Peripheral Arterial Vasodilation Research Articles

A Reappraisal of Nitrate Therapy

Nitroglycerin and the long-acting nitrates are beneficial in stable and unstable angina pectoris and acute myocardial infarction and as adjunctive therapy in congestive heart failure. Nitroglycerin compounds relax vascular smooth muscle, producing venous, arterial, and arteriolar dilatation. These actions are modulated by stimulation of intracellular cyclic guanosine monophosphate. Nitrate efficacy in ischemic heart disease is due to peripheral venous and arterial vasodilatation that results in decreased myocardial oxygen consumption. Nitrates also dilate coronary arteries and collaterals, reverse coronary vasoconstriction, and enlarge some coronary atherosclerotic lesions. Nitrates improve exercise performance in stable angina pectoris. Intravenous nitroglycerin should be used in the initial treatment of unstable angina. Nitrates may be beneficial in myocardial infarction for control of ischemic pain, acute hypertension, and left ventricular failure. In subjects with congestive heart failure, nitrates reduce symptoms and improve exercise tolerance. Nitrate tolerance is a problem with continuous nitrate therapy. Tolerance is most likely to occur with frequent dosing or the use of long-acting nitrates, particularly transdermal nitroglycerin disks, and can be prevented or reversed with intermittent-dosing regimens.

Clinical Pharmacology of Pinacidil, A Prototype for Drugs That Affect Potassium Channels

The clinical pharmacology of potassium channel openers has been reviewed using pinacidil as a prototype drug. When administered acutely or chronically, the hemodynamic and neuroendocrine profile is that of a peripheral arterial vasodilator. The drug produces decreases in peripheral vascular resistance, and subsequent blood pressure decreases are associated with reflex increments in heart rate. When studied, plasma catecholamines increased about twofold during chronic therapy. Plasma renin activity, however, was not increased during chronic therapy with pinacidil monotherapy. When patients were treated with pinacidil doses ranging from 12.5 to 75 mg b.i.d., 66.9% of patients had a decrease in supine diastolic blood pressure to below 91 mm Hg and 10 mm Hg less than baseline, whereas only 23.9% of patients had similar falls during placebo treatment. During maintenance therapy with pinacidil, the average blood pressure during the daytime dosing interval was 137.8 +/- 1.2/83.4 +/- 0.7 mm Hg (mean +/- SEM). Titration of pinacidil as monotherapy resulted in a characteristic adverse event profile dominated by the presence of dose-related edema. Other characteristic events included tachycardia, palpitations and headache. When pinacidil was given to patients unresponsive to hydrochlorothiazide (25 mg b.i.d.), similar efficacy relative to placebo was noted with a change of post-dose supine diastolic blood pressure in the pinacidil group of 13.5 +/- 0.8 mm Hg and 7.3 +/- 0.9 mm Hg in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)

'Second generation' dihydropyridine calcium antagonists. Greater vascular selectivity and some unique applications.

The newer dihydropyridine calcium antagonists are structurally related to nifedipine, but may provide greater vascular selectivity and wider clinical utility. Five new dihydropyridines-nisoldipine, nicardipine, nimodipine, felodipine and nitrendipine-are reviewed with regard to their preclinical pharmacology, haemodynamic effects and clinical indications. Nisoldipine is a potent arterial vasodilator with minimal electrophysiological and negative inotropic effects. Although data are still preliminary, the drug has shown some efficacy in both exertional angina and essential hypertension. The dosing interval is not yet clearly established, but may be twice daily. Utility in congestive heart failure awaits confirmation, but preliminary studies are promising. Nicardipine is an especially potent peripheral, cerebral and coronary arterial vasodilator that causes 10-fold less myocardial depression in animals than nifedipine, and may provide important cardioprotective effects during ischaemia. Human haemodynamic studies have confirmed nicardipine's lack of negative inotropism, its ability to reduce coronary and peripheral vascular resistance, and its lack of effect on cardiac conduction. Several controlled trials have documented its efficacy in exertional angina, vasospastic angina, and essential hypertension. Nicardipine's potential as an antiatherosclerotic agent is currently under investigation. Nimodipine is undergoing a unique clinical development programme aimed at cerebrovascular disorders. In almost all species, nimodipine selectively increases cerebral blood flow and reverses cerebral artery spasm without altering cerebral oxidative metabolism or systemic blood pressure. In humans, a large, double-blind, placebo-controlled trial in subarachnoid haemorrhage showed that nimodipine significantly reduced the severity of neurological deficits associated with delayed cerebral vasospasm. Several uncontrolled trials with larger numbers of patients support these results. Nimodipine has also proved useful in reducing cerebral artery spasm during intracranial surgery, and in the prophylactic treatment of migraine headaches. A preliminary study of nimodipine in acute stroke showed promising results in limiting neurological disability. Felodipine is a very potent systemic arterial vasodilator with negligible myocardial depressant activity. It is also a renal artery vasodilator. Unlike the other new dihydropyridines, felodipine prolongs the A-H interval on electrophysiological testing, but only to about 50% of that observed with verapamil. Felodipine is undergoing clinical trials in essential hypertension.(ABSTRACT TRUNCATED AT 400 WORDS)

Biological effects of organic nitroesters and their mechanism of action.

Organic nitroesters e.g. glyceryltrinitrate (NTG) are of great clinical importance in the treatment of angina pectoris. The most important of their biological effects is vasodilation of peripheral arteries, peripheral veins and coronary arteries. Other biological effects, of unknown clinical relevance, are effects on myocardial metabolism and on platelet aggregation. In recent years evidences have accumulated that the vasodilating effects of organic nitroesters are mediated via the cGMP-system, although the exact mechanism of activation of the cGMP-producing enzyme guanylate cyclase is still obscure. Further research about this may elucidate the mechanism behind the development of tolerance. Another theory concerning the mechanism behind the vasodilating properties of NTG is that arachidonic acid metabolites are involved. However no clearcut evidences have been presented to support this theory. We show in this paper results indicating that arachidonic acid metabolites are of no importance for the vasodilating effects of NTG, at least not in vitro. NTG has also been shown to decrease the intracellular Ca2+ -concentration, an effect probably mediated via cGMP but the exact underlying mechanism is not yet fully understood.

Peripheral Hemodynamic Effects of Intraventricular and Intracoronary Contrast Media in Man

The effects of intraventricular and intracoronary contrast media on the peripheral arterial and venous beds were directly measured with forearm plethysmography. Standard dose intraventricular radiographic contrast produces a potent peripheral arterial vasodilator effect accompanied by a hypotensive and tachycardic response, followed by peripheral venoconstriction, suggesting that the net hemodynamic response is mediated peripherally. Coronary arteriography is associated with a differing pattern of response, suggesting that the most important hemodynamic effects are mediated via myocardial depression with secondary peripheral vascular responses. Hemodynamic changes occur earlier than those following ventriculography and reflect peripheral arterial and venous constriction. Dose and osmolarity of the contrast are important determinants as well as the site of administration.

Lésions de la main par injection sous haute pression: Apport de l'anesthésie loco-régionale

In a reported case of accidental high pressure injection of white spirit into a finger, the authors emphasise the great contribution of regional anaesthesia maintained from the initial trauma until the lesions are stable. Trauma to the hand caused by injection of paint or grease solvents results in tissue destruction and later necrosis and fibrosis. Secondary amputations are required in many cases. Regional anaesthesia of the stellate ganglion and brachial plexus produces analgesia and vasodilatation of peripheral arteries by inhibition of the sympathetic tone. This vasodilatation limits the necrotic process and promotes the supply of drugs to the injured tissues. Regional anaesthesia is of great benefit for surgical excision and avoids extended amputation.

SYNCOPE IN AORTIC VALVULAR STENOSIS

Simultaneous, continuous ambulatory recordings of systemic and pulmonary arterial pressure and heart rate were made in four patients with aortic valvular stenosis (AS) to explore the mechanisms of syncope in the disorder. When compared with six normal volunteers, patients with AS showed a subnormal systemic arterial pressure response to graded submaximal exercise. Three near-syncopal episodes, occurring during abrupt symptom-limited exercise, were associated with simultaneous acute falls in systemic and pulmonary arterial pressure in the absence of cardiac arrhythmia. Acute reflex peripheral arterial and venous vasodilatation, which may be mediated by the effects of sudden changes in left-ventricular pressure on ventricular baroreceptor activity, plays a central role in the exertion-induced syncope of aortic stenosis.

Salutary effect of nifedipine in pacing-induced angina: relation to afterload reduction.

To determine the mechanisms responsible for beneficial effects of nifedipine in pacing-induced angina pectoris, 20 patients undergoing diagnostic cardiac catheterization were studied. Following left ventriculography and coronary arteriography, right atrial pacing was performed before and 30 min after administration of 20 mg of nifedipine sublingually. Heart rate was increased by 10-beat-per-minute (bpm) increments every 90 sec until angina occurred. Electrocardiogram, central aortic pressure, and pulmonary arterial occlusive pressure were monitored continuously. Mean paced heart rate at the onset of angina was increased from 107 +/- 12.6 bpm to 140.6 +/- 19.9 (P less than .001) after nifedipine. Systolic arterial pressure at the time of angina declined from 143 +/- 20 mm Hg to 112 +/- 23 mm Hg (P less than .001). Consequently, the double product heart rate X systolic blood pressure was not changed significantly at the onset of chest pain (149 +/- 28 mm Hg X 10(-2) vs. 142 +/- 28 mm Hg X 10(-2) ). Pulmonary arterial occlusive pressure also did not change significantly (10.4 +/- 4.4 vs. 10.5 +/- 5.9 mm Hg). Thus, nifedipine decreased myocardial oxygen demand at a given heart rate by reducing left ventricular afterload, but did not increase the rate pressure product threshold for ischemic pain. These results indicate that peripheral arterial vasodilator effects of nifedipine, with a resultant decrease in myocardial oxygen requirements, account for its antianginal effect in this setting in patients with fixed obstructive coronary artery disease.

Contrasting hemodynamic responses in severe heart failure: Comparison of captopril and other vasodilator drugs

Four studies were conducted in 36 patients with severe chronic heart failure to compare the central hemodynamic effects of captopril (CPT) to other vasodilator agents. While CPT produced less marked increases in cardiac output than did hydralazine (n = 14), nitroprusside (n = 15), or prazosin (n = 7), it produced decreases in left ventricular filling pressures similar to nitroprusside and prazosin but more than hydralazine. CPT and isosorbide dinitrate (n = 11) produced similar decreases in systemic vascular resistance and left ventricular filling pressure. However, cardiac output increased less with CPT than with nitrates, because heart rate slowed during CPT therapy. In addition, mean right atrial pressure decreased less with CPT than with nitrates, because CPT had minimal effects on limb venous capacitance and pulmonary arteriolar resistance. Alterations in left ventricular pressure-volume relationships likely contributed to the marked decreases in left ventricular filling pressures seen with CPT. In conclusion, the central hemodynamic effects of CPT differ significantly from other vasodilator drugs used in the treatment of heart failure patients. These effects cannot be characterized simply in terms of “balanced” peripheral arterial and venous vasodilation; CPT exerts highly complex effects on peripheral vessels as well as having actions independent of its peripheral vasodilator effects.

Calcium channel blocking agents in the treatment of cardiovascular disorders. Part II: Hemodynamic effects and clinical applications.

The calcium channel blocking agents have multiple hemodynamic effects that make them potentially valuable in treating many cardiovascular disorders. They are potent dilators of coronary and peripheral arteries and in isolated tissue preparations exert potent negative inotropic, chronotropic, and dromotropic effects. In intact animals the peripheral arterial vasodilatation induces reflex-mediated adrenergic activity, which opposes the direct negative inotropic, chronotropic, dromotropic, and hypotensive effects. The individual calcium channel blockers have different relative potencies on various cardiovascular functions. The net hemodynamic and electrophysiologic effect of each agent, therefore, results from a complex interplay of direct and reflex phenomena. The clinical efficacy of these agents in classic angina pectoris relates to their ability to decrease afterload, myocardial contractility, and heart rate and increase coronary blood flow. The agents have been used to prevent coronary spasm in Prinzmetal's variant angina. The negative inotropic effects of verapamil are valuable in improving the symptoms and hemodynamic disturbances of hypertrophic cardiomyopathy. The role of these agents in treating arterial hypertension, unstable angina pectoris, acute myocardial infarction, and ischemia during cardiopulmonary bypass needs to be determined.

HEMODYNAMIC EFFECTS OF AN ISOQUINOLINE DERIVATIVE IN THE TREATMENT OF HEMORRHAGIC SHOCK

Abstract The action of a new agent, 2-(3-ethylsulfinylpropyl) - 1,2,3,4 - tetrahydroisoquinoline, was observed in a series of dogs and in healthy human volunteers. This agent had inotropic and chronotropic effects on the heart and produced peripheral arterial vasodilation. It increased cardiac output to a moderate degree without significantly increasing oxygen consumption. The increase in heart rate was minimized by constant intravenous infusion at low doses. This agent should be evaluated further for the possible use in therapy of various hypotensive and shock states.

Hemodynamic effects of an isoquinoline derivative in the treatment of hemorrhagic shock

The action of a new agent, 2-(3-ethylsulfinylpropyl) - 1,2,3,4 - tetrahydroisoquinoline, was observed in a series of dogs and in healthy human volunteers. This agent had inotropic and chronotropic effects on the heart and produced peripheral arterial vasodilation. It increased cardiac output to a moderate degree without significantly increasing oxygen consumption. The increase in heart rate was minimized by constant intravenous infusion at low doses. This agent should be evaluated further for the possible use in therapy of various hypotensive and shock states.

Isoproterenol in the Treatment of Shock Due to Bacteremia with Gram-Negative Pathogens

A series of 12 patients with shock that followed bacteremia due to gram-negative pathogens is presented, and a case is reported. The hemodynamic alterations that occur in such patients are discussed. Initial therapy includes intravascular volume expansion and administration of glucocorticoids and antibiotic drugs; subsequent therapy, if necessary, includes administration of metaraminol and isoproterenol respectively. The problems encountered with this method of treatment are described. The use of isoproterenol (2.5 to 5 mg. in 500 ml. of 5 per cent dextrose in water administered intravenously at a rate of 0.5 to 2.0 ml. per minute) is suggested to correct the hemodynamic alterations usually present and permit further expansion of circulating blood volume with reduced risk of acute circulatory overload. Clinical use of this drug is recommended because of its positive ionotropic effect on the myocardium (beta-adrenergic stimulation) and direct peripheral arterial vasodilator effect (alpha-adrenergic blockade) that act to correct the hemodynamic alterations usually present in man in endotoxin shock.