The effects of 10 mg sublingual pentrinitrol and placebo on the exercise tolerance of 20 patients with angina pectoris were compared. The ten patients who received pentrinitrol had increases in exercise times and metabolic oxygen equivalents (METs) 15 and 60 minutes after administration, whereas no change occurred in ten comparable patients receiving placebo. Pentrinitrol produced lower preexercise systolic blood pressures and systolic blood pressures at point of angina. An increase in heart rate offset the effect of the reduced systolic blood pressure on double product (systolic blood pressure times heart rate). Sublingual pentrinitrol is an effective antianginal drug for at least 60 minutes.

Adult↗

PubMedDate not supplied

Enkephalin analogs and dermorphin in the conscious dog: structure-activity relationships.

Those structural features of enkephalins (ENK) responsible for in vitro organ bath and receptor binding activity have been investigated in detail in the conscious, chronically instrumented dog. Amide analogs of Leu5-ENK display reduced activity, which is restored by D-Ala2 substitutions. N-terminal L-Tyr is required for full opiate activity. Although proven delta-receptor agonists do appear generally more active, distinctions made in vitro between mu and delta binding are not apparent in the complex hemodynamic responses which occur in the intact unanesthetized dog. The amphibian skin peptide dermorphin, which contains D-Ala2, elevates heart rate, systemic arterial pressure, and induces vomiting with near maximal activity at a dose of 1.0 microgram/kg; this activity is inhibited by naloxone. This activity, coupled with dermorphin's apparent presence in mammalian tissue, suggests that it may represent another peptide factor in cardiovascular regulation. In the conscious dog, ENK elevate heart rate and systemic arterial pressure; this activity does not appear to be fully explained by in vitro receptor models.

Animals↗

PubMedDate not supplied

Methionine-enkephalin facilitates the cardiovascular response to epinephrine in the conscious dog.

Methionine-enkephalin (ME) is present in high concentrations in the adrenal medulla; it is co-stored with catecholamines in chromaffin vesicles, and released together with catecholamines during adrenal stimulation. We have examined the interactions of intravenously administered bolus doses of ME and epinephrine (EPI) in the conscious dog. EPI, 1.0 microgram/kg, increased mean arterial pressure (MAP) from 104 +/- 6 to 130 +/- 11 mm Hg, while reflexly reducing heart rate(HR) from 103 +/- 13 to 83 +/- 13 beats/min (bpm). ME, 5.0 micrograms/kg, increased MAP from 106 +/- 7 to 122 +/- 7 mm Hg and increased HR from 111 +/- 12 to 139 +/- 14 bpm. EPI and ME administered together increased MAP in apparently additive fashion from 106 +/- 6 to 153 +/- 12 mm Hg, and also increased HR from 102 +/- 10 to 114 +/- 17 bpm. ME, 1.0 microgram/kg, exerted a similar effect. Thus, in these concentrations, ME exerts a co-operative influence upon the EPI cardiovascular response in the conscious, neurologically intact dog, probably by inhibiting baroreceptor reflexes. These findings suggest a possible role for ENK as an excitatory stress hormone.

Animals↗

PubMedDate not supplied

Mechanism of the cardiovascular response to systemic intravenous administration of leucine-enkephalin in the conscious dog.

Leucine-enkephalin (Leu5-ENK) (35 micrograms/kg) increased heart rate and mean systemic arterial blood pressure following intravenous injection into chronically-instrumented, conscious dogs. Repeated injections at five-minute intervals were not associated with a diminished response. Naloxone (1 mg/kg) pre-treatment inhibited both heart rate and blood pressure increases. Prazosin (1 mg/kg) attenuated the increase in blood pressure but did not influence the heart rate response. Propranolol (1 mg/kg) attenuated the heart rate response but not the pressor response. Clonidine (30 micrograms/kg) attenuated the positive chronotropic effect of Leu5-ENK. Atropine (1 mg/kg) plus propranolol (1 mg/kg) blocked the heart rate response but the pressor effect was still present. The attenuation of the heart rate response by propranolol and the pressor response by prazosin suggests an adrenergic component to the enkephalin response; the reduction in the heart rate response by clonidine and atropine-propranolol indicates a role for cholinergic mechanisms in the chronotropic response. Hexamethonium (10 mg/kg) blocked the heart rate response and markedly inhibited the pressor response. Vagal interruption attenuated both heart rate and blood pressure responses. It is concluded that intravenous Leu5-ENK stimulates afferent pathways located in fibers which are contained in the vagosympathetic trunk to reflexly increase heart rate and blood pressure.

Animals↗

PubMedDate not supplied

The influence of the inter-dose time interval on the cardiovascular response to methionine-enkephalin in the conscious dog.

Intravenous injection of methionine-enkephalin (10 micrograms/kg) into the conscious dog increased both heart rate and mean systemic arterial pressure. Progressive shortening of the inter-dose time interval from 5 min to 1 min and then to 30 sec did not alter the response, as the maximal mean systemic arterial pressure elevation was maintained and the maximal heart rate response increased slightly. In contrast to the results after discrete bolus dosing, continuous infusion of methionine-enkephalin at a constant rate of 10 micrograms/kg/min produced an initial elevation in heart rate and mean arterial pressure, but these parameters then began to return toward pretreatment levels despite continuous infusion at the same rate, indicating receptor desensitization. This desensitization pattern is most compatible with receptors of the nicotinic-cholinergic type. These data indicate the importance of dosing techniques in assessing cardiovascular responses to systemically administered enkephalins.

Animals↗

PubMedDate not supplied

Cardiovascular interactions between methionine-enkephalin and substance P in the conscious dog.

Interactions between the undecapeptide Substance P (SP) and the pentapeptide methionine-enkephalin (Met5-ENK) have been described in isolated organ systems and in baroreceptor reflex mechanisms. Previous studies in our laboratory have demonstrated that systemically injected Met5-ENK simultaneously increases mean systemic arterial pressure (MAP) and heart rate (HR) in the conscious, chronically instrumented dog. We have now evaluated cardiovascular interactions between SP and Met5-ENK. In this model, SP injected intravenously produces a rapid and transient decrease in MAP and increase in HR over the dose range from 1.0 to 10.0 ng/kg. SP does not appear to appreciably alter subsequent responses to Met5-ENK. At SP doses of 1.0 ng/kg, the peak hemodynamic response to SP and Met5-ENK (35 micrograms/kg) given together appears to represent a simple summation effect of both drugs on HR and MAP. However, at higher SP doses (5.0 ng/kg), the SP response predominates and is little altered by the presence of Met5-ENK. Thus, Met5-ENK does appear capable of modulating the hemodynamic responses to SP over certain dose ranges.

Animals↗

PubMedDate not supplied

The effects of barbiturates upon the hemodynamic responses to intravenous methionine-enkephalin in dogs: modulation by the GABA complex.

In conscious animals, the intravenous administration of enkephalins increases heart rate (HR) and mean systemic arterial blood pressure (MAP); however, when given during barbiturate anesthesia, enkephalins reduce HR and MAP. We have investigated the potential role of the gamma-aminobutyric acid (GABA) complex (consisting of chloride-ion channel and binding sites for GABA, benzodiazepine, and barbiturate/picrotoxin) as the site of modulation of enkephalin responses by certain anesthetic agents in our chronically instrumented dog model. In our model, methionine-enkephalin (Met5-ENK) (35 micrograms/kg intravenously) increased HR and MAP, but following induction of general anesthesia with barbiturate (pentobarbital) or of sedation with benzodiazepine (diazepam), Met5-ENK produced vasodepressor responses despite differing levels of consciousness in the treated animals. Subsequent administration of picrotoxin restored pressor responses to Met5-ENK in the barbiturate-treated dogs, but not in those treated with benzodiazepine; picrotoxin did not alter the level of consciousness. Picrotoxin had no effect upon Met5-ENK responses in the conscious state. In contrast, alpha-chloralose, a convulsive anesthetic agent which does not appear to alter GABA complex activity, blunted but did not reverse pressor responses to Met5-ENK, despite causing a level of anesthesia similar to that produced by barbiturate. The observed pressor response to Met5-ENK during alpha-chloralose anesthesia was totally inhibited by naloxone, indicating that this response was still mediated by opiate receptors. Our data are compatible with modulation of enkephalin responses by GABA complex activity. Systemic enkephalins may generate afferent signals which may subsequently undergo GABA complex processing; the state of activation of the GABA complex may then determine whether systemic enkephalin signals are translated as vasopressor or vasodepressor responses.

Animals↗

PubMedDate not supplied

Systemic methionine-enkephalin evokes cardiostimulatory responses in the human.

The cardiovascular effects of bolus doses of methionine-enkephalin (Met5-ENK) (1 to 100 micrograms/kg) were studied in 9 subjects in whom, at cardiac catheterization for evaluation of chest pain, patent coronary arteries were found. Met5-ENK produced a simultaneous increase in blood pressure and heart rate beginning within 20 sec, reaching maximal values between 30 and 40 sec, and then terminating by 60 sec. Heart rate, systolic, diastolic, and mean arterial blood pressures increased significantly (p less than 0.0005); pulse pressure remained unchanged. Positive dose-effect relationships were observed for heart rate (p less than 0.002), systolic, diastolic, and mean arterial blood pressures (p less than 0.05). Naloxone (0.5 mg/kg), given to 4 subjects, prevented the heart rate and blood pressure changes associated with Met5-ENK administration, demonstrating that the cardiovascular changes were mediated by opiate receptors. Subjects also described cutaneous paresthesias which were not prevented by naloxone pretreatment. These data suggest a role for peripheral enkephalins in cardiovascular regulation.

Blood Pressure↗

PubMedDate not supplied

Hemodynamic actions of endothelin in conscious and anesthetized dogs.

The newly described endogenous peptide, endothelin, was administered to five chronically instrumented conditioned dogs. Endothelin produced significant and simultaneous increases in both heart rate (HR) and mean arterial pressure (MAP) in conscious dogs. Endothelin also produced significant increases in MAP in anesthetized animals. Ganglionic suppression induced by hexamethonium (10 mg/kg) and atropine (0.1 mg/kg) blocked HR responses and markedly inhibited the pressor responses to endothelin in conscious animals. These results suggest that endothelin in part acts to elevate blood pressure and heart rate through modification of autonomic nervous system tone. When endothelin and angiotensin II were administered in mole equivalent doses, angiotensin II produced a pressor response of greater magnitude than did endothelin in conscious animals.

Anesthesia, General↗

PubMedDate not supplied

Endothelin produces systemic vasodilation independent of the state of consciousness.

The effects of endothelin, ET-1, on pulmonary and systemic hemodynamics were studied in the open chest dog and changes in systemic arterial pressure in dogs under conscious and anesthetized states were compared. Rapid intravenous (IV) bolus injections of ET-1, 100-1,000 nanograms/kg, significantly decreased systemic arterial pressure, and significantly decreased systemic vascular resistance whereas left atrial pressure and pulmonary vascular resistance were not altered. Reductions in systemic arterial pressure in response to bolus injection of ET-1, 100 and 300 nanograms/kg IV, during conscious state and during anesthesia were similar, respectively. The present data suggest that ET-1 dilates the systemic vascular bed independent of the animal's state of consciousness. The present data also suggest that when compared to the systemic vascular bed, the pulmonary vascular bed is less responsive to bolus administration of ET-1.

Anesthesia, General↗

PubMedDate not supplied

Acute hypotension alters hemodynamic response to methionine-enkephalin in conscious dogs.

In the conscious dog, intravenous administration of methionine-enkephalin produces simultaneous increases in both heart rate (HR) and mean arterial blood pressure (MAP). This report describes both depressor and cardioaccelerator responses to methionine-enkephalin (10 micrograms/kg IV) in conscious dogs following acute hypotension induced by either bolus injection of isoproterenol (0.1-5.0 micrograms/kg IV) or infusion of sodium nitroprusside (SNP, 3-8 micrograms/kg/min). Cardiovascular responses to methionine-enkephalin were blocked by naloxone. Pretreatment of the dogs with the beta-adrenergic receptor antagonist propranolol failed to prevent the hypotensive response to methionine-enkephalin following SNP infusion. The results indicate that the hemodynamic responses to methionine-enkephalin can be altered by acute manipulation of blood pressure. These results may have implications relative to the role of endogenous opiates in regulation of blood pressure, especially in acute hypotensive states.

Animals↗