment lead a significant decrease in the systolic and diastolic blood pressure, at rest and during work both after 2 months and after 16 months treatment. Three mechanisms seem to be involved in the antihypertensive effect of pindolol: 1) a negative chronotropic effect on the heart, 2) a decrease in peripheral vascular resistance and 3) an increase in venous capacitance affecting the venous return. Comparison of the results after 2 and after 16 months of treatment suggests that a decrease in cardiac output is an early mechanism in the lowering of the blood pressure, while a decrease in vascular resistance seems to be more important after long-term treatment with pindolol.
Ten patients, mean age 48 years, with essential hypertension of stage I and II according to the WHO classification, were studied at rest and during work before and after an average of two and 16 months of oral treatment with the beta-adrenergic blocking agent, pindolol. The pindolol treatment caused a significant decrease in the systemic systolic and diastolic blood pressure, both at rest and during work. Three mechanisms seem to be involved in the antihypertensive effect of pindolol: (1) a negative chronotropic effect on the heart, (2) a decrease in peripheral vascular resistance, and (3) an increase in venous capacitance affecting the venous return. However, the significance of these mechanisms seems to differ when the situations after two months of treatment are compared with those after 16 months of treatment. In the beginning, a decrease in cardiac output seems to be the main cause of the lowering of the blood pressure; later, a decrease in systemic vascular resistance might be of greater importance.
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[Tyr8]-substance P, an undecapeptide having the structure Arg-Pro-Lys-Pro-Gln-Gln-Phe-Tyr-Gly-Leu-Met-NH2, has been synthesized by the solid-phase technique on a Beckman automatic peptide synthesizer, appropriately purified and biologically characterized. At twice the dosage, [Tyr8]-substance P showed the same biological activity response as synthetic substance P for stimulation of contraction of the isolated guinea pig ileum and for decrease in the systemic blood pressure of dogs. On the dog's blood pressure, no qualitative differences were observed, but on the isolated gut, the Tyr8 analog gave a more gradual increase in the muscle tone than synthetic substance P. [Tyr8]-substance P released, in vitro, the luteinizing and follicle-stimulating hormones at a very high dosage but did not release growth hormone, prolactin, or thyrotropin.
Ten patients, mean age 48 years, with essential hypertension of stage I and II according to the WHO classification, have been studied at rest and during work before and after on average 8 weeks oral treatment with a beta-adrenergic blocking agent, pindolol. The pindolol treatment caused a significant decrease in the systemic systolic and diastolic blood pressure, heart rate and cardiac output both at rest and during work. The systemic vascular resistance and the forearm vascular resistance decreased significantly after and during work, respectively. Forearm venous tone was significantly decreased at rest, during and after work. The plasma renin activity decreased. Three mechanisms seem to be involved in the antihypertensive effect of pindolol: 1) a negative chronotropic effect on the heart, 2) a decrease in peripheral vascular resistance, and 3) an increase in vascular capacitance affecting the venous return.
With the indirect immunofluorescence technique of Coons and collaborators the occurrence of substance P (SP)-like immunoreactivity was studied in spinal ganglia (L6-S1), the spinal cord (L6-S1) and the pad skin of the hind paw of the cat. In untreated cats a very dense network of SP-positive fibers was found in the spinal cord in Lissauer's fasciculus, in laminae I-III and a rather dense plexus was seen in the ventral horns, in the area around the central canal (laminae X) and in the medial parts of laminae VI and VII. SP-positive fibers were also observed in the connective tissue under the epithelium of the skin. However, in untreated cats no specific immunogluorescnece was observed in the spinal ganglia, dorsal roots or certain large peripheral nerve trunks. After certain experimental procedures such as local application of colchicine or compression of the dorsal root close to the spinal ganglion, SP-positive fluorescence was observed in a rather small number of neuronal cell bodies and in fibers. The fluorescent material was observed in the peripheral parts of the cytoplasm and the cell bodies were exclusively of the small type. Ten days after transection of the dorsal roots a marked decrease in the number of SP-positive fibers was observed in the substantia gelatinosa but not in the ventral horns. The present results give strong evidence for the occurrence of SP in a certain population of primary sensory neurons and support earlier findings that SP may act as a transmitter or modulator in these neurons.