Nifedipine-associated myocardial ischemia or infarction in the treatment of hypertensive urgencies.
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Administration, Oral↗
Biomedical subjects
G E Sander
Publications and source records attributed to G E Sander.
Non-opiate and peripheral-opiate cardiovascular effects of morphine in conscious dogs.
Morphine is generally regarded as having a centrally mediated depressant effect upon the cardiovascular system. We report here that in chronically instrumented conscious dogs, morphine produces a biphasic response; heart rate and mean arterial pressure initially increase followed by a reduction to below baseline levels. Differential inhibition by naloxone (NAL) and methylnaloxone (MRZ), a quaternary opiate antagonist which does not readily enter the CNS, suggests that the initial pressor response is mediated peripherally, while the latter occurring vasodepressor and bradycardic responses are mediated centrally. The initial tachycardia was not inhibited by NAL or MRZ, suggesting that this response is mediated by a non-opiate mechanism.
Animals↗
Alpha-adrenergic mechanisms in the pathophysiology of left ventricular heart failure--an analysis of their role in systolic and diastolic dysfunction.
Alpha-adrenoceptor (alpha-AR) mechanisms may contribute to systolic and diastolic dysfunction of the left ventricle. Centrally acting alpha 2-AR agonist drugs, including methyldopa, clonidine, and guanabenz, activate brainstem alpha 2-AR and this activation results in a decrease in overall sympathetic tone and an increase in parasympathetic tone. Peripherally acting alpha 1-AR antagonists, such as prazosin, inhibit the actions of catecholamines at post-synaptic receptor sites. Heart failure is characterized by hyperactivity of sympathetic pathways and parasympathetic withdrawal. In this situation, alpha 2-agonists reduce sympathetic activity and improve hemodynamic parameters of cardiac function; both acute and chronic administration of alpha 2-AR have been demonstrated to reduce serum catecholamine levels, heart rate, and arterial blood pressure, and to improve exercise performance. Diastolic dysfunction of the left ventricle is characterized by a marked decrease in ventricular compliance, often a result of hypertension and left ventricular hypertrophy; the end result is an increase in left ventricular filling pressure and pulmonary venous pressure. Treatment with alpha 2-AR, by decreasing sympathetic tone and blood pressure, and alpha 1-AR antagonists, by reducing blood pressure and by directly inhibiting the actions of catecholamines at alpha 1-AR, may produce a reduction in the degree of ventricular hypertrophy and improve diastolic performance of the left ventricle. Thus, therapeutic intervention in heart failure with either alpha 2-AR agonists or alpha 1-AR antagonists may favorably modulate these alterations in sympathetic tone and improve ventricular function.
Adrenergic alpha-Antagonists↗
Antianginal effects of clonidine.
The effects of clonidine, a central alpha-adrenoceptor agonist, were studied in 12 patients with chronic stable effort angina pectoris in an 18-week randomized, double-blind, two-period (6 weeks each) crossover study with a 3-week inter-period washout phase. Clonidine (200 micrograms as a single dose) produced a decrease in rate-pressure product at rest and during exercise and an increase in exercise tolerance, at 1 and 2 h after administration. Chronic administration of clonidine produced a decrease in rate-pressure product at rest and during exercise and an increase in exercise tolerance after 3 weeks (200 micrograms twice a day) and 6 weeks (400 micrograms twice a day) of treatment.
Angina Pectoris↗
Comparative cardiovascular responses to intravenous capsaicin, phenyldiguanide, veratrum alkaloids and enkephalins in the conscious dog.
Cardiovascular responses to intravenous bolus doses of certain exogenous substances (capsaicin, phenyldiguanide, cryptenamine, veratrine sulphate) which act on chemoreceptors in the pulmonary or proximal arterial circulation were compared to the naturally occurring chemoreceptor agonist, leucineenkephalin (Leu5-ENK) in the conscious dog. Capsaicin (40 micrograms/kg) and phenyldiguanide (40 micrograms/kg) produced hypotension and bradycardia 5 to 12 sec after injection (P less than 0.05) followed by hypertension (P less than 0.05). Cryptenamine (5 micrograms/kg) produced only hypotension and bradycardia (P less than 0.05) whereas Leu5-ENK (35 micrograms/kg) produced only hypertension and tachycardia (P less than 0.05). The hypotension and bradycardia produced by capsaicin and phenyldiguanide occurred earlier than the pressor response to Leu5-ENK, capsaicin, and phenyldiguanide and the depressor response to veratrine (P less than 0.05). Cryptenamine (5 micrograms/kg) and Leu5-ENK (35 micrograms/kg) when given together had additive effects on heart rate but interacted significantly in influencing blood pressure (P less than 0.05). It is concluded that the early response to capsaicin and phenyldiguanide are compatible with stimulation of known pulmonary chemoreceptors (including J receptors) whereas the pressor effect of phenyldiguanide and Leu5-ENK and the depressor response to veratrum alkaloids are due to activation of receptors in the proximal arterial circulation. The influence of Leu5-ENK on the haemodynamic response to veratrine suggest that ENK may modulate the Bezold-Jarisch reflex.
Animals↗
Methionine-enkephalin does not alter human platelet aggregatory response.
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Adenosine Diphosphate↗
Cardiovascular activities of intravenous methionine-enkephalin-Arg6-Phe7 and methionine-enkephalin-Arg6-Gly7-Leu8 in the conscious dog.
The preproenkephalin A molecule from the adrenal medulla contains the opioid peptides methionine-enkephalin (Met-ENK), leucine-enkephalin (Leu-ENK), methionine-enkephalin-Arg6-Phe7 (heptapeptide), and methionine-enkephalin-Arg6-Gly7-Leu8 (octapeptide). In the conscious, chronically instrumented dog, Met-ENK and Leu-ENK simultaneously increase heart rate and systemic arterial pressure following intravenous administration. In 19 of 23 dogs, heptapeptide produced a response identical to Met-ENK and Leu-ENK, which was inhibited by naloxone but unaffected by the dipeptidyl carboxypeptidase inhibitor SQ20881. However, in four dogs, heptapeptide produced only a fall in systemic pressure associated with an increase in heart rate despite characteristic Met-ENK responses in the same dogs; naloxone did not appear to alter this hypotensive response. Octapeptide produced slight increases in systemic pressure and heart rate. These data suggest that heptapeptide may possess intrinsic cardiovascular activity at opiate receptors; however, in certain dogs, non-opiate mechanisms, perhaps histamine release, may predominate.
Animals↗
Unusual variant of eosinophilic fasciitis.
We have reported an unusual case of eosinophilic fasciitis with a prolonged prodrome of asymptomatic eosinophilia, episodic extremity swelling, and extreme eosinophilia. Such a case has not previously been reported.
Adult↗
Central alpha-adrenergic agonists in chronic heart failure and ischemic heart disease.
Central alpha-adrenoceptor agonists (methyldopa, clonidine, guanabenz) decrease sympathetic outflow and renin and vasopressin secretion as well as increase parasympathetic activity. These drugs are commonly employed as antihypertensives. Two other conditions, chronic heart failure and ischemic heart disease, may also benefit from central alpha-adrenergic stimulation. In both acute and chronic heart failure, central alpha-adrenoceptor agonists reduced cardiac work load by decreasing heart rate, systemic arterial pressure and reducing venous tone. Also, plasma catecholamines were decreased. Exercise at comparable work loads was achieved at a lower pressure-rate product and effort capacity was sometimes increased. Central alpha-adrenoceptor agonists increased effort capacity in patients with ischemic heart disease and angina pectoris. Again, the benefits are thought to be decreased heart rate, systemic arterial blood pressure and rate-pressure products during exercise; catecholamines are reduced in these patients as well. Central alpha-adrenoceptor agonists offer another avenue of approach to alter neurohumoral factors in congestive heart failure and ischemic heart disease and thereby produce beneficial hemodynamic response.
Adrenergic alpha-Agonists↗
Ventilatory response to intravenous methionine enkephalin in awake dogs.
In conscious, microfilaria-free, adult mongrel dogs, i.v. bolus administration of methionine enkephalin (Met5-ENK) produced a transient elevation of both inspiratory minute ventilation (VI) and heart rate (HR). Both VI and HR increased progressively with increasing doses of Met5-ENK over the range of 6 to 18 micrograms/kg, thereafter plateauing at doses up to 36 micrograms/kg. Maximum changes in VI and HR occurred within 30 to 45 sec after injection, both variables returning to control levels in approximately 2 min. In four out of five dogs, mean inspiratory flow (tidal volume/inspiratory time), and consequently, tidal volume, accounted for this enkephalin-mediated increase in ventilation. In one of the dogs, respiratory rate, rather than tidal volume, increased after Met5-ENK. This change in respiratory rate was due to an increase in "effective timing" of the respiratory cycle, the latter defined as the ratio of inspiratory time to total respiratory time. Despite significant changes in VI and HR, neither end tidal oxygen nor carbon dioxide levels were significantly different from control after i.v. injections of Met5-ENK. Pretreatment with naltrexone methylbromide, a quaternary opiate antagonist that does not cross the blood-brain barrier, abolished all enkephalin-induced changes in VI and HR, thus suggesting that systemic enkephalins modulate ventilation via opiate receptors outside the blood-brain barrier. Activation of these receptors produce an increase in both cardiovascular and respiratory activity, as one might expect during stress conditions. These data further support a potential role for peripheral enkephalins as excitatory stress hormones.
Animals↗
Time-dependent antihypertensive effect of carteolol--a beta-adrenoceptor antagonist with partial agonist activity.
The antihypertensive effect of carteolol (0.5 to 60 mg daily), a beta-adrenoceptor antagonist with partial agonist activity, was studied in a double-blind parallel protocol. A 3-wk placebo period was followed by an 8-wk treatment period during which patients received 0.5, 2.5, 20, and 60 mg in an increasing (group 1) or decreasing (group 2) manner for successive 2-wk intervals, followed by a 2- to 6-wk withdrawal period. Resting supine and standing blood pressures (BP) and heart rates (HR) were measured at each visit. Isometric handgrip exercise and treadmill exercise were used to evaluate beta-blockade. Plasma carteolol concentration was measured by radioimmunoassay. Recumbent BP fell from 154 +/- 10/100 +/- 2 to 143 +/- 10/84 +/- 11 mm Hg for group 1 and from 153 +/- 10/100 +/- 3 to 138 +/- 14/78 +/- 8 mm Hg for group 2 after 8 wk of treatment. HR was unchanged. The greater reduction in BP for each dose was observed with the later administrations, but was not related to serum concentration. beta-Blockade was evident at all doses of carteolol. Carteolol is an effective antihypertensive. Duration of carteolol therapy, independent of dosage, is important in its effectiveness.
Adult↗
Plasma kinin levels in acute renovascular hypertension in dogs.
The role of kinins in the hypertensive response to acute renal artery constriction (RAC) was examined in the dog. RAC resulted in an increase in systemic arterial pressure (SAP) from 144 +/- 6 to 155 +/- 4 mm HG (p less than 0.05). Simultaneously, arterial plasma bradykinin decreased from 2.3 +/- 0.2 to 1.4 +/- 0.1 ng/ml (p greater than 0.01), while renal venous bradykinin remained unchanged (2.3 +/- 0.2 to 2.0 +/- 0.4 ng/ml, p greater than 0.05). At the same time urinary kallikrein decreased from 55 +/- 6 to 33 +/- 4 milliesterase units (mEU)/min (p less than 0.05), while urinary kinin decreased from 3.2 +/- 0.4 to 1.9 +/- 0.3 ng/min (p less than 0.05). There was a significant correlation between the decrease in arterial bradykinin and the rise in SAP induced by RAC (p less than 0.01). Administration of the dipeptidyl hydrolase inhibitor SQ20881 during RAC reduced angiotensin-converting enzyme levels from 578 +/- 86 to 10 +/- 0.0 mU/ml (p less than 0.005). There was an associated increase in arterial bradykinin (1.4 +/- 0.1 to 5.8 +/- 0.8 ng/ml, p less than 0.001), renal venous bradykinin (2.0 +/- 0.4 to 5.7 +/- 0.5 ng/ml, p less than 0.005), and urinary kinin (1.9 +/- 0.3 to 5.0 +/- 0.7 ng/min, p less than 0.01) in conjunction with return of SAP to control levels. Urinary kallikrein, however, remained depressed following SQ20881 (33 +/- 4 to 30 +/- 5 mEU/min, p greater than 0.05). These results suggest that (1) decreases in circulating BK may potentiate the vasoconstrictor effect of angiotensin II and contribute to the hypertension induced by RAC, and (2) urinary kallikrein is an unreliable marker of changes in plasma bradykinin in this model of hypertension.
Angiotensin II↗
The effect of intravenous clonidine hydrochloride on the isolated forearm venous segment in heart failure.
The effects of intravenous (IV) clonidine (150 micrograms) on the isolated forearm venous segment of ten patients with heart failure were studied. Clonidine reduced pressure in the isolated venous segment of all patients (12.8 +/- 2.1 to 10.6 +/- 1.4 mm Hg, p less than 0.005). In addition, IV clonidine decreased the pressor response to mental arithmetic (2.9 +/- 0.3 mm Hg to 1.8 +/- 0.3 mm Hg, p less than 0.05), while the pressor response to deep breath was slightly enhanced (4.5 +/- 0.8 mm Hg to 6.1 +/- 0.7 mm Hg, p less than 0.05).
Adult↗
Interactions of leucine-enkephalin with alpha-adrenoceptors in the conscious dog.
Leucine-enkephalin (Leu-ENK) administered systemically to the conscious dog increases heart rate and blood pressure, a response prevented by naloxone and hence mediated by opiate receptors. Clonidine attenuates the heart rate increase without affecting the pressor response. Propranolol also reduces the magnitude of the heart rate increase but to a lesser degree than does clonidine. Clonidine appears to inhibit the Leu-ENK-induced heart rate increase by both a centrally mediated increase in vagal tone and a peripheral presynaptic alpha 2-agonist effect. The presence of a pressor response to Leu-ENK after prazosin pretreatment suggests that Leu-ENK may also increase blood pressure independently of the alpha 1-adrenoceptor. Thus, Leu-ENK appears to act via a naloxone-sensitive receptor (perhaps a vagal afferent chemoreceptor), the response involving both sympathetic and parasympathetic mechanisms. The pressor response may also involve a direct effect on peripheral vessels or a non-alpha 1-adrenergic efferent pathway.
Animals↗
Elevation of arterial blood pressure in conscious dogs by Des-Tyr1-D-Ala2-leucine-enkephalinamide.
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Animals↗
MIF-1 does not act like naloxone in antagonizing the cardiovascular activity of leucine-enkephalin in the conscious dog.
MIF-1 (Pro-Leu-Gly-NH2), a hypothalamic tripeptide, has been demonstrated to stimulate naloxone in antagonizing the effects of opioid peptides in a number of experimental systems including enkephalin-induced analgesia in the tail-flick assay, beta-endorphin induced hypothermia and hypomotility, deprivation-induced drinking, and analgesia in goldfish. MIF-1, however, has no effect upon the activity of enkephalins in the mouse vas deferens or enkephalin binding in the rat striatum. We have studied the interactions of MIF-1 with Leu5-enkephalin (Leu5-ENK) in the conscious, chronically instrumented dog. Although naloxone inhibits both the elevations of heart rate and blood pressure produced by IV Leu5-ENK in the conscious state and the depressions in these variables produced by Leu5-ENK after pentobarbital anesthesia, MIF-1 has no effect upon the Leu5-ENK response in either state. However, both naloxone and MIF-1 seem to raise mean arterial pressure in the conscious dog. These results indicate that MIF-1 does not act like naloxone in antagonizing the peripheral effects of Leu5-ENK and lend further support to the existence of mechanistic differences among opiate-mediated behavior, analgesia, and cardiovascular activity.
Animals↗
Cardiopulmonary pharmacology of enkephalins in the conscious dog.
Various enkephalins (ENK) have been reported to alter heart rate, systemic blood pressure, and respiratory function but with variable results. We previously found that pentobarbital anesthesia reversed the increases in heart rate and systemic arterial blood pressure produced by Leu5-ENK in the dog. We have now studied the cardiopulmonary responses to systemically injected enkephalins in the awake, chronically instrumented dog. In these unanesthetized dogs, Leu5-ENK, Met5-ENK, and an ENK dimer increased heart rate, systemic arterial pressure, and respiratory rate in a dose-dependent fashion. D-Phe4, Met5-ENK, an analog with behavioral activity but without analgesic or in vitro opiate effects was inactive. Leu5-ENK was studied in detail; typically, heart rate and systemic pressure increased within 20 sec and returned to baseline in less than 180 sec. Intra-arterial injections produced a smaller increase in heart rate than did intravenous injections, but similar increases in systemic arterial blood pressure were recorded. These cardiovascular responses suggest that systemically injected enkephalins suppress baroreceptor reflexes and may have a role in cardiopulmonary regulation.
Animals↗
Inhibition of the partially purified canine lung angiotensin I converting enzyme by opioid peptides.
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Angiotensin-Converting Enzyme Inhibitors↗