Administration Of Calcium Antagonists Research Articles

Analysis of peripheral vascular actions of the new calcium antagonist isradipine

Isradipine usually dilates the vessels of the heart, brain, and skeletal muscle in experimental animals (measured with tracer microspheres). This selectivity for certain regional blood vessels is influenced by changes in the experimental conditions. In rabbits, the vessels of skeletal muscle and brain became more sensitive to isradipine after a modest 24-hour salt supplementation. Interestingly, these are vascular beds that are not constricted by the infusion of angiotensin II. Blockade of beta-adrenoceptors with pindolol blunted the increase in heart rate and cardiac output elicited by isradipine in conscious rabbits. The pattern of isradipine effects on the vascular periphery was unchanged qualitatively by beta-adrenoceptor blockade. Pretreatment of anesthetized rabbits with the angiotensin-converting enzyme inhibitor spirapril strongly changed the pattern of peripheral vasodilation of isradipine. Regions of the circulation normally not dilated or even constricted after calcium antagonist administration (liver, spleen, and pancreas) showed either no constriction (spleen) or vasodilatation. Activation of the renin-angiotensin system hence participates in modulating regional peripheral effects of calcium antagonists, and, if this system is unresponsive, then the calcium antagonist-induced dilatation extends over a broader range of vascular beds.

Calcium antagonists and exercise performance.

Calcium antagonists lead to a relaxation of smooth vascular muscles and exert a cardiodepressive effect. They make up a heterogeneous group, with primarily substances of the nifedipine and verapamil type playing the most important role in the treatment of cardiocirculatory diseases. The principal indications include coronary heart disease and hypertension. During physical exercise, following the administration of calcium antagonists, VO2max and endurance performance are not impaired. The rate of perceived exertion does not increase to any greater extent in comparison with placebo. Nifedipine leads to an increase of noradrenaline (norepinephrine) as an expression of a reflex activation of the sympathetic system and to a slight increase in heart rate, while calcium antagonists of the verapamil type lower heart rate by 10 to 15 beats/min during physical exercise as a result of their intrinsic negative chronotropic effect. Cardiac output, in spite of the drop in heart rate, remains unchanged. Neither carbohydrate metabolism nor lipid metabolism, including lipolysis, which provide the essential energy-yielding substrates during exercise, are affected by calcium antagonists. Potassium likewise remains unchanged. The response of the hormones insulin, growth hormone and cortisol is the same with calcium antagonists both during incremental graded exercise and during prolonged exercise as with placebo. In comparison with the administration of only calcium antagonists, the combination of calcium antagonists and beta-blockers impairs physical performance. The diminishment in performance, however, is markedly less pronounced than with beta-blocker monotherapy. Unimpaired performance is crucial for physically active patients. Especially for patients performing regular physical activity who suffer from mild hypertension, calcium antagonists provide a viable therapeutic alternative to beta-blockers.

Abnormal heart rate control in vasospastic angina: effects of calcium antagonists

We examined the effects of administration of calcium antagonists on the heart rate response to treadmill exercise in 11 patients with vasospastic angina and 8 healthy young volunteers. The exercise test was performed by walking on a treadmill at a constant speed and grade according to a scheme of pseudo-randomized sequence for 19 min. The dynamic property of heart rate response to exercise was evaluated by using a frequency analytic procedure. The exercise test was also studied in 21 age-matched normal controls without drug administration. Administration of calcium antagonists revealed no significant effects on heart rate and blood pressure at rest in young healthy subjects or in patients with vasospastic angina. Young volunteers showed the same normal properties of heart rate response to exercise before and after calcium antagonists. Vasospastic angina showed abnormal heart rate response to exercise and revealed characteristically different transfer function from that in normal controls. These characteristics were not affected by treatment with calcium antagonists except for a slight, uniform decrease of gain of the system over the whole frequency range. Accordingly, the present exercise test can feasibly be used in the diagnosis and management of vasospastic angina even when calcium antagonists are administered to the patients.

Pathophysiological Background for the Use of Calcium Antagonists

Correlation between blood pressure (BP) and total peripheral vascular resistance (TPR), hypotensive mechanisms of calcium antagonists, and cardiovascular responses to norepinephrine with and without administration of calcium antagonists were investigated in normotensive and genetic essential hypertensive humans. Supine resting decreased BP, heart rate (HR), stroke volume (SV), and cardiac output (CO), and, in contrast, it increased TPR. After 1 h supine rest, BP was positively correlated with TPR (r = 0.710; number = 45, p less than 0.001), but it was not correlated with CO. Intravenous infusion of the calcium antagonist diltiazem lowered BP and TPR, without apparently affecting HR, SV, and CO. In contrast, the calcium antagonist nifedipine diminished BP and TPR while increasing HR, SV, and CO. Norepinephrine elevated BP and TPR and decreased HR, SV, and CO. Prior administration of nifedipine inhibited elevation of TPR after treatment with norepinephrine. In contrast, prior administration of propranolol did not inhibit norepinephrine-induced BP and TPR elevation. From the results it may be concluded that elevation of BP is dependent on alteration of TPR, but not CO, in essential hypertensive humans. The arterial vasodilating effects of calcium antagonists induce a fall in both TPR and BP and inhibit norepinephrine-induced TPR increase. This suggests that abnormal contraction and relaxation of systemic arterial smooth muscle is a primary cause of the development and persistence of high BP in genetic (main gene) essential hypertensive humans.

Mechanism of action of angiotensin II and bradykinin on prostaglandin synthesis and vascular tone in the isolated rat kidney. Effect of Ca++ antagonists and calmodulin inhibitors.

We have studied the effect of angiotensin II and bradykinin on prostaglandin output and vascular tone during extracellular calcium depletion and administration of calcium antagonists and calmodulin inhibitors to elucidate the mechanism of action in the isolated rat kidney perfused with Tyrode's solution. Administration of angiotensin II (0.028-0.28 nmol) or bradykinin (0.28-2.8 nmol) enhanced the output of prostaglandin E2 and 6-keto-prostaglandin F1 alpha in a dose-dependent manner. Angiotensin II, but not bradykinin, produced renal vasoconstriction. Omission of calcium from the medium or infusion of calcium entry blockers, diltiazem (60 microM), or nimodipine (47 microM), failed to alter prostaglandin output elicited by angiotensin II or bradykinin; however, the effect of angiotensin II to produce renal vasoconstriction was inhibited. If calcium was omitted from the medium, the intracellular calcium antagonists, 8-(diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride (23 microM), dantrolene sodium (31 microM), or ryanodine (2 microM), attenuated prostaglandin output caused by angiotensin II but not bradykinin. Calmodulin inhibitors, trifluoperazine (2 microM), napthalene sulfonamide hydrochloride (2 microM), or calmidazolium (2 microM), diminished prostaglandin output elicited by angiotensin II, but not that caused by bradykinin. Trifluoperazine, but not naphthalene sulfonamide or calmidazolium, attenuated the renal vasoconstrictor effect of angiotensin II. Prostaglandin output induced by angiotensin II and bradykinin were inhibited by mepacrine and indomethacin, whereas, the prostaglandin output caused by exogenous arachidonic acid (33 nmol) was abolished by indomethacin but was unaltered by mepacrine, calcium antagonists, and calmodulin inhibitors. From these data, we conclude that angiotensin II produces renal vasoconstriction by a mechanism dependent on extracellular calcium but not calmodulin, whereas angiotensin II-induced prostaglandin output depends on intracellular calcium and calmodulin. In contrast, bradykinin appears to stimulate prostaglandin synthesis by a calcium/calmodulin-independent mechanism.

Lack of inhibition of anterior pituitary hormone release during chronic treatment with calcium antagonists.

Calcium antagonists are widely used for the treatment of cardiovascular disorders, especially ischaemic heart disease. It has been demonstrated that these drugs, either in vitro or acutely administered in humans, inhibit the basal and stimulated secretion of pituitary hormones by blocking calcium influx through slow calcium channels. To see if a similar effect could be detected after their chronic administration, we studied the basal, TRH- and LHRH-stimulated TSH, PRL, LH and FSH release in 18 male subjects with chronic stable angina before and on the 30th day of oral treatment with verapamil (n = 8;80 mg three times a day) or with nifedipine (n = 10; 10 mg three times a day). Neither drug had any effect on basal TSH, PRL, LH and FSH values or on their response to the specific hypothalamic-releasing hormones. These results suggest that the chronic administration of calcium antagonists, at the usual therapeutic doses, does not effect the process of stimulus-secretion coupling of anterior pituitary hormones, ruling out any impairment of the related target glands which have been expected on the basis of previous studies.

Postinfarction angina caused by coronary artery spasm

SUMMARY Recurrent ST-segment elevations inleads where new Q wavesdeveloped wererepeatedly recorded insixpatients during a recoveryphase ofacutemyocardial infarction. SuchST-segment elevations weretransient, occurred with orwithout chest pain, andreturned tocontrol levels. Noenzymatic changes signifying recurrent myocardial necrosis werefound after eachepisode. Selective coronarycineangiography in onepatient demonstrated a mildsegmental stenosis inthecoronaryartery perfusing theinfarcted area;this artery becamecompletely occluded after administration ofi.v. ergonovine. Administration ofcalcium antagonists effectively reduced thefrequency ofpostinfarction angina andST-segment elevations. Theclinical features suggest that thepostinfarction anginainthese patients isproduced bycoronaryarterial spasm andthat coronaryarterial spasm may causeseverelife-threatening dysrhythmias. SPONTANEOUSANGINAoccurs frequently inpatients withacutemyocardial infarction (AMI). Postinfarction angina isgenerally considered tobea poorprognostic sign because itmayresult inanextensionofmyocardial infarction (MI).' However, little isknownabout themechanisms of postinfarction angina occurring atrest. Inthe presence ofsevere stenosis inacoronary artery, very small increases inheart rate orother determinants of myocardial oxygenconsumption, whichcanoccur evenatrest, maybeenough toalter themyocardial oxygensupply-demand relationship.2-4 Schuster and Bullkley5 recently suggested that aninterruption of collateral blood flowcaused byacute occlusion ofa donorartery mayberesponsible forpostinfarction angina. Coronary arterial spasmisanother possible cause ofpostinfarction angina. Oliva andBreckinridge6 indicated that spasmwaspresent intheoccluded artery inasmanyas40%ofpatients withAMI.However, there hasbeennoreport ofpatients inwhomcoronary arterial spasmwasresponsible forpostinfarction angina. Inthis report, wedescribe theclinical features ofsix patients thatstrongly suggest thatpostinfarction angina wasproduced bycoronary arterial spasm. Materials andMethods Sixpatients admitted withAMI toourcoronary careunit(CCU)hadrecurrent ST-segment elevations. Thediagnosis ofAMIwasmadeonthebasis of severe prolonged chest pain andelectrocardiographic findings ofabnormal Q waveswithST-segment elevations. Thediagnosis wasconfirmed byevolutionary ECGchanges andelevations ofserumenzymes.7 There werethree males andthree females, ages43-72years